Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

KLF6 (Zf9, COPEB), an ubiquitous transcription factor, maps to chromosome 10p. Recently, KLF6 was found to have a more generalized role in tumorigenesis as a candidate tumor suppressor gene for some tumors. However, results from other published studies seem not to be in agreement with data from previous studies. Gene-expression analysis is increasingly important in biological research. Loss of expression is one of the mechanisms to functionally inactivate a tumor suppressor gene. To investigate the expression change of KLF6 gene associated with HCC as a step toward a better understanding of the molecular pathophysiology, and to provide the basis for analysis of KLF6 gene in HCC carcinogenesis. We analyzed the expression of KLF6 mRNA in 26 samples of HCC tissues and hepatoma cell lines(Hep3B and HepG2) detected by Real-Time quantitative RT-PCR (qRT-PCR) and conventional RT-PCR assay. To confirm and extend the data obtained at RNA level, we performed detailed immunoblotting analysis on HCC tissues and hepatoma cell lines using a rabbit polyclonal antibody specific for KLF6. NKLF6 detected by qRT-PCR from HCC and corresponding noncancerous tissues was 0.04+/-0.038 and 0.116+/-0.101, respectively. These data demonstrated that KLF6 mRNA level was significantly decreased in HCC, compared with corresponding noncancerous tissues (t =3.683 , P<0.001). The frequency of Hepatoma Cell Lines with KLF6 down-regulation detected by conventional PT-PCR, seems to be consistent with a previous study using real-time PCR assays in tumor samples. KLF6 expression levels were determined by Western blot. Compared to the matched surrounding tissues, a clear decrease of KLF6 protein levels in tumor tissues was observable (t=13.59, P<0.001). Hepatoma cell lines also showed low-level of KLF6 protein (P<0.01) expression. Immunohistochemistry and immunocytochemistry showed a faint diffused staining in the HCC tissues and hepatoma cell lines, and endogenous KLF6 protein was detected mostly in the cytoplasm. KLF6 gene appeared markedly reduced in HCC tissues and hepatoma cell lines. Frequent down-regulation of KLF6 strongly suggested that it is a candidate of tumor suppressor gene for HCC.
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PMID:Loss of expression of Kruppel-like factor 6 in primary hepatocellular carcinoma and hepatoma cell lines. 1755 Jan 40

Scirrhous hepatocellular carcinoma (scirrhous HCC) is a rare histological subtype of HCC characterized by marked fibrosis along the sinusoid spaces. Carcinogenetic processes and pathological features at earlier stages of scirrhous HCC remain unclarified. In the present report two cases of minute scirrhous HCC suggesting different carcinogenesis, are described. The first case involved a 54-year-old man with liver cirrhosis related to HCV infection. This patient died of ruptured splenic aneurysm. At autopsy a hepatic tumor measuring 1.8 cm was found, and this tumor had a nodule-in-nodule appearance. Histologically, the inner part of the tumor was well-differentiated HCC with prominent collagen fiber deposition along the sinusoids (scirrhous HCC), whereas the outer part was a high-grade dysplastic nodule. The other patient was a 75-year-old woman who died of hepatic failure due to liver cirrhosis probably related to non-alcoholic steatohepatitis. At autopsy a hepatic tumor (1.2 cm in diameter) was incidentally found in the cirrhotic liver, and was histologically scirrhous HCC without dysplastic nodule elements. Carcinoma cells proliferated along the cirrhotic fibrous septa and replaced regenerative nodules. These two cases suggested that scirrhous HCC could occur in dysplastic nodules (the former case) and also develop de novo in cirrhotic liver (the latter case).
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PMID:Minute scirrhous hepatocellular carcinomas undergoing different carcinogenetic processes. 1758 44

