cyclin-d1 and Hepatitis-C--Chronic

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide with highest incidence in Asia and Africa. MicroRNAs (miRNAs), a class of non-coding single stranded RNA, which not only post transcriptionally regulate gene expression but also respond to signaling molecules to affect cell functions such as Wnt/β-catenin signaling specifically in HCC. The goal of this study is to investigate the crosstalk between Wnt/β-catenin signaling proteins and microRNAs expression in HCC patients.. Fresh tissue samples of 30 primary HCC patients and 10 control subjects were included. Expression level of 13 different miRNAs (miR-10a- miR-106b- miR-99a- miR-148a- miR-125b- miR-30e- miR-183- miR-155- miR-199a- miR-199a3p- miR-24- miR-122 and miR-215) were examined using real-time PCR assay. Five proteins involved in the Wnt/β-catenin pathway (β-catenin, APC, c-myc, survivin and cyclin D1) were analysed by immunohistochemistry technique. The correlation between miRNAs expression levels with protein expressions was assessed.. Up-regulation of miR-155 and miR-183 was reported in HCC patients compared to normal controls and this up-regulation was significantly correlated with liver cirrhosis in the case of miR-155 (p<0.05) referring to their oncogenic activity. Down-regulation was observed for 11 miRNAs in HCC indicating their tumour suppression activity. MiRNA-10a, miR-30e, miR-215, miR-125b and miR-148a were significantly correlated with the expression of important players in Wnt/β-catenin pathway including β-catenin, APC and c-myc (p<0.05). Detailed analysis revealed that miR-215 is associated with the grade of the disease and miR-125b is associated with HCV infection.. Collectively, our data showed potential role of miR-10a, miR-30e, miR-215, miR-125b and miR-148a as important mediators in HCC progression. Furthermore, their association with Wnt/β-catenin cascade proteins could be exploited to develop new therapeutic target strategies in HCC.

Topics: Adenomatous Polyposis Coli Protein; Aged; beta Catenin; Carcinoma, Hepatocellular; Case-Control Studies; Cyclin D1; Down-Regulation; Female; Gene Expression; Hepatitis C, Chronic; Humans; Inhibitor of Apoptosis Proteins; Liver Cirrhosis; Liver Neoplasms; Male; MicroRNAs; Middle Aged; Neoplasm Grading; Proto-Oncogene Proteins c-myc; Survivin; Up-Regulation; Wnt Signaling Pathway

To investigate gender-specific liver estrogen receptor (ER) expression in normal subjects and patients with hepatitis C virus (HCV)-related cirrhosis and hepatocellular carcinoma (HCC).. Liver tissues from normal donors and patients diagnosed with HCV-related cirrhosis and HCV-related HCC were obtained from the NIH Liver Tissue and Cell Distribution System. The expression of ER subtypes, ERα and ERβ, were evaluated by Western blotting and real-time RT-PCR. The subcellular distribution of ERα and ERβ was further determined in nuclear and cytoplasmic tissue lysates along with the expression of inflammatory [activated NF-κB and IκB-kinase (IKK)] and oncogenic (cyclin D1) markers by Western blotting and immunohistochemistry. The expression of ERα and ERβ was correlated with the expression of activated NF-κB, activated IKK and cyclin D1 by Spearman's correlation.. Both ER subtypes were expressed in normal livers but male livers showed significantly higher expression of ERα than females (. Gender differences were observed in ERα expression in normal livers. Alterations in ER subtype expression observed in diseased livers may influence gender-related disparity in HCV-related pathogenesis.

Topics: Adult; Aged; Carcinoma, Hepatocellular; Cell Nucleus; Cyclin D1; Cytoplasm; Disease Susceptibility; Estrogen Receptor alpha; Estrogen Receptor beta; Female; Hepacivirus; Hepatitis C, Chronic; Humans; I-kappa B Kinase; Liver; Liver Neoplasms; Male; Middle Aged; NF-kappa B; Phosphorylation; Sex Factors

