Molecular Carcinogenesis via MedWorm.com

Single-nucleotide polymorphisms in the p53 pathway genes modify cancer risk in BRCA1 and BRCA2 carriers of Jewish-Ashkenazi descent

Molecular Carcinogenesis — Sat, 20 Mar 2010 00:00:00 +0100

Germline mutations in the BRCA1 and BRCA2 genes are associated with a significantly increased lifetime risk for developing breast and/or ovarian cancer. However, incomplete penetrance and substantial variability in age of disease onset among carriers of the same mutation suggests the involvement of additional modifier genes and/or environmental factors. Somatic inactivating mutations in the p53 gene and genes of the p53 pathway often accompany BRCA1/2-associated tumors. Therefore, we assessed whether these genes are modifiers of penetrance. We genotyped Jewish-Ashkenazi women for functional single-nucleotide polymorphisms (SNPs) in the AKT1 (C>T rs3730358) and the PERP (C>T rs2484067) genes that affect p53-mediated apoptosis, as well as two tag-SNPs in the CHEK2 (C>T rs743184) and the ZBRK...

Downregulation of HDPR1 is associated with poor prognosis and affects expression levels of p120-catenin and [beta]-catenin in nonsmall cell lung cancer

Molecular Carcinogenesis — Tue, 16 Mar 2010 00:00:00 +0100

In conclusion, the function of HDPR1 on regulating p120ctn may play an important role in human lung carcinogenesis. Restoration of HDPR1 gene may be a new therapeutic target of lung cancer. © 2010 Wiley-Liss, Inc. (Source: Molecular Carcinogenesis)

Naturally occurring asteriscunolide A induces apoptosis and activation of mitogen-activated protein kinase pathway in human tumor cell lines

Molecular Carcinogenesis — Mon, 15 Mar 2010 00:00:00 +0100

Sesquiterpene lactones have attracted much attention because they display a wide range of biological activities, including antitumor properties. Here, we show the effects of the naturally occurring sesquiterpene lactone asteriscunolide A (AS) on viability of human melanoma, leukemia and cells that overexpress antiapoptotic proteins, namely Bcl-2 and Bcl-xL. All cell lines were sensitive to this compound, with IC50 values of [sim]5 µM. The cytotoxic effects of AS were accompanied by a G2-M phase arrest of the cell cycle and a concentration- and time-dependent appearance of apoptosis as determined by DNA fragmentation, translocation of phosphatidylserine to the cell surface and sub-G1 ratio. Apoptosis was associated with caspase-3 activity and poly(ADP-ribose) polymerase cleavage and was pr...

Stathmin1 overexpression associated with polyploidy, tumor-cell invasion, early recurrence, and poor prognosis in human hepatoma

Molecular Carcinogenesis — Mon, 15 Mar 2010 00:00:00 +0100

In conclusion, STMN1 overexpression could predict early tumor recurrence and poor prognosis, particularly at early stage of hepatoma. Overexpression of STMN1 promoted polyploidy formation, tumor-cell invasion, and intrahepatic metastasis, suggesting that STMN1 can be a target for anti-cancer therapy of human hepatoma. © 2010 Wiley-Liss, Inc. (Source: Molecular Carcinogenesis)

Genetic polymorphisms in DNA repair genes XPC, XPD, and XRCC4, and susceptibility to Helicobacter pylori infection-related gastric antrum adenocarcinoma in Guangxi population, China

Molecular Carcinogenesis — Mon, 15 Mar 2010 00:00:00 +0100

This study, including 361 GAAs and 616 controls without any evidence of tumors, was designed to evaluate the association between the polymorphisms of DNA repair genes XPC Ala499Val (RS#2228000) and Lys939Gln (RS#2228001), XPD Lys751Gln (RS#13181), and XRCC4 Ala247Ser (RS#3734091) and Ser298Asn (RS#1805377), and GAA risk for Guangxi population by means of TaqMan-PCR analysis. Increased risks of GAA were found for individuals with H. pylori positive [odds ratio (OR), 2.48; 95% confidence interval (CI), 1.84-3.33] or cagA positive (OR, 7.34; 95% CI, 5.46-9.87). No differences were observed among the studied groups with regard to the genotype distribution of XPC codons 499 and 939 and of XRCC4 codon 247; but XPD codon 751 genotypes with Gln [ORs (95% CI) were 2.67 (1.98-3.58) and 3.97 (2.64-5....

Dietary energy restriction, in part through glucocorticoid hormones, mediates the impact of 12-O-tetradecanoylphorbol-13-acetate on jun D and fra-1 in sencar mouse epidermis

Molecular Carcinogenesis — Mon, 15 Mar 2010 00:00:00 +0100

This study measured protein levels of c-jun, jun B, jun D, c-fos, fra-1, and fra-2 and examined their contribution to AP-1:DNA binding by electrophoretic mobility shift assay (EMSA) with supershift analysis in the epidermis of control and DER Sencar mice exposed to TPA. TPA significantly increased c-jun, jun B, c-fos, fra-1, and fra-2 and decreased jun D within 3-6 h after treatment. AP-1:DNA binding reached a maximum 2.5-fold induction over controls 4 h after TPA treatment and antibodies to jun B, jun D, and fra-2 in the EMSA binding reaction resulted in supershifts in both acetone- and TPA-treated mice 1-6 h after treatment. The effect of corticosterone (CCS) and DER on the AP-1 proteins and on the composition of the AP-1:DNA complex was measured in adrenalectomized (adx) mice. DER reduc...

The neural cell adhesion molecule is involved in the metastatic capacity in a murine model of lung cancer

Molecular Carcinogenesis — Sat, 27 Feb 2010 00:00:00 +0100

Neural cell adhesion molecule (NCAM) is involved in cell growth, migration, and differentiation. Its expression and/or polysialylation appear to be deregulated in many different cancer types. We employed the lung tumor cell line LP07, syngeneic in BALB/c mice to investigate the role of NCAM in malignant progression. LP07 cells express the three main NCAM isoforms, all of them polysialylated. This cells line, pretreated with an anti-NCAM antibody and inoculated intravenously (i.v.) into syngeneic mice, developed less and smaller lung metastases. In vitro studies showed that NCAM bound antibody inhibited cell growth, mainly due to an increase in apoptosis, associated with a decrease of cyclin D1 and enhanced expression of active caspase 3 and caspase 9. Anti-NCAM-treated LP07 cells showed im...

5,7,3[prime]-trihydroxy-3,4[prime]-dimethoxyflavone-induced cell death in human Leukemia cells is dependent on caspases and activates the MAPK pathway

Molecular Carcinogenesis — Sat, 20 Feb 2010 00:00:00 +0100

In this study we investigated the effect of 5,7,3[prime]-trihydroxy-3,4[prime]-dimethoxyflavone (THDF) on viability of nine human tumor cell lines and found that it was highly cytotoxic against leukemia cells. THDF induced G2-M phase cell-cycle arrest and apoptosis through a caspase-dependent mechanism involving cytochrome c release, processing of multiple caspases (caspase-3, -6, -7, and -9) and cleavage of poly(ADP-ribose) polymerase. Overexpression of the protective mitochondrial proteins Bcl-2 and Bcl-xL conferred partial resistance to THDF-induced apoptosis. This flavonoid induced the phosphorylation of members of the mitogen-activated protein kinases (MAPKs) family and cell death was attenuated by inhibition of c-jun N-terminal kinases/stress-activated protein kinases (JNK/SAPK) and ...

A potential microRNA signature for tumorigenic conazoles in mouse liver

Molecular Carcinogenesis — Fri, 19 Feb 2010 00:00:00 +0100

Triadimefon, propiconazole, and myclobutanil are conazoles, an important class of agricultural fungicides. Triadimefon and propiconazole are mouse liver tumorigens, while myclobutanil is not. As part of a coordinated study to understand the molecular determinants of conazole tumorigenicity, we analyzed the microRNA expression levels in control and conazole-treated mice after 90 d of administration in feed. MicroRNAs (miRNAs) are small noncoding RNAs composed of approximately 19-24 nucleotides in length, and have been shown to interact with mRNA (usually 3[prime] UTR) to suppress its expression. MicroRNAs play a key role in diverse biological processes, including development, cell proliferation, differentiation, and apoptosis. Groups of mice were fed either control diet or diet containing 1...

Grape seed proanthocyanidin suppression of breast cell carcinogenesis induced by chronic exposure to combined 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone and benzo[a]pyrene

Molecular Carcinogenesis — Wed, 10 Feb 2010 00:00:00 +0100

Breast cancer is the most common type of cancer among women in northern America and northern Europe; dietary prevention is a cost-efficient strategy to reduce the risk of this disease. To identify dietary components for the prevention of human breast cancer associated with long-term exposure to environmental carcinogens, we studied the activity of grape seed proanthocyanidin extract (GSPE) in suppression of cellular carcinogenesis induced by repeated exposures to low doses of environmental carcinogens. We used combined carcinogens 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and benzo[a]pyrene (B[a]P), at picomolar concentrations, to repeatedly treat noncancerous, human breast epithelial MCF10A cells to induce cellular acquisition of cancer-related properties of reduced dependence ...

AMPK-mediated phosphorylation of murine p27 at T197 promotes binding of 14-3-3 proteins and increases p27 stability

Molecular Carcinogenesis — Tue, 09 Feb 2010 00:00:00 +0100

The tuberous sclerosis complex 2 (Tsc2) gene product, tuberin, acts as a negative regulator of mTOR signaling, and loss of tuberin function leads to tumors of the brain, skin, kidney, heart, and lungs. Previous studies have shown that loss of tuberin function affects the stability and subcellular localization of the cyclin-dependent kinase inhibitor (CKI) p27, although the mechanism(s) by which tuberin modulates p27 stability has/have not been elucidated. Previous studies have also shown that AMP-activated protein kinase (AMPK), which functions in an energy-sensing pathway in the cell, becomes activated in the absence of tuberin. Here we show that in Tsc2-null tumors and cell lines, AMPK activation correlates with an increase in p27 levels, and inhibition of AMPK signaling decreases p27 le...

