Browsing by Subject "Liver Cancer."

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Open Access
Acquired tolerance of hepatocellular carcinoma cells to selenium-deficiency : a selective survival mechanism
(2003) Irmak, Meliha Burcu
Selenium-deficiency causes liver necrosis. Selenium is protective against viral hepatitis and hepatocellular carcinoma (HCC). The underlying molecular mechanisms of selenium effects are ill-known. In this study in vitro response of hepatocellular carcinoma-derived cell lines to selenium-deficiency is examined alone or in conjunction with Vitamin E and Copper/Zinc. Here we show that in vitro selenium-deficiency in a subset HCC-derived ‘hepatocyte-like’ cell lines causes oxidative stress and apoptosis. The oxidative stress and consequent cell death induced by selenium-deficiency on these cells are reverted by the antioxidant effect of Vitamin E. However, ten among thirteen HCC cell lines are tolerant to selenium-deficiency and escape its deadly consequences. Nine of ten tolerant cell lines have integrated hepatitis B Virus (HBV) DNA in their genomes, and some display p53-249 mutation, indicating past exposure to HBV or aflatoxins, established factors for oxidative stress and cancer risk. Thus, as demonstrated by the gain of survival capacity of apoptosis sensitive cell lines with Vitamin E, such malignant cells have acquired a selective survival advantage that is prominent under selenium-deficient and oxidative stress conditions.
Open Access
Hepatocellular carcinoma viral etiology and molecular mechanisms
(2003) Yıldız, Esra
Hepatocellular carcinoma (HCC) is one of the most frequent carcinomas throughout the world, being responsible for more than 1 million deaths annually and has a strong association with several etiological factors including aflatoxinB1, alcohol and Hepatitis virus B and C. Several studies suggested that HCV subtype 1b causes more severe liver diseases including HCC in a high manner and resistance to antiviral therapy. So, it is important to know genotype and some characteristics of HCV which are unique for the countries to develop better strategies regarding public health. By using direct sequencing information from 5`UTR and NS5B regions we identified subtype 1b as a predominant hepatitis C virus genome in Turkey. Next, the full genome sequence of a Turkish 1b isolate (HCV-TR1) was obtained by cloning of polypeptide-encoding region into 7 overlapping fragments. Although major structural and functional motifs of HCV proteins were maintained in HCV-TR1, it displayed amino acid substitutions in 6 out of 9 major cytotoxic T-cell epitopes. Several HCV proteins have been reported to contribute hepatocellular malignancy by interaction with critical cellular proteins involved in hepatocyte proliferation and survavil. Such studies often use HCC-derived cell lines as experimental models. As a prerequisite to future studies about the Turkish HCV 1b isolate in term of its contribution to HCC developments we investigated on phenotypic characterization of HCC cell lines. We provide experimental evidence that α-fetoprotein-producing HCC lines display in vitro liver stem cell-like properties with self-renewing capability and multi-lineage differentiation potential, even after single-cell cloning. However, their ability to generate fully differentiated normal progeny was disrupted, even if they modulate their differentiation program in response to external factors. These features qualify AFP-producing HCCs as “mis-specified” liver stem cell cancers whose cellular programs are deviated from repopulating liver to forming malignant tumors. Interestingly, stem-like cells described here have been used extensively to study the role HCV proteins. Our observations offer new opportunities for addressing the potential role of HCV in the misspecification of liver stem cells in relation with viral hepatocellular carcinogenesis.
Open Access
Identification of genes involved in hepatocellular carcinoma : evaluation of hCdc4 and B-Raf genes
(2003) Sürücü, Banu
Hepatocellular carcinoma (HCC), the major type of primary liver cancer, is one of the most common cancers worldwide. Development and progression of HCC occur as a multistep process, requiring the activation of oncogenes and the inactivation of several tumor suppressor genes. Although, inactivation of tumor suppressor genes, including p53, Axin and activation of oncogene β-catenin, have been shown to be involved in HCC development, the molecular mechanism of hepatocarcinogenesis is still unclear. The identification of additional genes that are involved in hepatocarcinogenesis is, not only, an important task to understand this process, but also for development of novel strategies for prevention or therapy. The aim of this study was to elucidate a possible function of hCdc4 and B-Raf genes in HCCs. A gene or genes on chromosome 4q have been implicated in hepatocarcinogenesis by the observation of frequent deletions of this region in HCCs. More recently, hCdc4, a gene in this region has been proposed as a candidate tumor suppressor gene. hCdc4 is an F-box protein which is shown to be involved in ubiquitination of cyclin E, thus targeting it for destruction. Cyclin E overexpression, is reported to be a frequent event in different cancers including HCC suggesting a problem in its destruction. 15 HCC cell lines were analysed for expression and mutation of hCdc4 gene by RT-PCR and direct sequencing of PCR products. No abnormal transcript and mutation observed in HCC cell lines tested. Our findings suggest that alteration of this gene is not a frequent event in hepatocarcinogenesis. iv B-Raf, which is one of the human isoforms of RAF, is activated by oncogenic Ras (leading to cooperative effects in cells responding to growth factor signals). B-Raf mutations are found in a wide range of cancers. Eventhough, mutational activation of Ras is not a frequent event in human hepatocarcinogenesis, few Ras mutations were reported in HCC cases. Thus activation of oncogenic MAP kinase pathway by another component of this pathway such as BRAF is worth to analyze. HCC cell lines and tumours were searched for B-Raf mutations. Activating BRAF missense mutations were identified in 2/72 HCCs (3%). Our results suggest that B-Raf may be occasionally involved in hepatocarcinogenesis. Thus MAP kinase pathway might be involved in hepatocarcinogenesis but neither B-Raf nor Ras are the major players of this pathway in this event. For this reason, other members of this pathway should be evaluated for mutations in HCC.