The aim of this study is to clarify the existence and the form of HCV RNA and HBV DNA genome integration and genetic instability in liver tissue with HBsAg-negative and anti-HCV-positive HCC. We investigated 16 Japanese patients with HBsAg-negative and anti-HCV-positive HCC. HBV genome integration into host cell genome by Southern hybridization and PCR was examined. Moreover, we analyzed loss of heterozygosity (LOH) and replication errors (RER) of chromosomes 2p, 3p and 17p using the PCR and an autosequencer to determine the three microsatellite regions D2S123, D3S1067, TP53. Eight (50.0%) of 16 were found to have integrated genome of HBV in tumor tissue (T) by PCR. In even the non-tumor regions (NT), seven patients (43.8%) were found to have HBV genome integration. The coincidence between T and NT was found in 4 (25%). Integration of HBV-X gene in T was revealed in three (18.7%), and HBV-integration was confirmed in all NT. No integration of the X gene alone was found in the liver tissue. Five (37.5%) of eight HBV DNA integrated cases simultaneously had HCV RNA minus strand. Concerning the genetic instability, RER were detected in two of 16 (12.5%). RER at 2p; D2S123 was observed in one of 16 (6.2%) and at 3p; D3S1067 was observed in one (6.2%). LOH at the D2S123 locus was observed in one of 12 tumors with heterozygosity (8.3%). There was no genetic instability (LOH or RER) of TP53 which was p53 locus on 17p in T. There was only one case of eight HBV DNA integrated cases (6.2%) with genetic instability of RER of 3p simultaneously in T. In conclusion, the majority of HBsAg-negative and anti-HCV-positive HCC liver tissue was found to have HCV-RNA and HBV DNA integration, and in some samples, HBV DNA integration and genetic instability were concurrently confirmed. It is speculated that multistep carcinogenesis may have been proposed for HCC oncogenetic progression.
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PMID:HBV genome integration and genetic instability in HBsAg-negative and anti-HCV-positive hepatocellular carcinoma in Japan. 1837 22

Hypoxia inducible factor-1alpha (HIF-1alpha) was well correlated with carcinogenesis and tumor progression in many kinds of cancer. In this study, high expression of HIF-1alpha was found in 37 of the 72 (51.39%) tumor specimens, and significantly correlated with venous invasion and lymphonode invasion. Patients with high expression of HIF-1alpha had a significantly shorter overall survival rate and disease-free survival rate than those with low expression. Multivariate analysis showed high HIF-1alpha expression was a borderline independent factor of overall survival. HIF-1alpha expression was also found to be significantly correlated with the expression of hepatitis B virus X protein (HBx), and over-expressed HBx upregulated HIF-1alpha protein expression in vitro. These results suggested that HIF-1alpha, which was partially regulated by HBx, might be a prognostic marker of HBV-related HCC patients.
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PMID:The expression of hypoxia-inducible factor-1alpha in hepatitis B virus-related hepatocellular carcinoma: correlation with patients' prognosis and hepatitis B virus X protein. 1846 38

Cholesterol metabolism is deregulated in carcinogenesis, and cancer cells exhibit enhanced mitochondrial cholesterol content whose role in cell death susceptibility and cancer therapy has not been investigated. Here, we describe that mitochondria from rat or human hepatocellular carcinoma (HC) cells (HCC) or primary tumors from patients with HC exhibit increased mitochondrial cholesterol levels. HCC sensitivity to chemotherapy acting via mitochondria is enhanced upon cholesterol depletion by inhibition of hydroxymethylglutaryl-CoA reductase or squalene synthase (SS), which catalyzes the first committed step in cholesterol biosynthesis. HCC transfection with siRNA targeting the steroidogenic acute regulatory protein StAR, a mitochondrial cholesterol-transporting polypeptide which is overexpressed in HCC compared with rat and human liver, sensitized HCC to chemotherapy. Isolated mitochondria from HCC with increased cholesterol levels were resistant to mitochondrial membrane permeabilization and release of cytochrome c or Smac/DIABLO in response to various stimuli including active Bax. Similar behavior was observed in cholesterol-enriched mitochondria or liposomes and reversed by restoring mitochondrial membrane order or cholesterol extraction. Moreover, atorvastatin or the SS inhibitor YM-53601 potentiated doxorubicin-mediated HCC growth arrest and cell death in vivo. Thus, mitochondrial cholesterol contributes to chemotherapy resistance by increasing membrane order, emerging as a novel therapeutic niche in cancer therapy.
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PMID:Mitochondrial cholesterol contributes to chemotherapy resistance in hepatocellular carcinoma. 1859 25