Ursolic acid induces PC-3 cell apoptosis via activation of JNK and inhibition of Akt pathways in vitro

Molecular Carcinogenesis — Tue, 09 Feb 2010 00:00:00 +0100

Ursolic acid (UA), a pentacyclic triterpenoid compound, has been demonstrated to have an antiproliferative effect in various tumors. We investigated the cell killing effects of UA in the human hormone refractory prostate cancer cell line, PC-3 cells. Also, the molecular mechanisms underlying its antigrowth effect were explored. We found that UA treatment in vitro can effectively inhibit PC-3 cell viability in a dose-dependent manner by inducing apoptosis, demonstrated by annexin V-FITC/propidium iodide staining. Both extrinsic and intrinsic apoptotic pathways appear to be triggered by UA treatment, because inhibiting activation of both caspase-8 and -9 could prevent UA-induced apoptosis in PC-3 cells. The c-Jun N-terminal kinase (JNK) was found to be activated, followed by Bcl-2 phosphoryl...

The effect of c-myc on stem cell fate influences skin tumor phenotype

Molecular Carcinogenesis — Tue, 09 Feb 2010 00:00:00 +0100

Nonmelanoma skin cancers (NMSCs) consist of a variety of tumor types including basal cell carcinoma, squamous cell carcinoma, a variety of hair follicle tumors, and sebaceous gland tumors. Genetic alterations that alter the fate of multipotent stem cells are believed to influence NMSC phenotype. We previously generated a transgenic mouse line which constitutively expressed c-myc under the control of the K14 promoter (K14.MYC2). These mice exhibited an increase in size and number of sebaceous glands, suggesting that c-myc diverted multipotential stem cells to a sebaceous lineage. Our goal in the current study was to determine if alterations in the commitment of multipotent stem cells to different cell fates would influence tumor phenotype. To this end, we exposed K14.MYC2 mice to a chemical...

The 24th Aspen Cancer Conference: Mechanisms of toxicity, carcinogenesis, cancer prevention and cancer therapy 2009

Molecular Carcinogenesis — Fri, 15 Jan 2010 00:00:00 +0100

(Source: Molecular Carcinogenesis)

The expression of SIAH1 is downregulated and associated with Bim and apoptosis in human breast cancer tissues and cells

Molecular Carcinogenesis — Fri, 15 Jan 2010 00:00:00 +0100

In this study, our aims were to examine the relationship between SIAH1 and Bcl-2-interacting mediator of cell death (Bim) and to explore the effects of SIAH1 on the breast carcinogenesis. Immunohistochemical analysis in 231 cases of breast tissues showed that the expression of SIAH1 and Bim were significantly decreased in the breast carcinogenesis. Moreover, SIAH1 expression was significantly correlated with Bim. Both SIAH1 and Bim expression were significantly higher in well to moderately differentiated and in early-stage breast cancer. Reverse transcription (RT)-polymerase chain reaction (PCR) and Western blot analysis in paired breast cancer tissues and breast cell lines found that the expression of SIAH1 was lower in the breast cancer tissues and cell lines. SIAH1 inducing apoptosis of...

Loss of syndecan-1 is associated with malignant conversion in skin carcinogenesis

Molecular Carcinogenesis — Fri, 15 Jan 2010 00:00:00 +0100

In this study we show that sdc-1 expression is significantly reduced in basal cell, squamous cell, and metastatic human skin cancers compared to normal human skin. In experimental mouse skin tumor induction, compared to wildtype (wt) BALB/c mice, papilloma formation in sdc-1 null mice was reduced by 50% and the percent of papillomas converting to squamous cell carcinoma (SCC) was enhanced. sdc-1 expression on wt mouse papillomas decreased as they converted to SCC. Furthermore, papillomas forming on sdc-1 null mice expressed suprabasal [alpha]3 and [beta]4 integrins; suprabasal [beta]4 integrin is a marker of a high risk for progression. While the proliferative response to phorbol-12-myristate-13-acetate (TPA) did not differ among the genotypes, sdc-1 null mice had an enhanced inflammatory ...

Enhanced expression of cancer testis antigen genes in glioma stem cells

Molecular Carcinogenesis — Fri, 15 Jan 2010 00:00:00 +0100

Cancer stem cells are an important target for effective therapy, since they show tumorigenicity, chemoresistance, and radioresistance. We isolated cancer stem cells from glioma cell lines and tissues and examined the expression of cancer testis antigen (CTA) genes as potential target molecules for cancer vaccine therapy. CTA genes were highly and frequently expressed in cancer stem cells compared with differentiated cells. In addition, histone acetylation levels in the promoter regions of CTA genes were high in cancer stem cells and low in differentiated cells, while DNA methylation analysis of the promoter regions revealed hypomethylation in cancer stem cells. This epigenetic difference between cells leads to heterogeneous expression of CTA genes in the tumor mass, which consists of cells...

Opposing actions of insulin and arsenite converge on PKC[delta] to alter keratinocyte proliferative potential and differentiation

Molecular Carcinogenesis — Fri, 15 Jan 2010 00:00:00 +0100

When cultured human keratinocytes reach confluence, they undergo a program of changes replicating features of differentiation in vivo, including exit from the proliferative pool, increased cell size, and expression of specialized differentiation marker proteins. Previously, we showed that insulin is required for some of these steps and that arsenite, a human carcinogen in skin and other epithelia, opposes the differentiation process. In present work, we show that insulin signaling, probably through the IGF-I receptor, is required for the increase in cell size accompanying differentiation and that this is opposed by arsenite. We further examine the impact of insulin and arsenite on PKC[delta], a known key regulator of keratinocyte differentiation, and show that insulin increases the amount,...

Eugenol precludes cutaneous chemical carcinogenesis in mouse by preventing oxidative stress and inflammation and by inducing apoptosis

Molecular Carcinogenesis — Thu, 31 Dec 2009 00:00:00 +0100

The present study was designed to investigate the protective efficacy of eugenol against skin cancer and probe into the mechanistic aspects. Skin tumors were initiated by applying 160 nmol DMBA and promoted by twice weekly applications of 8.5 nmol TPA for 28 wk. All mice developed tumors by 13 wk of promotion. However, in mice pretreated with 30 µL eugenol, no tumors were detected until 8 wk (following anti-initiation protocol) and until 14 wk (following antipromotion protocol) of tumor promotion. PCNA and TUNEL immunohistochemistry of tumors revealed eugenol to ameliorate cell proliferation and elevate apoptosis respectively. The effect of eugenol was assessed on specific stages of carcinogenesis. Initiation with DMBA led to a significant upregulation of p53 expression with a concomitant...

Vitamin D receptor ligands, adenomatous polyposis coli, and the vitamin D receptor FokI polymorphism collectively modulate [beta]-catenin activity in colon cancer cells

Molecular Carcinogenesis — Wed, 30 Dec 2009 00:00:00 +0100

We report herein that [beta]-catenin-mediated transcription is most effectively suppressed by the VDR FokI variant F/M4 when 1,25D is limiting. Using Caco-2 colorectal cancer (CRC) cells, it was observed that VDR ligands, 1,25D and LCA, both suppress [beta]-catenin transcriptional activity, though 1,25D exhibited significantly greater inhibition. Moreover, 1,25D, but not LCA, suppressed endogenous expression of the [beta]-catenin target gene DKK-4 independent of VDR DNA-binding activity. These results support [beta]-catenin sequestration away from endogenous gene targets by 1,25D-VDR. This activity is most efficiently mediated by the FokI gene variant F/M4, a VDR allele previously associated with protection against CRC. Interestingly, we found the inhibition of [beta]-catenin activity by 1...

Stat3 is required for anchorage-independent growth and metastasis but not for mammary tumor development downstream of the ErbB-2 oncogene

Molecular Carcinogenesis — Tue, 22 Dec 2009 00:00:00 +0100

The oncogenic transcription factor Stat3 is constitutively active in a high percentage of human tumors including mammary adenocarcinomas and is reported to participate in the ErbB-2 oncogene signaling. In order to assess the role of signal transducer and activator of transcription 3 (Stat3) in mammary tumorigenesis downstream of ErbB-2, we generated mice expressing the activated rat ErbB-2 (neu) but lacking Stat3 in the mammary epithelium. Stat3 is apparently not required for neu-driven mammary tumorigenesis as tumors developed similarly in both Stat3-sufficient and Stat3-deficient glands. However, short hairpin RNA (shRNA)-mediated Stat3 silencing in a neu-overexpressing tumor-derived cell line completely abolished both neu-driven anchorage-independent growth and lung metastasis. Our data...

Association between activation of atypical NF-[kappa]B1 p105 signaling pathway and nuclear [beta]-catenin accumulation in colorectal carcinoma

Molecular Carcinogenesis — Mon, 21 Dec 2009 00:00:00 +0100

Recent studies have demonstrated that increased expression of coding region determinant-binding protein (CRD-BP) in response to [beta]-catenin signaling leads to the stabilization of [beta]-TrCP1, a substrate-specific component of SCF E3 ubiquitin ligase complex, resulting in an accelerated degradation of I[kappa]B[alpha] and activation of canonical nuclear factor-[kappa]B (NF-[kappa]B) pathway. Here, we show that the noncanonical NF-[kappa]B1 p105 pathway is constitutively activated in colorectal carcinoma specimens, being particularly associated with [beta]-catenin-mediated increased expression of CRD-BP and [beta]-TrCP1. In the carcinoma tissues exhibiting high levels of nuclear [beta]-catenin the phospho-p105 levels were increased and total p105 amounts were decreased in comparison to ...

Dietary folate and vitamin B6 are not associated with p53 mutations in esophageal adenocarcinoma

Molecular Carcinogenesis — Sat, 19 Dec 2009 00:00:00 +0100

Recent studies have suggested an association between dietary folate, and related B-vitamins, and risk for cancer, potentially mediated by the p53 tumor suppressor gene. The aim of this study was to explore the effect of dietary folate and vitamin B6 intake on p53 in the molecular pathogenesis of esophageal adenocarcinoma (EADC). For each participant, a structured questionnaire was used to obtain detailed sociodemographic and lifestyle risk factors, including diet, from which folate and vitamin B6 intake were calculated. Risks for p53 mutations, p53 mutations at CpG sites, and p53 protein overexpression among EADC cases (n = 54) were calculated using logistic regression with dietary folate and vitamin B6 intake as predictive variables, adjusting for age, gender, smoking, and alcohol consump...