To assess the distribution of proteins coded by genes reported as relevant for the molecular classification of hepatocellular carcinoma (HCC).. In this retrospective cross-sectional study, the following clinicopathological data were analyzed in 80 autopsied HCC patients: sex, age, ethnicity, alcohol intake, infection with hepatitis B and/or C virus, infection with human immunodeficiency virus, prior treatment, basic and immediate causes of death, liver weight, presence of cirrhosis, number and size of nodules, gross pattern, histological grade and variants, architectural pattern, invasion of large veins, and presence and location of extrahepatic metastases. The protein products of genes known to be involved in molecular pathogenesis of HCC, including epidermal growth factor receptor (EGFR), MET, keratin 19 (K19), vimentin, beta-catenin, mechanistic target of rapamycin (mTOR), extracellular signaling-related kinase (ERK)1, ERK2, Ki67, cyclin D1, caspase 3 and p53, were detected by immunohistochemistry on tissue microarrays. The expression levels were scored and statistically assessed for correlation with HCC parameters.. Infection with hepatitis C virus was identified in 49% of the 80 autopsy patients, cirrhosis in 90%, advanced tumors in 95%, and extrahepatic metastases in 38%. Expression of K19, p53 and ERK1 correlated to high-grade lesions. Expression of ERK1, nuclear beta-catenin, cyclin D1 and ERK2 correlated to higher rates of cell proliferation as determined by Ki67. Expression of MET, EGFR (> 0) and caspase 3 correlated with lower histological grades. Expression of EGFR correlated to that of caspase 3, and overexpression of EGFR (≥ 200/300) was observed in low-grade tumors more frequently (grades 1 and 2: 67% vs grade 3: 27% and grade 4: 30%). Expression of ERK1 was associated with that of K19 and vimentin, whereas expression of ERK2 was associated with that of cyclin D1, MET and membrane beta-catenin. Expression of vimentin was strongly correlated with that of K19.. Expression of K19, p53, ERK1, ERK2, vimentin and nuclear beta-catenin was related to higher-grade markers, as opposed to expression/overexpression of EGFR, MET and caspase 3.

Topics: Adult; Aged; Aged, 80 and over; Autopsy; beta Catenin; Brazil; Carcinoma, Hepatocellular; Case-Control Studies; Caspase 3; Cross-Sectional Studies; Cyclin D1; ErbB Receptors; Female; Hepatitis B, Chronic; Hepatitis C, Chronic; HIV Infections; Humans; Immunohistochemistry; Keratin-19; Ki-67 Antigen; Liver Cirrhosis; Liver Neoplasms; Male; Middle Aged; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Proto-Oncogene Proteins c-met; Retrospective Studies; Tissue Array Analysis; TOR Serine-Threonine Kinases; Tumor Suppressor Protein p53; Vimentin

Hepatitis C virus (HCV) infection usually induces chronic hepatic inflammation, which favors the initiation and progression of hepatocellular carcinoma (HCC). Moreover, microRNA-155 (miR-155) plays an important role in regulating both inflammation and tumorigenesis. However, little is known about whether and how miR-155 provides the link between inflammation and cancer. In this study we found that miR-155 levels were markedly increased in patients infected with HCV. MiR-155 transcription was regulated by nuclear factor kappa B (NF-κB), and p300 increased NF-κB-dependent miR-155 expression. The overexpression of miR-155 significantly inhibited hepatocyte apoptosis and promoted cell proliferation, whereas miR-155 inhibition induced G(0) /G(1) arrest. Up-regulated miR-155 resulted in nuclear accumulation of β-catenin and a concomitant increase in cyclin D1, c-myc, and survivin. Gain-of-function and loss-of-function studies demonstrated that miR-155 promoted hepatocyte proliferation and tumorigenesis by increasing Wnt signaling in vitro and in vivo, and DKK1 (Wnt pathway inhibitor) overexpression inhibited the biological role of miR-155 in hepatocytes. Finally, adenomatous polyposis coli (APC), which negatively regulates Wnt signaling, was identified as the direct and functional target of miR-155.. HCV-induced miR-155 expression promotes hepatocyte proliferation and tumorigenesis by activating Wnt signaling. The present study provides a better understanding of the relationship between inflammation and tumorigenesis, and thus may be helpful in the development of effective diagnosis and treatment strategies against HCV-HCC.

Topics: Adenomatous Polyposis Coli Protein; Adult; Aged; Animals; Apoptosis; beta Catenin; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Proliferation; Cell Transformation, Neoplastic; Chemokine CXCL10; Cyclin D1; Female; G1 Phase Cell Cycle Checkpoints; Hepacivirus; Hepatitis C, Chronic; Hepatocytes; Humans; Inhibitor of Apoptosis Proteins; Intercellular Signaling Peptides and Proteins; Liver Neoplasms; Male; Mice; Mice, Inbred BALB C; Mice, Nude; MicroRNAs; Middle Aged; NF-kappa B; p300-CBP Transcription Factors; Proto-Oncogene Proteins c-myc; RNA, Viral; Survivin; Transfection; Up-Regulation; Wnt Signaling Pathway