The multistep process of hepatic carcinogenesis is mirrored by the morphologic classification of lesions detectable in cirrhosis, that include large regenerative nodules (LRN), low grade dysplastic nodules (LGDN) and high grade dysplastic nodules (HGDN). The latter belong to the "bordeline malignancy" cathegory requiring an accurate distinction from well-differentiated and early hepatocellular carcinoma. Nodules in cirrhosis are usually detected by non-invasive imaging techniques, being the latter unable to discriminate malignant from non-malignant forms, particularly in the 1-2 cm sized group. Liver biopsy is essential in providing practical diagnostic information to hepathologists in the management of cirrhotic patients with US detectable nodules. The histologic diagnosis on liver samples is based on the accurate search of a set of cyto-architectural features (cell atypia, cell crowding, trabecular thickness, microacini etc) and by a supplement of histochemical (Gomori staining) and immunocytochemical stainings. The latter rely upon the search of both well established and novel markers, targeted to evaluate stromal invasion (CK7/19), the vascular pattern (ASMA and CD34) or tumor markers (HSP70 and Glipican 3 among others). Still, the diagnostic sensitivity is limited by the type and size of sampling and by its representativity of the entire lesion. The best diagnostic approach thus requires the integration of clinical, morphological and immunocytochemical information with imaging data (US pattern, perfusional pattern, helical CT/MR pattern). Molecular data are still under evaluation as to their diagnostic efficacy in this controversial field. Discrepancies have emerged recently between Eastern and Western interpretation of these lesions, particularly in the cathegory of "borderline" nodules, that are mostly labelled as early, well differentiated HCC by eastern pathologists and as HGDN by western pathologists. Novel and more objective phenotypical and molecular markers are needed to discriminate within the grey area of borderline lesions that, epidemiologically, are likely distinct between eastern and western geographic areas. These tools might allow a better understanding of the boundaries of the process going from high grade dysplasia to in situ HCC and from the latter to microinvasive HCC and advanced HCC, for a proper clinical management and optimal therapy.
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PMID:Hepatocellular dysplastic nodules. 1872 69

Various molecular changes characterizing organ-specific carcinogenesis have been identified in human tumors; however, the molecular mechanisms of the genomic changes specific for each cancer are not well defined. A transgenic (Tg) mouse model with constitutive expression of the nucleotide-editing enzyme, activation-induced cytidine deaminase (AID), develops tumors in various organs as a result of the mutagenic activities of AID. This phenotypic character of AID Tg mice allowed us to analyze the organ-specific genetic changes in tumor-related genes commonly triggered by AID-mediated mutagenesis. Among the 80 AID Tg mice analyzed, 11 mice developed hepatocellular carcinomas, and 7 developed lung cancers. In addition, 1 developed the gastric cancer and 3 developed gastric adenomas. Organ-specific preferences for nucleotide changes were observed in some of the tumor-related genes in each epithelial tissue of the AID Tg mice. Of note, the c-myc and K-ras genes were the preferential targets of the mutagenic activity of AID in lung and stomach cancers, respectively, whereas mutations in the p53 and beta-catenin genes were commonly observed in all 3 organs. Quantitative RT-PCR analyses revealed that alpha-fetoprotein, insulin-like growth factor-2 and cyclin D1 genes were specifically upregulated in HCC, whereas upregulation of the matrix metalloproteinase-7 gene was more marked in lung cancer. Our findings suggest that AID, a DNA mutator that plays a critical role linking inflammation to human cancers, might be involved in the generation of organ-specific genetic diversity in oncogenic pathways during cancer development.
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PMID:Organ-specific profiles of genetic changes in cancers caused by activation-induced cytidine deaminase expression. 1878 63