Intracisternal A particle genes: Distribution in the mouse genome, active subtypes, and potential roles as species-specific mediators of susceptibility to cancer

Molecular Carcinogenesis — Fri, 18 Dec 2009 00:00:00 +0100

This study identified the major "active" subtypes of IAPs (subtype 1/1a) that are responsible for newly transposed IAP insertions described in the literature, and confirmed that (1) polymorphisms for IAP insertions exist among different mouse strains and (2) promoter activity of the LTRs can be modulated by chemicals. This study further identified all the genes in the C57BL/6 mouse genome with IAP subtype 1 and 1a sequences inserted in their proximity, and the major biofunctional categories and cellular signaling networks of those genes. Since many "IAP-associated genes" play important roles in the regulation of cell proliferation, cell cycle, and cell death, the associated IAPs, upon activation, can affect cellular responses to xenobiotics and disease processes, especially carcinogenesis....

Curcumin inhibits the Sonic Hedgehog signaling pathway and triggers apoptosis in medulloblastoma cells

Molecular Carcinogenesis — Fri, 18 Dec 2009 00:00:00 +0100

Medulloblastoma is an aggressive primary brain tumor that arises in the cerebellum of children and young adults. The Sonic Hedgehog (Shh) signaling pathway that plays important roles in the pathology of this aggressive disease is a promising therapeutic target. In the present report we have shown that curcumin has cytotoxic effects on medulloblastoma cells. Curcumin suppressed also cell proliferation and triggered cell-cycle arrest at G2/M phase. Moreover, curcumin inhibited the Shh-Gli1 signaling pathway by downregulating the Shh protein and its most important downstream targets GLI1 and PTCH1. Furthermore, curcumin reduced the levels of [beta]-catenin, the activate/phosphorylated form of Akt and NF-[kappa]B, which led to downregulating the three common key effectors, namely C-myc, N-myc,...

Lysosomal destabilization and cathepsin B contributes for cytochrome c release and caspase activation in embelin-induced apoptosis

Molecular Carcinogenesis — Fri, 27 Nov 2009 00:00:00 +0100

XIAP is an important antiapoptotic protein capable of conferring resistance to cancer cells. Embelin, the small molecular inhibitor of XIAP, possesses wide spectrum of biological activities with strong inhibition of nuclear factor kappa B and downstream antiapoptotic genes. However, the mechanism of its cell death induction is not known. Our studies using colon cancer cells lacking p53 and Bax suggest that both lysosomes and mitochondria are prominent targets of embelin-induced cell death. Embelin induced cell-cycle arrest in G1 phase through p21, downstream of p53. In the absence of p21, the cells are sensitized to death in a Bax-dependent manner. The loss of mitochondrial membrane potential induced by embelin was independent of Bax and p53, but lysosomal integrity loss was strongly influ...

A novel tumor suppressor gene RhoBTB2 (DBC2): Frequent loss of expression in sporadic breast cancer

Molecular Carcinogenesis — Wed, 25 Nov 2009 00:00:00 +0100

RhoBTB2 was isolated recently as a tumor suppressor gene from human chromosome 8p21.3. Although RhoBTB2 was found to be frequently lost in breast cancer lines, expression status of RhoBTB2 in sporadic breast cancer tissues and its clinical and prognostic value, however, remain unclear. Tissue samples from breast cancer patients and normal controls and cell samples from cell lines were collected and reverse transcription (RT)-PCR was used to monitor the presence of RhoBTB2 mRNA. The protein expression of RhoBTB2 was detected by immunohistochemical staining. Cumulative survival time was assessed by the Kaplan-Meier method and Cox regression model. We discovered that RhoBTB2 expression was lacking in a breast ductal epithelial carcinoma cell line T-47D but was expressed in other types of tumo...

Pachymic acid inhibits cell growth and modulates arachidonic acid metabolism in nonsmall cell lung cancer A549 cells

Molecular Carcinogenesis — Fri, 13 Nov 2009 00:00:00 +0100

In this study, we examined the effect of PA on the proliferation of human nonsmall cell lung cancer A549 cells. Furthermore, we investigated the influences of nontoxic levels of PA on AA metabolism. Additionally, the cellular events and signal transduction pathways influenced by PA were also examined. Our results showed that PA (1) inhibited anchorage-dependent and -independent A549 growth in a concentration-dependent manner, (2) induced apoptosis and disrupted mitochondrial membrane potential in A549 cells, and at nonlethal levels, (3) decreased IL-1[beta]-induced activation of cPLA2 and COX-2, (4) suppressed IL-1[beta]-induced activation of mitogen-activated protein kinases (MAPKs), and (5) inhibited IL-1[beta]-stimulated nuclear factor kappa B (NF-[kappa]B) signaling pathways. We specul...

Up regulation of GW112 Gene by NF[kappa]B promotes an antiapoptotic property in gastric cancer cells

Molecular Carcinogenesis — Thu, 12 Nov 2009 00:00:00 +0100

To clarify the regulatory mechanism of GW112 gene expression, 5[prime]-flanking region of the human GW112 gene was isolated and characterized in the present study. 5[prime]-RACE analysis showed a single transcription start site, which is located 142 nucleotides upstream of the translation initiation site. Transient transfection studies with serial deletion constructs and close examination of the sequences identified a putative NF[kappa]B binding sequence between -442 and -430, which could be responsible for efficient expression of the GW112 gene. Indeed, GW112 gene was found to be regulated by NF[kappa]B signals including overexpressed p65 and I[kappa]B[alpha], IKK inhibitor, and proteasome inhibitor. Binding of NF[kappa]B to its putative site was confirmed by EMSA and ChIP assays. These r...

The tumor suppressor parafibromin is required for posttranscriptional processing of histone mRNA

Molecular Carcinogenesis — Wed, 11 Nov 2009 00:00:00 +0100

In this study, we identify a novel role of parafibromin in the regulation of replication-dependent histones. Both in vitro and in vivo analyses reveal a posttranscriptional role of parafibromin in histone mRNA processing. Downregulation of parafibromin through RNA interference or in vivo mutations lead to uncleaved histone mRNA with polyadenylated tails. These results indicate that parafibromin regulates the 3[prime] processing of histone RNA, an essential component of the cell cycle. © 2009 Wiley-Liss, Inc. (Source: Molecular Carcinogenesis)

Silibinin inhibits human nonsmall cell lung cancer cell growth through cell-cycle arrest by modulating expression and function of key cell-cycle regulators

Molecular Carcinogenesis — Wed, 11 Nov 2009 00:00:00 +0100

Recent studies show that silibinin possesses a strong antineoplastic potential against many cancers; however, its efficacy and underlying molecular mechanisms in nonsmall cell lung cancer (NSCLC) are not well defined. Herein, we assessed silibinin activity on prime endpoints and key molecular targets such as cell number, cell-cycle progression, and cell-cycle regulatory molecules in three cell lines representing different NSCLC subtypes, namely large cell carcinoma cells (H1299 and H460) and a bronchioalveolar carcinoma cell line (H322). Silibinin treatment (10-75 µM) inhibited cell growth and targeted cell-cycle progressing causing a prominent G1 arrest in dose- and time-dependent manner. In mechanistic studies, silibinin (50-75 µM) modulated the protein levels of cyclin-dependent kinas...

Fem1b, a proapoptotic protein, mediates proteasome inhibitor-induced apoptosis of human colon cancer cells

Molecular Carcinogenesis — Wed, 11 Nov 2009 00:00:00 +0100

In conclusion, the proapoptotic protein Fem1b is downregulated by the proteasome in malignant colon cancer cells and mediates proteasome inhibitor-induced apoptosis of these cells. Therefore, Fem1b could represent a novel molecular target to overcome apoptosis resistance in therapy of colon cancer. © 2009 Wiley-Liss, Inc. (Source: Molecular Carcinogenesis)

The synergistic anticancer effect of troglitazone combined with aspirin causes cell cycle arrest and apoptosis in human lung cancer cells

Molecular Carcinogenesis — Wed, 11 Nov 2009 00:00:00 +0100

In this report we demonstrate for the first time that, when administered in combination, TGZ and ASA can produce a strong synergistic effect in growth inhibition and G1 arrest in lung cancer CL1-0 and A549 cells. Examination by colony formation assay revealed an even more profound synergy. In Western blot, combined TGZ and ASA also could downregulate Cdk2, E2F-1, cyclin B1, cyclin D3 protein, and the ratio of phospho-Rb/Rb. Importantly, apoptosis was synergistically induced by the combination treatment, as evidenced by caspase-3 activation and PARP cleavage. The involvement of PI3K/Akt inhibition and p27 upregulation, as well as hypophosphorylation of Rac1 at ser71, were demonstrated. Taken together, these results suggest that clinically achievable concentrations of TGZ and ASA used in com...

Cytochrome P450 1B1 mRNA untranslated regions interact to inhibit protein translation

Molecular Carcinogenesis — Wed, 11 Nov 2009 00:00:00 +0100

In this study CYP1B1 mRNA and protein expression was measured in a panel of cell lines indicating that CYP1B1 regulation is altered in tumor cell lines in vitro. Interrogation of ONCOMINE revealed that CYP1B1 mRNA is not significantly overexpressed in tumors compared to normal tissues, suggesting CYP1B1 is subject to posttranscriptional control. Analysis of the CYP1B1 mRNA revealed a complex 5[prime] untranslated region (UTR) containing a small upstream open-reading frame (uORF). These features are present in mRNAs subject to translational control so the effect of the 5[prime]UTR was tested using in vitro translation in CHO-K1 cells. The 5[prime]UTR significantly inhibited luciferase reporter gene translation, and mutation of the uORF start codon abolished the inhibitory effect. The 5[prim...

A novel strategy to inhibit FAK and IGF-1R decreases growth of pancreatic cancer xenografts

Molecular Carcinogenesis — Tue, 03 Nov 2009 00:00:00 +0100

Deregulation of insulin-like growth factor-1 receptor (IGF-1R) and focal adhesion kinase (FAK) signaling pathways plays an important role in cancer cell proliferation and metastasis. In pancreatic cancer cells, the crosstalk and compensatory mechanisms between these two pathways reduce the efficacy of the treatments that target only one of the pathways. Ablation of IGF-1R signaling by siRNA showed minimal effects on the survival and growth of pancreatic cancer cells. An increased activity of FAK pathway was seen in these cells after IGF-1R knockdown. Further inhibition of FAK pathway using Y15 significantly decreased cell survival, adhesion, and promoted apoptosis. The combination of Y15 treatment and IGF-1R knockdown also showed significant antitumor effect in vivo. The current study demo...

