Transient and etiology-related transcription regulation in cirrhosis prior to hepatocellular carcinoma occurrence

AIM： To search for transcription dysregulation that could （1） differentiate hepatocellular carcinoma （HCC）-free from HCC-related cirrhosis （2） differentiate HCC-free cirrhosis related to HCV from that related to alcohol intake. METHODS： Using microarray analysis, we compared transcript levels in HCC-free cirrhosis （alcoholism： 7; hepatitis C： 7）, HCC-associated cirrhosis （alcoholism： 10; hepatitis C： 10） and eight control livers. The identified transcripts were validated by qRT-PCR in an independent cohort of 45 samples （20 HCC-free cirrhosis; 15 HCC-associated cirrhosis and 10 control livers）. We also confirmed our results by immunohistochemistry.RESULTS： In HCC-free livers, we identified 70transcripts which differentiated between alcoholicrelated-cirrhosis, HCV-related cirrhosis and control livers. They mainly corresponded to down-regulation. Dysregulation of Signal Transduction and Activator of Transcription-3 （STAT-3） was found along with related changes in STAT-3 targets which occurred in an etiology-dependent fashion in HCC-free cirrhosis. In contrast, in HCC, such transcription dysregulations were not observed. CONCLUSION： We report that transcriptional dysregulations exist in HCC-free cirrhosis, are transiently observed prior to detectable HCC onset and may be appear like markers from cirrhosis to HCC transition.

Genome-wide differences in hepatitis C-vs alcoholism-associated hepatocellular carcinoma

AIM:To look at a comprehensive picture of etiology- dependent gene abnormalities in hepatocellular carcinoma in Western Europe. METHODS:With a liver-oriented microarray,transcript levels were compared in nodules and cirrhosis from a training set of patients with hepatocellular carcinoma (alcoholism,12;hepatitis C,10)and 5 controls.Loose or tight selection of informative transcripts with an abnormal abundance was statistically valid and the tightly selected transcripts were next quantified by qRTPCR in the nodules from our training set(12+10) and a test set(6+7). RESULTS:A selection of 475 transcripts pointed to significant gene over-representation on chromosome 8 (alcoholism)or-2(hepatitis C)and ontology indicated a predominant inflammatory response(alcoholism)or changes in cell cycle regulation,transcription factors and interferon responsiveness(hepatitis C).A stringent selection of 23 transcripts whose differences betweenetiologies were significant in nodules but not in cirrhotic tissue indicated that the above dysregulations take place in tumor but not in the surrounding cirrhosis.These 23 transcripts separated our test set according to etiologies. The inflammation-associated transcripts pointed to limited alterations of free iron metabolism in alcoholic vs hepatitis C tumors. CONCLUSION:Etiology-specific abnormalities(chromo- some preference;differences in transcriptomes and related functions)have been identified in hepatocellular carcinoma driven by alcoholism or hepatitis C.This may open novel avenues for differential therapies in this disease.