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Hepatocellular carcinoma (HCC)

ABSTRACT: BACKGROUND & AIMS: Expression of microRNAs (miRNAs) in metastatic foci of hepatocellular carcinoma (HCC) is unknown. We identified metastasis-related miRNAs in recurrent cases after living donor liver transplantation (LDLT). Methods: We performed a comprehensive analysis of primary HCC (T), noncancerous liver (N), and resected recurrent (metastatic) HCC (M) using microarray analyses to identify metastasis-related miRNAs in in three patients with post-transplant recurrence. The RNA samples from three cases that underwent resection of recurrences after LDLT were made available for miRNA microarray analysis. The three cases included a 57-year-old man (case 1) with peritoneal recurrence and infected by hepatitis B virus (HBV), and a 48-year-old woman (case 2) and a 51-year-old man (case 3) with lung recurrences and hepatitis C virus (HCV) infection. Microarray analysis was performed for each RNA sample from the (T), (N) in the explanted liver, and (M). A sample containing equal amounts of RNAs from histologically normal livers of three living donors (NL: normal liver) was analyzed as a control.

ORGANISM(S): Human gammaherpesvirus 8 Rattus norvegicus Mus musculus Human alphaherpesvirus 1 JC polyomavirus Betapolyomavirus macacae Murid gammaherpesvirus 4 Homo sapiens Human immunodeficiency virus 1 Human betaherpesvirus 5 Betapolyomavirus hominis human gammaherpesvirus 4 Murid betaherpesvirus 1

PROVIDER: GSE41874 | GEO | 2013/10/25

SECONDARY ACCESSION(S): PRJNA178365

REPOSITORIES: GEO

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Project description:BACKGROUND: Hepatocellular carcinoma (HCC) is a common complication of chronic viral hepatitis. In support of this notion, we have reported that hepatitis B surface antigen (HBsAg)-specific CD8+ T lymphocytes critically contribute to inducing chronic liver cell injury that exerts high carcinogenic potential in a hepatitis B virus (HBV) Tg mouse model. The dynamics of the molecular signatures responsible for hepatocellular carcinogenesis are not fully understood. The current study was designed to determine the serial changes in gene expression profiles in a model of chronic immune-mediated hepatitis. METHODS: Three-month-old HBV Tg mice were immunologically reconstituted with bone marrow cells and splenocytes from syngeneic nonTg donors. Liver tissues were obtained every three months until 18 months at which time all mice developed multiple liver tumors. Nitrative DNA lesions and hepatocyte turnover were assessed immunohistochemically. Gene expression profiles were generated by extracting total RNA from the tissues and analyzing by microarray. RESULTS: The nitrative DNA lesions and the regenerative proliferation of hepatocytes were increased during the progression of chronic liver disease. In a gene expression profile analysis of liver samples, the chemokine- and T cell receptor (TCR)-mediated pathways were enhanced during chronic hepatitis, and the EGF- and VEGF-mediated pathways were induced in HCC. Among these molecules, the protein levels of STAT3 were greatly enhanced in all hepatocyte nuclei and further elevated in the cytoplasm in HCC tissue samples at 18 months, and the levels of phosphorylated TP53 (p-p53-Ser 6 and -Ser 15) were increased in liver tissues. CONCLUSIONS: HBV-specific immune responses caused unique molecular signatures in the liver tissues of chronic hepatitis and triggered subsequent carcinogenic gene expression profiles in a mouse model. The results suggest a plausible molecular basis responsible for HBV-induced immune pathogenesis of HCC.

Project description:Gene-expression profiles of hepatitis C-related, early-stage liver cirrhosis Background & Aims: Liver cirrhosis affects 1%M-bM-^HM-^R2% of population and is the major risk factor of hepatocellular carcinoma (HCC). Hepatitis C cirrhosis-related HCC is the most rapidly increasing cause of cancer death in the US. Non-invasive methods have been developed to identify patients with asymptomatic, early-stage cirrhosis, increasing the burden of HCC surveillance, but biomarkers are needed to identify patients with cirrhosis who are most in need of surveillance. We investigated whether a liver-derived 186-gene signature previously associated with outcomes of patients with HCC is prognostic for patients newly diagnosed with cirrhosis but without HCC. Methods: We performed gene expression profile analysis of formalin-fixed needle biopsies from the livers of 216 patients with hepatitis C-related early-stage (Child-Pugh class A) cirrhosis who were prospectively followed for a median of 10 years at an Italian center. We evaluated whether the 186-gene signature was associated with death, progression of cirrhosis, and development of HCC. Results: Fifty-five (25%), 101 (47%), and 60 (28%) patients were classified as having poor-, intermediate-, and good-prognosis signatures, respectively. In multivariable Cox regression modeling, the poor-prognosis signature was significantly associated with death (P=.004), progression to advanced cirrhosis (P<.001), and development of HCC (P=.009). The 10-year rates of survival were 63%, 74%, and 85% and the annual incidences of HCC were 5.8%, 2.2%, and 1.5% for patients with poor-, intermediate-, and good-prognosis signatures, respectively. Conclusions: A 186-gene signature used to predict outcomes of patients with HCC is also associated with outcomes of patients with hepatitis C-related early-stage cirrhosis. This signature might be used to identify patients with cirrhosis in most need of surveillance and strategies to prevent their development of HCC. 216 liver biopsy specimens

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Hepatocellular carcinoma (HCC)

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