Inhibition of focal adhesion kinase and src increases detachment and apoptosis in human neuroblastoma cell lines

Molecular Carcinogenesis — Mon, 02 Nov 2009 00:00:00 +0100

Neuroblastoma is the most common extracranial solid tumor of childhood. Focal adhesion kinase (FAK) is an intracellular kinase that is overexpressed in a number of human tumors including neuroblastoma, and regulates both cellular adhesion and survival. We have studied the effects of FAK inhibition upon neuroblastoma using adenovirus-containing FAK-CD (AdFAK-CD). Utilizing an isogenic MYCN+/MYCN- neuroblastoma cell line, we found that the MYCN+ cells are more sensitive to FAK inhibition with AdFAK-CD than their MYCN negative counterparts. In addition, we have shown that phosphorylation of Src is increased in the untreated isogenic MYCN- neuroblastoma cells, and that the decreased sensitivity of the MYCN- neuroblastoma cells to FAK inhibition with AdFAK-CD is abrogated by the addition of the...

Genetic variation in MicroRNA genes and risk of oral premalignant lesions

Molecular Carcinogenesis — Thu, 22 Oct 2009 23:00:00 +0100

MicroRNAs (miRNAs) have been reported to play a key role in oncogenesis and, recently, studies have examined the role miRNAs might play in the risk of premalignant lesions. To our knowledge, no study has investigated the association between miRNA polymorphisms and risk of oral premalignant lesions (OPLs). We genotyped 31 single nucleotide polymorphisms (SNPs) among 21 miRNA-related genes in a case-control study including 136 OPL patients and 136 matched controls. Patients with at least one variant allele of mir26a-1:rs7372209 had a significantly increased risk of OPL (OR, 2.09; 95% CI, 1.23-3.56). Likewise, patients with at least one variant allele of DICER:rs3742330 had a significantly increased risk of OPL (OR, 2.09; 95% CI, 1.03-4.24). To assess the cumulative effects, we performed a co...

Coding microsatellite instability analysis in microsatellite unstable small intestinal adenocarcinomas identifies MARCKS as a common target of inactivation

Molecular Carcinogenesis — Wed, 21 Oct 2009 23:00:00 +0100

In conclusion, we herein present a cMSI profile of MSI-H small intestinal adenocarcinomas identifying MARCKS as a frequent target of mutation. Loss of MARCKS protein expression suggests a significant role of MARCKS inactivation in the pathogenesis of small intestinal adenocarcinomas. © 2009 Wiley-Liss, Inc. (Source: Molecular Carcinogenesis)

Aryl hydrocarbon nuclear translocator (hypoxia inducible factor 1[beta]) activity is required more during early than late tumor growth

Molecular Carcinogenesis — Mon, 12 Oct 2009 23:00:00 +0100

c4 is a derivative of the mouse hepatoma cell line, Hepa-1, that harbors a mutation in the aryl hydrocarbon receptor nuclear translocator gene (Arnt, or hypoxia inducible factor 1[beta] [HIF-1[beta]]) leading to loss of activity. Clone 3 cells were generated by introducing a doxycycline-repressible Arnt expression vector into c4 cells. Clone 3 cells were injected subcutaneously into immunosuppressed mice, which were treated with doxycyline (a) throughout the growth of the subsequent tumor xenografts, or (b) from day 7 through to the end of the experiment (day 30), or not treated (c). Tumors in all groups grew exponentially between days 14 and 30, and at rates that were indistinguishable from each other. However, tumors in group a were smaller than those of the other two groups throughout t...

Werner syndrome gene variants in human sarcomas

Molecular Carcinogenesis — Sun, 11 Oct 2009 23:00:00 +0100

Werner syndrome is an autosomal inherited disease that is characterized by premature aging. The gene mutated in Werner syndrome (WS), WRN, encodes both a 3[prime] [rarr] 5[prime] DNA helicase and a 3[prime] [rarr] 5[prime] DNA exonuclease. Among the WS phenotypes is an exceptionally high incidence of sarcomas. We asked whether spontaneous sarcomas, not known to be associated with WS, also harbor mutations or unreported single nucleotide polymorphisms (SNPs) in WRN. We analyzed RNA or DNA sequences within the helicase and exonuclease domains from 51 and 69 matched sarcoma and adjacent normal tissues, respectively. Among a total of 13 nucleotide variants detected, we identified three novel nonsynonymous substitutions: c.611C>T, c.809_810insT, and c.1882C>G. We further characterized one, c.61...

E2F2 suppresses Myc-induced proliferation and tumorigenesis

Molecular Carcinogenesis — Thu, 01 Oct 2009 23:00:00 +0100

Deregulation of E2F transcriptional activity as a result of alterations in the p16-cyclin D-Rb pathway is a hallmark of cancer. However, the roles of the different E2F family members in the process of tumorigenesis are still being elucidated. Studies in mice and humans suggest that E2F2 functions as a tumor suppressor. Here we demonstrate that E2f2 inactivation cooperates with transgenic expression of Myc to enhance tumor development in the skin and oral cavity. In fact, hemizygosity at the E2f2 locus was sufficient to increase tumor incidence in this model. Loss of E2F2 enhanced proliferation in Myc transgenic tissue but did not affect Myc-induced apoptosis. E2F2 did not behave as a simple activator of transcription in epidermal keratinocytes but instead appeared to differentially regulat...

Association of selected polymorphisms of CCND1, p21, and caspase8 With colorectal cancer risk

Molecular Carcinogenesis — Tue, 29 Sep 2009 23:00:00 +0100

It has been well elucidated that the signal transduction of cell-cycle control pathway and apoptosis pathway plays an important role in the normal growth and differentiation of organisms. To test the hypothesis that mutants of key genes involved in cell-cycle regulation and apoptosis might contribute to the increased risk of colorectal cancer (CRC), a population-based case-control study was carried out in Jiashan County, Zhejiang Province. The study population was composed of 373 CRC cases and 838 controls. Five genetic variants including CCND1 G870A, p21 codon31 C/A, p21 3[prime]UTR C/T, caspase8 IVS12-19G/A, and caspase8 6n del/ins were genotyped. The associations of the polymorphisms with CRC were estimated by logistical regression model after adjustment for the important covariates. Th...

Rotenone induces apoptosis in MCF-7 human breast cancer cell-mediated ROS through JNK and p38 signaling

Molecular Carcinogenesis — Wed, 23 Sep 2009 23:00:00 +0100

Rotenone is an inhibitor of the mitochondrial electron transport chain complex I, resulting in the generation of reactive oxygen species (ROS). Rotenone has been shown to display anticancer activity through the induction of apoptosis in various cancer cells. However, the underlying mechanism is still not fully understood. Here, rotenone showed a strong growth inhibitory effect against human breast cancer MCF-7 cells. DNA flow cytometric analysis, chromatin condensation, and poly (ADP-ribose) polymerase (PARP) cleavage indicated rotenone actively induced apoptosis in MCF-7 cells. The antiapoptotic protein, Bcl-2, was decreased, whereas the apoptotic protein, Bax, was increased in a time-dependent manner in rotenone-induced apoptosis. Moreover, the treatment of rotenone in MCF-7 cells caused...

Cold-inducible RNA-binding protein contributes to human antigen R and cyclin E1 deregulation in breast cancer

Molecular Carcinogenesis — Tue, 22 Sep 2009 23:00:00 +0100

The cell cycle regulator cyclin E1 is aberrantly expressed in a variety of human cancers. In breast cancer, elevated cyclin E1 correlates with poor outcome, as do high cytoplasmic levels of the stress-induced RNA-binding protein human antigen R (HuR). We showed previously that increased cytoplasmic HuR elevates cyclin E1 in MCF-7 breast cancer cells by stabilizing its mRNA. We show here that cold-inducible RNA-binding protein (CIRP) co-regulates cyclin E1 with HuR in breast cancer cells. CIRP had been shown to interact with HuR in Xenopus laevis oocytes and to be decreased in endometrial cancer. To investigate if human CIRP and HuR co-regulate cyclin E1, HuR and CIRP levels were altered in MCF-7 cells and effects on cyclin E1 assessed. Altering HuR expression resulted in a reciprocal chang...

Aberrant DNA methylation occurs in colon neoplasms arising in the azoxymethane colon cancer model

Molecular Carcinogenesis — Tue, 22 Sep 2009 23:00:00 +0100

Mouse models of intestinal tumors have advanced our understanding of the role of gene mutations in colorectal malignancy. However, the utility of these systems for studying the role of epigenetic alterations in intestinal neoplasms remains to be defined. Consequently, we assessed the role of aberrant DNA methylation in the azoxymethane (AOM) rodent model of colon cancer. AOM induced tumors display global DNA hypomethylation, which is similar to human colorectal cancer. We next assessed the methylation status of a panel of candidate genes previously shown to be aberrantly methylated in human cancer or in mouse models of malignant neoplasms. This analysis revealed different patterns of DNA methylation that were gene specific. Zik1 and Gja9 demonstrated cancer-specific aberrant DNA methylatio...

Expression and function of CD9 in melanoma cells

Molecular Carcinogenesis — Tue, 22 Sep 2009 23:00:00 +0100

CD9, a member of the tetraspanin family, functions as an organizer in "tetraspanin webs," through interacting with other cell adhesion molecules. It plays a role in differentiation, fertilization, and cell migration. We investigated the expression and function of CD9 in melanoma. CD9 protein expression in B16 mouse melanoma and six human melanoma cell lines was decreased compared to normal melanocytes. B16F1 clones stably overexpressing CD9 had reduced ability to form colonies in soft agar; however, paradoxically these overexpressing clones had increased ability to invade Matrigel. Similarly, transient overexpression of CD9 in the human metastatic melanoma cell line WM9 dramatically decreased anchorage-independent growth, while transient overexpression of CD9 in the radial growth phase cel...