A majority of patients with HCC present with advanced disease and are not candidates for liver transplantation, surgical resection, or regional therapy. Systemic cytotoxic chemotherapy agents are minimally effective, can have significant toxicity, and have not been shown to improve patient survival. Hepatocellular carcinomas are inherently chemotherapy-resistant tumors and are known to overexpress the multidrug resistance genes. Hepatocellular carcinoma is a very heterogeneous disease in terms of its etiology, molecular carcinogenic mechanisms, and biological behavior, which complicate our ability to identify rational molecular therapeutic "targets." Nearly every pathway involved in carcinogenesis is altered to some degree in HCC. Changes in hepatocyte growth factor expression, intracellular signaling, protease and matrix metalloproteinase expression, and oncogene expression are seen in HCC. The recent demonstration, in randomized clinical trials, of survival benefit for HCC patients treated with the oral agent sorafenib is encouraging progress in the development of molecularly targeted anticancer agents in HCC.
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PMID:Molecular targeted therapy for hepatocellular carcinoma. 1914 8

The role played by the microenvironment in cancer induction, promotion and progression is crucial. Emerging evidence suggests that cytokines, chemokines and growth factors are major players in carcinogenesis. Therefore, a detailed understanding of factors and mechanisms associated with the processes leading from inflammation to cancer could improve the therapeutic strategies against this disease. We have used hepatocarcinoma as our model in this study. We evaluated the serum levels of 50 different cytokines, chemokines and growth factors in patients affected by HCC with chronic HCV-related hepatitis and liver cirrhosis using multiplex biometric ELISA-based immunoassay. Our data showed that some pro-inflammatory molecules were significantly up-regulated in these patients, and highlighted the complexity of the cytokine network in this disease. This work suggests the need to monitor these proteins in order to define a profile that could characterize patients with HCC or to help identify useful markers. This could lead to better definition of the disease state, and to an increased understanding of the relationships between chronic inflammation and cancer.
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PMID:Serum cytokine levels in patients with hepatocellular carcinoma. 2047 63

The Wnt/beta-catenin signaling pathway regulates various aspects of development and plays important role in human carcinogenesis. Nemo-like kinase (NLK), which is mediator of Wnt/beta-catenin signaling pathway, phosphorylates T-cell factor/lymphoid enhancer factor (TCF/LEF) factor and inhibits interaction of beta-catenin/TCF complex. Although, NLK is known to be a tumor suppressor in Wnt/beta-catenin signaling pathway of colon cancer, the other events occurring downstream of NLK pathways in other types of cancer remain unclear. In the present study, we identified that expression of NLK was significantly up-regulated in the HCCs compared to corresponding normal tissues in five selected tissue samples. Immunohistochemical analysis showed significant over-expression of NLK in the HCCs. Targeted-disruption of NLK suppressed cell growth and arrested cell cycle transition. Suppression of NLK elicited anti-mitogenic properties of the Hep3B cells by simultaneous inhibition of cyclinD1 and CDK2. The results of this study suggest that NLK is aberrantly regulated in HCC, which might contribute to the mitogenic potential of tumor cells during the initiation and progression of hepatocellular carcinoma; this process appears to involve the induction of CDK2 and cyclin D1 and might provide a novel target for therapeutic intervention in patients with liver cancer.
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PMID:Targeted disruption of Nemo-like kinase inhibits tumor cell growth by simultaneous suppression of cyclin D1 and CDK2 in human hepatocellular carcinoma. 2051 28


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