Genetic reduction of circulating insulin-like growth factor-1 inhibits azoxymethane-induced colon tumorigenesis in mice

Molecular Carcinogenesis — Wed, 16 Sep 2009 23:00:00 +0100

We examined markers of proliferation and apoptosis in the colons of the LID and wild-type mice to see if these were consistent with tumorigenesis. We observed a decrease in proliferation in the colons of the LID mice and an increase in apoptosis. Finally, we examined cytokine levels to determine whether IGF-1 interacts with inflammatory pathways to affect colon tumorigenesis. We observed a significant reduction in the levels of 7 out of 10 cytokines that were measured in the LID mice as compared to wild-type littermates. Results from this pilot study support the hypothesis that reductions in circulating IGF-1 levels may prevent colon tumorigenesis and affect both proliferation and apoptosis. Future experiments will investigate downstream genes of the IGF-1 receptor. © 2009 Wiley-Liss, Inc...

N-acetyl cysteine and penicillamine induce apoptosis via the ER stress response-signaling pathway

Molecular Carcinogenesis — Mon, 31 Aug 2009 23:00:00 +0100

This study was designed to identify the genes responsible for apoptosis induction by NAC and PEN. We found that glucose-regulated protein 78 (GRP78) was upregulated in HeLa cells following treatment with NAC or PEN. GRP78 is a central regulator of endoplasmic reticulum (ER) stress and has been used as a marker of ER stress. Additionally, both the activating transcription factor 6 (ATF6) protein and X box-binding protein 1 (XBP1) mRNA were processed, which facilitates the expression of C/EBP homologous protein (CHOP), a key-signaling component of ER stress-induced apoptosis. Furthermore, the PERK-ATF4 pathway, which also induces the expression of CHOP, was activated in NAC-treated cells. The role of the ER stress pathway was further confirmed through the small interfering RNA (siRNA)-mediat...

Occupational exposure to polycyclic aromatic hydrocarbons influenced neither the frequency nor the spectrum of FGFR3 mutations in bladder urothelial carcinoma

Molecular Carcinogenesis — Sun, 30 Aug 2009 23:00:00 +0100

Occupational exposure to polycyclic aromatic hydrocarbons (PAH) is associated with an increased risk of urothelial carcinoma (UC). FGFR3 is found mutated in about 70% of Ta tumors, which represent the major group at diagnosis. The influence of PAH on FGFR3 mutations and whether it is related to the emergence or shaping of these mutations is not yet known. We investigated the influence of occupational PAH on the frequency and spectrum of FGFR3 mutations. We included on 170 primary urothelial tumors from five hospitals from France. Patients (median age, 64 yr) were interviewed to gather data on occupational exposure to PAH, revealing 104 non- and possibly PAH exposed patients, 66 probably and definitely exposed patients. Tumors were classified as follows: 75 pTa, 52 pT1, and 43 [ge]pT2. Tumo...

Gastric cancer risk predisposition and prognostic significance of vascular endothelial growth factor (VEGF) gene polymorphisms - A case-control study in an Omani population

Molecular Carcinogenesis — Wed, 12 Aug 2009 23:00:00 +0100

Vascular endothelial growth factor (VEGF) plays a central role in angiogenesis, tumor growth, and metastasis. We investigated the associations between VEGF gene polymorphisms and gastric cancer (GC) risk predisposition and prognostic characteristics in an Omani population, an ethnic group which has not been studied previously. We analyzed three VEGF polymorphisms (+405 G/C, -460 T/C, and +936 C/T) by the extraction of genomic DNA from peripheral blood of 130 GC patients and 130 control subjects followed by VEGF genotyping using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) analysis. There were no significant associations between the VEGF polymorphisms and GC risk. There were significant correlations between the +405 C/C genotype and both poor tumor different...

Betuletol 3-methyl ether induces G2-M phase arrest and activates the sphingomyelin and MAPK pathways in human leukemia cells

Molecular Carcinogenesis — Tue, 11 Aug 2009 23:00:00 +0100

Betuletol 3-methyl ether (BME) is a natural phenylbenzo-[gamma]-pyrone that inhibits cell proliferation in human tumor cell lines and induces apoptotic cell death in HL-60 cells. Here we show that BME displays strong cytotoxic properties in several human leukemia cell lines (U937, K-562, THP-1, Jurkat, and Molt-3) and in cells that over-express two anti-apoptotic proteins, namely Bcl-2 and Bcl-xL. BME arrested HL-60 cells at G2-M phase of the cell cycle, which was associated with the accumulation of cyclin B1 and p21Cip1. Fluorescence microscopy experiments suggest that BME blocked the cell cycle in mitosis. The in vivo tubulin polymerization assay shows that BME inhibits tubulin polymerization and causes similar changes of cellular microtubule network as colchicine. Our results demonstrat...

Curcumin-induced apoptosis in ovarian carcinoma cells is p53-independent and involves p38 mitogen-activated protein kinase activation and downregulation of Bcl-2 and survivin expression and Akt signaling

Molecular Carcinogenesis — Tue, 11 Aug 2009 23:00:00 +0100

In this study we show that curcumin exhibited time- and dose-dependent cytotoxicity against monolayer cultures of ovarian carcinoma cell lines with differing p53 status (wild-type p53: HEY, OVCA429; mutant p53: OCC1; null p53: SKOV3). In addition, p53 knockdown or p53 inhibition did not diminish curcumin killing of HEY cells, confirming p53-independent cytotoxicity. Curcumin also killed OVCA429, and SKOV3 cells grown as multicellular spheroids. Nuclear condensation and fragmentation, as well as DNA fragmentation and poly (ADP-ribose) polymerase-1 cleavage in curcumin-treated HEY cells, indicated cell death by apoptosis. Procaspase-3, procaspase-8, and procaspase-9 cleavage, in addition to cytochrome c release and Bid cleavage into truncated Bid, revealed that curcumin activated both the ex...

Inactivation of SNF5 cooperates with p53 loss to accelerate tumor formation in Snf5+/-;p53+/- mice

Molecular Carcinogenesis — Tue, 11 Aug 2009 23:00:00 +0100

Malignant rhabdoid tumors (MRTs) are poorly differentiated pediatric cancers that arise in various anatomical locations and have a very poor outcome. The large majority of these malignancies are caused by loss of function of the SNF5/INI1 component of the SWI/SNF chromatin remodeling complex. However, the mechanism of tumor development associated with SNF5 loss remains unclear. Multiple studies have demonstrated a role for SNF5 in the regulation of cyclin D1, p16INK4A, and pRbf activities suggesting it functions through the SWI/SNF complex to affect transcription of genes involved in cell cycle control. Previous studies in genetically engineered mouse models (GEMM) have shown that loss of SNF5 on a p53-null background significantly accelerates tumor development. Here, we use established GE...

Necdin: A multi functional protein with potential tumor suppressor role?

Molecular Carcinogenesis — Wed, 22 Jul 2009 23:00:00 +0100

Necdin (NDN), a member of the melanoma-associated antigen (MAGE) family of proteins was first identified in mouse stem cells of embryonal carcinoma origin induced to differentiate by treatment with retinoic acid. The human gene maps to chromosome 15q11. This imprinted region is implicated in the pathogenesis of Prader-Willi syndrome (PWS), a neurodevelopmental disorder, where NDN is one of multiple genes silenced by deletion, maternal uniparental disomy or translocation. Due to this association, much interest has focused on the role of NDN in neuronal development and differentiation. However, a considerable number of studies have identified additional functions of NDN. Taken together these studies suggest a pleiotropic protein with diverse functions some of which may be relevant to tumorig...

Involvement of p53 in oroxylin A-induced apoptosis in cancer cells

Molecular Carcinogenesis — Tue, 21 Jul 2009 23:00:00 +0100

In this study, we investigate whether p53 is involved in oroxylin A-triggered viability inhibition and apoptosis induction in cancer cells. In a panel of different cancer cell lines, more potent inhibitory effects of oroxylin A were observed in wtp53 cells than those in mtp53 or p53-null cells. Moreover, p53-siRNA-transfected HepG2 cells showed lower levels of apoptosis induced by oroxylin A than control-siRNA-transfected cells. Likewise, after oroxylin A treatment, p53-null K-562 cells displayed promoted apoptosis rate when transfected with wtp53 plasmid. Western blot and real-time RT-PCR assay revealed that oroxylin A markedly upregulated p53 protein expression in HepG2 and p53-overexpressing K-562 cells, but had no influence on p53 mRNA synthesis. Furthermore, after co-treatment with cy...

Colocalization of MnSOD expression in response to oxidative stress

Molecular Carcinogenesis — Tue, 21 Jul 2009 23:00:00 +0100

In this study, we investigated the expression and localization of MnSOD in response to the exposure to bile salts in an esophageal epithelial cell line. Het-1A cells were seeded at 5 × 105 and 107 and incubated with taurocholate, cholate, glycochlate, deoxycholate, and the mixture of these bile salts. Mitochondria and cytoplasma were separated, and the expression and localization of MnSOD was determined by Western blot and immunocytochemical assay. Proliferation rates were strongly inhibited in the groups with taurocholate and bile salts mixture at 4 h, with 0.367 ± 0.042 and 0.396 ± 0.046, respectively, compared to 0.684 ± 0.054 in untreated groups (P < 0.05). An increased apoptotic rate compared to untreated group (3.65 ± 0.59) were significantly increased in taurocholate group and ...

Adenylosuccinate synthetase 1 gene is a novel target of deletion in lung adenocarcinoma

Molecular Carcinogenesis — Tue, 14 Jul 2009 23:00:00 +0100

Tobacco smoke consists of numerous carcinogens whose effect on lung tumor development includes the induction of mutations in key genes as well as the induction of chromosome instability (CIN). Consequently, carcinogen-induced mouse lung adenocarcinomas (LAC) display many more recurrent site- and chromosome-specific changes in DNA copy number compared with noninduced LAC. Here we identified the Adenylosuccinate synthetase 1 (Adss1) gene located on distal chromosome 12q as a focus of bi-allelic or homozygous deletion (HD) in LAC. HDs of Adss1 were detected in 10 out of 84 carcinogen-induced mouse primary LAC and mouse LAC cell lines. In only four of these cases did the deletions affect either Siva1 or Inverted-formin 2 (Inf2), which immediately flank the Adss1 locus, indicating that Adss1 is...

PI3K signaling maintains c-myc expression to regulate transcription of E2F1 in pancreatic cancer cells

Molecular Carcinogenesis — Mon, 13 Jul 2009 23:00:00 +0100

In this study we demonstrate that PI3K signaling controls transcription of the E2F1 gene and show that E2F1 is essential for S-phase progression of PDAC cells. On the molecular level, PI3K signaling controls c-myc protein abundance in a glycogen synthase kinase-3 (GSK3)-dependent fashion. c-myc binds to the E-box of the E2F1 gene in PDAC cells and this binding is under control of the PI3K-signaling pathway. Together, we demonstrate that PI3K-GSK3-dependent control of c-myc protein expression is connected to the transcription of the E2F1 gene in PDAC cells, leading to S-phase progression of the cell cycle. © 2009 Wiley-Liss, Inc. (Source: Molecular Carcinogenesis)

MSH6 G39E polymorphism and CpG island methylator phenotype in colon cancer

Molecular Carcinogenesis — Mon, 06 Jul 2009 23:00:00 +0100

The objective of our investigation was to evaluate associations between the MSH6 G39E (116G>A) polymorphism and CpG island methylator phenotype (CIMP) and BRAF V600E mutations in tumors from a sample of 1048 individuals with colon cancer and 1964 controls from Utah, Northern California, and Minnesota. The G39E polymorphism (rs1042821) was determined by the five prime nuclease assay. CIMP was determined by methylation-specific polymerase chain reaction (PCR) of CpG islands in MLH1, methylated in tumors (MINT)1, MINT2, MINT31, and CDKN2A. The BRAF V600E mutation was determined by sequencing exon 15. In microsatellite stable tumors, homozygous carriers of the G39E polymorphism had an increased risk of CIMP+ colon cancer (odds ratio (OR) 2.2, 95% confidence interval (CI) 1.1, 4.2) and BRAF V60...

Insulin-like growth factor type I receptor gene expression and obesity in esophageal adenocarcinoma

Molecular Carcinogenesis — Sun, 05 Jul 2009 23:00:00 +0100

The objective of this exploratory study was to evaluate the role of the insulin-like growth factor I receptor (IGF-IR) in esophageal adenocarcinoma (EADC). Using quantitative PCR, we studied IGF-IR mRNA expression in 52 well-characterized surgically resected EADC and matched histologically normal esophageal tissues, and examined IGF-IR expression levels in relation to clinicopathologic characteristics, body mass index (BMI), and the common IGF-IR polymorphism (G1013A), recently proposed to modify risk of obesity for EADC. Expression levels of IGF-IR mRNA were not significantly different between EADC and matched histologically normal esophageal epithelia. Although no significant associations were found between IGF-IR expression and BMI, tumor differentiation, stage or survival, when stratif...

Desipramine inhibits the growth of a mouse skin squamous cell carcinoma cell line and affects glucocorticoid receptor-mediated transcription

Molecular Carcinogenesis — Sat, 04 Jul 2009 23:00:00 +0100

The purpose of this study was to examine the effect of tricyclic antidepressant desipramine (DMI) on the growth inhibition and translocation of the glucocorticoid receptor (GR) from the cytoplasm to the nucleus in cancerous and noncancerous cell lines and the effect of DMI on GR-mediated transcription. Nontumorigenic, immortalized keratinocytes cell line (3PC), papilloma (MT1/2), and squamous cell carcinoma (Ca3/7) cell lines were initially used to study the cell growth inhibition by DMI. Although, the growth of all three cell lines was suppressed by DMI, it was more effective in Ca3/7 cells. Therefore, we next examined the effect of DMI on Ca3/7 cells, resistant to growth inhibition by the synthetic glucocorticoid fluocinolone acetonide (FA). DMI inhibited cell proliferation in a time-dep...

Epigenetic inactivation of Homeobox A5 gene in nonsmall cell lung cancer and its relationship with clinicopathological features

Molecular Carcinogenesis — Wed, 24 Jun 2009 23:00:00 +0100

In this study, we have investigated the methylation status of the promoter region of the HOXA5 gene in nonsmall cell lung cancers (NSCLCs) using nested and standard methylation-specific PCR (MSP) and correlated the methylation status with clinicopathological features. With standard MSP analysis, HOXA5 methylation were found in 113 (81.3%) of 139 NSCLCs and 72 (51.8%) in their corresponding nonmalignant lung tissues. RT-PCR and immunohistochemical analysis showed that HOXA5 methylation correlates with gene expression. Moreover, in the patients with stage I disease, HOXA5 methylation was more frequent in smokers than in never-smokes (P = 0.01). There was no influence of HOXA5 methylation on survival in all NSCLCs or at stages II-IV. However, in the patients with stage I disease, HOXA5 methyl...

Two genetic variants in prostate stem cell antigen and gastric cancer susceptibility in a chinese population

Molecular Carcinogenesis — Tue, 23 Jun 2009 23:00:00 +0100

We examined genotypes and haplotypes of PSCA, rs2294008C/T and rs2976392G/A in 716 patients with cardia gastric carcinoma (CGC), 1020 patients with noncardia gastric carcinoma (NCGC), and 1020 controls. We found that individuals with at least one copy of the rs2294008T allele (CT or TT genotype) had an elevated risk for developing NCGC compared with those without this allele (OR = 1.35, 95% CI = 1.13-1.61). Individuals with at least one copy of the rs2976392A allele (GA or AA genotype) had nonsignificantly increased risk for NCGC compared with those without this allele (OR = 1.20, 95% CI = 1.01-1.43). Stratification analysis showed that the increased risk associated with the SNPs was restricted in female subjects. Moreover, the rs2294008T and rs2976392A allele carriers were predisposed to ...

Inositol hexaphosphate downregulates both constitutive and ligand-induced mitogenic and cell survival signaling, and causes caspase-mediated apoptotic death of human prostate carcinoma PC-3 cells

Molecular Carcinogenesis — Wed, 17 Jun 2009 23:00:00 +0100

Constitutively active mitogenic and prosurvival signaling cascades due to aberrant expression and interaction of growth factors and their receptors are well documented in human prostate cancer (PCa). Epidermal growth factor (EGF) and insulin-like growth factor-1 (IGF-1) are potent mitogens that regulate proliferation and survival of PCa cells via autocrine and paracrine loops involving both mitogen-activated protein kinase (MAPK)- and Akt-mediated signaling. Accordingly, here we assessed the effect of inositol hexaphosphate (IP6) on constitutive and ligand (EGF and IGF-1)-induced biological responses and associated signaling cascades in advanced and androgen-independent human PCa PC-3 cells. Treatment of PC-3 cells with 2 mM IP6 strongly inhibited both growth and proliferation and decrease...

Activation of p53/p21/PUMA alliance and disruption of PI-3/Akt in multimodal targeting of apoptotic signaling cascades in cervical cancer cells by a pentacyclic triterpenediol from Boswellia serrata

Molecular Carcinogenesis — Wed, 17 Jun 2009 23:00:00 +0100

This study reports the apoptotic cell death in human cervical cancer HeLa and SiHa cells by a pentacyclic triterpenediol (TPD) from Boswellia serrata by a mechanism different from reported in HL-60 cells. It caused oxidative stress by early generation of nitric oxide and reactive oxygen species that robustly up regulated time-dependent expression of p53/p21/PUMA while conversely abrogating phosphatidylinositol-3-kinase (PI3K)/Akt pathways in parallel. TPD also decreased the expression of PI3K/pAkt, ERK1/2, NF-[kappa]B/Akt signaling cascades which coordinately contribute to cancer cell survival through these distinct pathways. The tumor suppressor p53 pathway predominantly activated by TPD further up-regulated PUMA, which concomitantly decreased the Bcl-2 level, caused mitochondrial membran...

Using cells devoid of RAS proteins as tools for drug discovery

Molecular Carcinogenesis — Thu, 11 Jun 2009 23:00:00 +0100

Mutational activation of RAS proteins occurs in nearly 30% of all human tumors. To date direct pharmacological inhibition of RAS oncoproteins has not been possible. As a consequence, current strategies are focusing on the development of inhibitors that target those kinases acting downstream of RAS proteins, including those of the RAF/MEK/ERK and PI3K/AKT pathways. Most of these inhibitors have undesired off-target effects that mask the potential therapeutic effect of blocking their targeted kinases. To facilitate the screening of selective inhibitors, we have generated lines of mouse embryonic fibroblasts that lack endogenous Ras proteins. These cells proliferate due to ectopic expression of either Ras oncoproteins that selectively activate the Raf/Mek/Erk pathway such as H-RasG12V/D38E or...

The suppression of MAD1 by AKT-mediated phosphorylation activates MAD1 target genes transcription

Molecular Carcinogenesis — Thu, 11 Jun 2009 23:00:00 +0100

MAX dimerization protein 1 (MAD1) is a transcription suppressor that antagonizes MYC-mediated transcription activation, and the inhibition mechanism occurs mainly through the competition of target genes' promoter MYC binding sites by MAD1. The promoter binding proteins switch between MYC and MAD1 affects cell proliferation and differentiation. However, little is known about MAD1's regulation process in cancer cells. Here, we present evidence that AKT inhibits MAD1-mediated transcription repression by physical interaction with and phosphorylation of MAD1. Phosphorylation reduces the binding affinity between MAD1 and its target genes' promoter and thereby abolishes its transcription suppression function. Mutation of the phosphorylation site from serine to alanine rescues the DNA-binding abil...

Cellular dichotomy between anchorage-independent growth responses to bFGF and TPA reflects molecular switch in commitment to carcinogenesis

Molecular Carcinogenesis — Thu, 11 Jun 2009 23:00:00 +0100

We have investigated gene expression patterns underlying reversible and irreversible anchorage-independent growth (AIG) phenotypes to identify more sensitive markers of cell transformation for studies directed at interrogating carcinogenesis responses. In JB6 mouse epidermal cells, basic fibroblast growth factor (bFGF) induces an unusually efficient and reversible AIG response, relative to 12-O-tetradecanoyl phorbol-13-acetate (TPA)-induced AIG which is irreversible. The reversible and irreversible AIG phenotypes are characterized by largely nonoverlapping global gene expression profiles. However, a subset of differentially expressed genes were identified as common to reversible and irreversible AIG phenotypes, including genes regulated in a reciprocal fashion. Hepatic leukemia factor (HLF...

Differential alterations in metabolic pattern of the spliceosomal uridylic acid-rich small nuclear RNAs (UsnRNAs) during malignant transformation of 20-methylcholanthrene-induced mouse CNCI-PM-20 embryonic fibroblasts

Molecular Carcinogenesis — Fri, 05 Jun 2009 04:00:00 +0100

Differential alterations of the spliceosomal Uridylic acid rich small nuclear RNAs (UsnRNAs) (U1, U2, U4, U5, and U6) are reported to be associated with cellular proliferation and development, but definitive information is scarce and also elusive. An attempt is made in this study to analyze the metabolic patterns of major spliceosomal UsnRNAs, during tumor development, in an in vitro carcinogenesis model of 20-methylcholanthrene (MCA)-transformed Swiss Mouse Embryonic Fibroblast (MEF), designated as CNCI-PM-20. MEF cells, after treatment with 20-MCA, progressed through a sequence of passages with distinct and heritable changes, finally becoming neoplastic at passage-42 (P42). A differential expression pattern of major UsnRNAs was observed during this process. The abundance of U1 was 20% be...

Effect of polymorphisms in the 3[prime] untranslated region (3[prime]-UTR) of vascular endothelial growth factor gene on gastric cancer and peptic ulcer diseases in Japan

Molecular Carcinogenesis — Wed, 03 Jun 2009 04:00:00 +0100

A complex interaction of host genetic and environmental factors may be relevant in the development of Helicocobacter pylori-related gastric carcinogenesis. We investigated the effect of vascular endothelial growth factor (VEGF) gene polymorphisms on the risk of gastric cancer (GC) and peptic ulcer diseases in a Japanese population. The G1612A(rs10434) and C936T(rs3025039) polymorphisms in the 3[prime] untranslated region (3[prime]-UTR) of VEGF gene were genotyped in a total of 844 subjects including 385 GC, 143 ulcer including 98 gastric ulcer (GU), 45 duodenal ulcer (DU), and 316 nonulcer subjects. The 1612A carrier held a significantly higher risk of GC when compared to both noncancer and nonulcer (overall noncancer vs. GC; OR = 1.61, 95% CI = 1.17-2.21, P = 0.0038, nonulcer vs. GC; OR =...

Neurofibromin physically interacts with the N-terminal domain of focal adhesion kinase

Molecular Carcinogenesis — Sun, 31 May 2009 04:00:00 +0100

In this report, we show for the first time physical interaction between neurofibromin and focal adhesion kinase (FAK), the protein that localizes at focal adhesions. We show that neurofibromin associates with the N-terminal domain of FAK, and that the C-terminal domain of neurofibromin directly interacts with FAK. Confocal microscopy demonstrates colocalization of NF1 and FAK in the cytoplasm, perinuclear and nuclear regions inside the cells. Nf1+/+ MEF cells expressed less cell growth during serum deprivation conditions, and adhered less on collagen and fibronectin-treated plates than Nf1-/- MEF cells, associated with changes in actin and FAK staining. In addition, Nf1+/+ MEF cells detached more significantly than Nf1-/- MEF cells by disruption of FAK signaling with the dominant-negative ...

Diallyl trisulfide-induced apoptosis in human cancer cells is linked to checkpoint kinase 1-mediated mitotic arrest

Molecular Carcinogenesis — Thu, 21 May 2009 04:00:00 +0100

In conclusion, the results of the present study indicate that Chk1 dependence of DATS-induced mitotic arrest in human cancer cells is not influenced by the p53 status and cells arrested in mitosis upon DATS exposure are driven to apoptotic DNA fragmentation. © 2009 Wiley-Liss, Inc. (Source: Molecular Carcinogenesis)

The Ron receptor tyrosine kinase is not required for adenoma formation in ApcMin/+ mice

Molecular Carcinogenesis — Tue, 19 May 2009 04:00:00 +0100

The Ron receptor tyrosine kinase is overexpressed in approximately half of all human colon cancers. Increased Ron expression positively correlates with tumor progression, and reduction of Ron levels in human colon adenocarcinoma cells reverses their tumorigenic properties. Nearly all colon tumors demonstrate loss of the adenomatous polyposis coli (APC) tumor suppressor, an early initiating event, subsequently leading to [beta]-catenin stabilization. To understand the role of Ron in early stage intestinal tumorigenesis, we generated Apc-mutant (ApcMin/+) mice with and without Ron signaling. Interestingly, we report here that significantly more ApcMin/+ Ron-deficient mice developed higher tumor burden than ApcMin/+ mice with wild-type Ron. Even though baseline levels of intestinal crypt prol...

Specific IKK[beta] inhibitor IV blocks streptonigrin-induced NF-[kappa]B activity and potentiates its cytotoxic effect on cancer cells

Molecular Carcinogenesis — Fri, 15 May 2009 04:00:00 +0100

Many anticancer agents activate NF-[kappa]B, which plays an important role in the survival of cancer cells. Inhibition of NF-[kappa]B activity may therefore potentiate the efficacy of anticancer agents. We found that a previously used anticancer agent Streptonigrin (SN) was also a potent NF-[kappa]B inducer. Using a specific IKK[beta] inhibitor IV (Podolin et al., J Pharmacol Exp Ther 2005; 312: 373-381), we revealed that the activation of NF-[kappa]B was mediated through DNA damage-induced activation of IKK complex. Furthermore, we demonstrated that SN-induced DNA damage was unrelated to reactive oxygen species but to the hydroquinone form of SN converted by the NAD(P)H:quinine oxidoreductase (NQO1). The study suggests that the combination of SN with IKK inhibitor may improve efficacy ove...

Urothelial overexpression of insulin-like growth factor-1 increases susceptibility to p-cresidine-induced bladder carcinogenesis in transgenic mice

Molecular Carcinogenesis — Thu, 07 May 2009 04:00:00 +0100

To establish a role for insulin-like growth factor-1 (IGF-1) in bladder cancer susceptibility, we tested the effect of p-cresidine, a potent bladder carcinogen, in transgenic (TG) mice with human IGF-1 expression in the bladder driven by the bovine keratin 5 promoter (referred to as BK5.IGF-1 TG mice). Indomethacin was also tested to determine if the cyclooxygenase (COX) pathway is a target for bladder cancer prevention in this model. Thirty-three female BK5.IGF-1 TG mice and 29 female nontransgenic littermates were randomized to the following treatments: (1) AIN-76A diet; (2) AIN-76A diet with 0.5% p-cresidine; or (3) AIN-76A diet with 0.5% p-cresidine + 0.00075% indomethacin. BK5.IGF-1 TG mice, with twofold greater total serum IGF-1 than nontransgenic mice, exhibited greatly increased su...

Regulation of CDX2 expression in esophageal adenocarcinoma

Molecular Carcinogenesis — Mon, 04 May 2009 04:00:00 +0100

Reflux of acidic gastric contents and bile acids into the lower esophagus has been identified to have a central role in esophageal malignancy and is reported to upregulate caudal-related homologue 2 (CDX2), a regulatory gene involved in embryonic development and axial patterning of the alimentary tract. The aim of this study was to characterize the expression of CDX2 in a well-defined series of human esophageal tissues, comprising reflux-induced esophagitis, premalignant Barrett esophagus (BE), and primary esophageal adenocarcinoma (EADC). To explore potential molecular regulatory mechanisms, we also studied the expression of [beta]-catenin, SOX9, and CDX2 promoter methylation in esophageal tissues, in addition to the effect of bile acids and nitric oxide (NO) on CDX2 expression in the nor...

Cyclin D1b variant promotes cell invasiveness independent of binding to CDK4 in human bladder cancer cells

Molecular Carcinogenesis — Mon, 04 May 2009 04:00:00 +0100

Alternative splicing in the cyclin D1 gene produces cyclin D1b variant which lacks a C-terminal region containing the threonine-286 (T286) phosphorylation site required for nuclear export. We have shown that the expression of the cyclin D1b variant is detected in about 60% of human bladder cancer tissues (15/26) and cell lines (3/5). To examine the role of the cyclin D1b variant in bladder carcinogenesis, we introduced wild-type cyclin D1a, cyclin D1b variant or mutant cyclin D1-T286A cDNAs into a human bladder cancer cell line, SBT991, in which cyclin D1b transcript was not expressed, and compared their oncogenic activities. Ectopic expression of cyclin D1b promoted cell invasiveness and anchorage-independent growth of the cancer cells. On the other hand, cyclin D1-T286A enhanced anchorag...

Regulation of peroxisome proliferator-activated receptor-[beta]/[delta] by the APC/[beta]-CATENIN pathway and nonsteroidal antiinflammatory drugs

Molecular Carcinogenesis — Mon, 04 May 2009 04:00:00 +0100

Studies indicate that peroxisome proliferator-activated receptor-[beta]/[delta] (PPAR[beta]/[delta]) can either attenuate or potentiate colon cancer. One hypothesis suggests that PPAR[beta]/[delta] is upregulated by the adenomatous polyposis coli (APC)/[beta]-CATENIN pathway and a related hypothesis suggests that PPAR[beta]/[delta] is downregulated by nonsteroidal antiinflammatory drugs (NSAIDs). The present study examined these possibilities using in vivo and in vitro models. While APC/[beta]-CATENIN-dependent expression of CYCLIN D1 was observed in vivo and in vitro, expression of PPAR[beta]/[delta] was not different in colon or intestinal polyps from wild-type or Apcmin heterozygous mice or in human colon cancer cell lines with mutations in APC and/or [beta]-CATENIN. No difference in th...

Li-Fraumeni and Li-Fraumeni-like syndrome mutations in p53 are associated with exonic methylation and splicing regulatory elements

Molecular Carcinogenesis — Sat, 18 Apr 2009 04:00:00 +0100

Mutations in codon 133 of p53, which cause the loss of the [Delta]133 isoform(s) expression, are very frequent in the Li-Fraumeni (LF) and Li-Fraumeni-like (LFL) syndromes. In sporadic cancers, silent p53 mutations are correlated with exonic splicing enhancers (ESEs) and exonic methylated sites. The present study shows that mutations in splice sites are also very frequent in LF/LFL syndromes, while missense mutations are less common compared to other familial or sporadic cancers (P = 0 in both cases). Furthermore, it is shown that the codons at which LF/LFL germline missense mutations occur, correlate with CpG-containing ESEs (r = 0.181, P = 0.014) which are all methylated in p53. While both silent and LF/LFL missense mutations correlate with SC35 motifs, only the latter are associated wit...

Epigenetic modulation of the retinoid X receptor [alpha] by green tea in the azoxymethane-ApcMin/+ mouse model of intestinal cancer

Molecular Carcinogenesis — Fri, 17 Apr 2009 04:00:00 +0100

We investigated the possible mechanisms of inhibition of colorectal carcinogenesis by green tea (GT) in azoxymethane-treated (AOM) ApcMin/+ mice. Mice received water or a 0.6% (w/v) solution of GT as the only source of beverage. GT treatment commenced at the 8th week of age and lasted for 8 wk. The treatment caused a statistically significant reduction in the number of newly formed tumors (28%, P < 0.05). Immunohistochemical analysis showed that GT decreased the levels of [beta]-catenin and its downstream target cyclin D1. To probe a mechanism, we further investigated the expression of retinoic X receptor alpha (RXR[alpha]) in AOM/ApcMin/+ tumors. Our results show that RXR[alpha] is selectively downregulated in AOM/ApcMin/+ mouse intestinal tumors. In contrast, other retinoic receptors inc...

HMGB1: The jack-of-all-trades protein is a master DNA repair mechanic

Molecular Carcinogenesis — Thu, 09 Apr 2009 04:00:00 +0100

The high mobility group protein B1 (HMGB1) is a highly abundant protein with roles in several cellular processes, including chromatin structure and transcriptional regulation, as well as an extracellular role in inflammation. HMGB1's most thoroughly defined function is as a protein capable of binding specifically to distorted and damaged DNA, and its ability to induce further bending in the DNA once it is bound. This characteristic in part mediates its function in chromatin structure (binding to the linker region of nucleosomal DNA and increasing the instability of the nucleosome structure) as well as transcription (bending promoter DNA to enhance the interaction of transcription factors), but the functional consequences of HMGB1's binding to damaged DNA is still an area of active investig...

No somatic genetic change in the paxillin gene in nonsmall-cell lung cancer

Molecular Carcinogenesis — Tue, 07 Apr 2009 04:00:00 +0100

The paxillin gene (PXN) encodes a focal adhesion associated protein that could be involved in the progression of lung cancer through its interactions with the actin cytoskeleton and key signal transduction oncogenes. PXN mutations and PXN amplifications were recently identified in nonsmall-cell lung cancer (NSCLC) and amplifications were associated with MET increased copy number. The description of tumors with two to three mutations in the PXN gene and the overrepresentation of GC to AT transitions were unexpected and needed confirmation. The aim of this study was to validate the incidence of PXN somatic alterations in NSCLC and to correlate them to other common genetic alterations. PXN mutations and copy number changes at PXN, EGFR, and MET loci were analyzed on DNAs from frozen tumor sam...

Mitochondrial bioenergetic background confers a survival advantage to HepG2 cells in response to chemotherapy

Molecular Carcinogenesis — Fri, 03 Apr 2009 04:00:00 +0100

Cancer cells mainly rely on glycolysis for energetic needs, and mitochondrial ATP production is almost inactive. However, cancer cells require the integrity of mitochondrial functions for their survival, such as the maintenance of the internal membrane potential gradient ([Delta][Psi]m). It thus may be predicted that [Delta][Psi]m regeneration should depend on cellular capability to produce sufficient ATP by upregulating glycolysis or recruiting oxidative phosphorylation (OXPHOS). To investigate this hypothesis, we compared the response to an anticancer agent chloroethylnitrosourea (CENU) of two transformed cell lines: HepG2 (hepatocarcinoma) with a partially differentiated phenotype and 143B (osteosarcoma) with an undifferentiated one. These cells types differ by their mitochondrial OXPHO...

Cyclooxygenase-2 Gly587Arg variant is associated with differential enzymatic activity and risk of esophageal squamous-cell carcinoma

Molecular Carcinogenesis — Fri, 03 Apr 2009 04:00:00 +0100

In this study, we investigated SNPs in the COX-2 coding region and their impact on risk of ESCC. The coding region of COX-2 in DNAs from 30 Han Chinese individuals was sequenced to identify SNPs. Different coding region variants identified were cloned and expressed in MCE-7 cells for the measurement of COX-2 enzymatic activity. Genotypes were determined by PCR-RFLP in 1026 patients with ESCC and 1270 controls and odds ratios (ORs) and 95% confidence intervals (CI) were computed by logistic regression model. A SNP at exon 10 (1759G>A, rs3218625) was identified, which causes 587Gly to 587Arg amino acid substitution. Enzymatic assays using different recombinant COX-2 variants showed that COX-2-587Arg had significantly higher activity towards arachidonic acid than COX-2-587Gly (13.8 ± 3.2 U/m...

Characterization of the 3p12.3-pcen region associated with tumor suppression in a novel ovarian cancer cell line model genetically modified by chromosome 3 fragment transfer

Molecular Carcinogenesis — Fri, 03 Apr 2009 04:00:00 +0100

The genetic analysis of nontumorigenic radiation hybrids generated by transfer of chromosome 3 fragments into the tumorigenic OV-90 ovarian cancer cell line identified the 3p12.3-pcen region as a candidate tumor suppressor gene (TSG) locus. In the present study, polymorphic microsatellite repeat analysis of the hybrids further defined the 3p12.3-pcen interval to a 16.1 Mb common region containing 12 known or hypothetical genes: 3ptel-ROBO2-ROBO1-GBE1-CADM2-VGLL3-CHMP2B-POU1F1-HTR1F-CGGBP1-ZNF654-C3orf38-EPHA3-3pcen. Seven of these genes, ROBO1, GBE1, VGLL3, CHMP2B, CGGBP1, ZNF654, and C3orf38, exhibited gene expression in the hybrids, placing them as top TSG candidates for further analysis. The expression of all but one (VGLL3) of these genes was also detected in the parental OV-90 cell li...

Cisplatin resistance conferred by the RAD51D (E233G) genetic variant is dependent upon p53 status in human breast carcinoma cell lines

Molecular Carcinogenesis — Fri, 03 Apr 2009 04:00:00 +0100

We describe in this report that the Rad51d (E233G) genetic variant confers increased cisplatin resistance and cell growth phenotypes in human breast carcinoma cell lines with a mutant p53 gene (BT20 and T47D) but not with a wild-type p53 gene (MCF-7). Treatment with a p53 specific inhibitor, pifithrin [alpha], restored this resistant phenotype in the MCF-7 cell line. Additionally, Rad51d (E233G) conferred increased cisplatin resistance of an MCF7 cell line in which p53 expression was stably knocked down by shRNAp53, indicating that the effect of this variant is dependent upon p53 status. Further study of Rad51d (E233G) will provide mechanistic insight towards the role of RAD51D in cellular response to anticancer agents and as a potential target for cancer therapy. Mol. Carcinog. © 2009 Wi...

Frequent occurrence of RASSF1A promoter hypermethylation and merkel cell polyomavirus in merkel cell carcinoma

Molecular Carcinogenesis — Sat, 28 Mar 2009 04:00:00 +0100

Merkel cell carcinoma (MCC) is one of the most aggressive cancers of the skin. It has recently been reported that integration of a Merkel cell polyomavirus (MCPyV) in receptor tyrosine phosphates type G (PTPRG) gene occurs in MCC, and that viral infections are associated with epigenetic silencing of tumor suppressor genes (TSG) in cancer. To examine whether a correlation between TSG inactivation and viral infection can be found in MCC, we investigated the promoter hypermethylation of RASSF1A, TP73, PTPRG, FHIT, and CDKN2A and the presence of MCPyV and SV40 in 98 MCC by PCR. Hypermethylation of RASSF1A was frequently found in 42 of 83 (51%) of MCC. Methylation of CDKN2A was present in 9 of 41 (22%) of MCC. Hypermethylation of TP73 (0%), PTPRG (4%), and FHIT (0%) was infrequent in MCC. Inter...

Modulation of invasive properties of CD133(+) glioblastoma stem cells: A role for MT1-MMP in bioactive lysophospholipid signaling

Molecular Carcinogenesis — Thu, 26 Mar 2009 04:00:00 +0100

Future breakthroughs in cancer therapy must accompany targeted agents that will neutralize cancer stem cells response to circulating growth factors. Since the brain tissue microenvironmental niche is a prerequisite for expression of the stem cell marker CD133 antigen in brain tumors, we investigated the invasion mechanisms specific to CD133(+) U87 glioblastoma cells in response to lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P), two circulating bioactive lysophospholipids and potent inducers of cancer. A CD133(+) U87 glioma cell population was isolated from parental U87 glioblastoma cells using magnetic cell sorting technology. The CD133(+)-enriched cell population grew as neurospheres and showed enhanced maximal response to both LPA ([sim]5.0-fold) and S1P ([sim]2.5-fold) at...

Targeted disruption of Bcl-xL in mouse keratinocytes inhibits both UVB- and chemically induced skin carcinogenesis

Molecular Carcinogenesis — Mon, 23 Mar 2009 04:00:00 +0100

In this study, the functional role of Bcl-xL in skin carcinogenesis was investigated using skin-specific Bcl-xL-deficient mice. In this model, Bcl-xL expression is disrupted in the basal compartment of mouse epidermis using the bovine keratin 5 (K5) promoter to drive expression of Cre recombinase (K5.Cre × Bcl-xLfl/fl mice). A significant increase in apoptosis induced by either UVB irradiation or 7,12-dimethylbenz[a]anthracene (DMBA) treatment was observed in the epidermis of Bcl-xL-deficient mice. Furthermore, an increase in apoptotic cells was noted in hair follicle keratinocytes, including those located in the bulge region. Cell proliferation was not affected by Bcl-xL deficiency following exposure to either UVB or 12-O-tetradecanoylphorbol-13-acetate (TPA). Bcl-xL-deficient mice were ...

Every microsatellite is different: Intrinsic DNA features dictate mutagenesis of common microsatellites present in the human genome