MicroRNA profiling in hepatocellular tumors is associated to clinical features and oncogene/tumor suppressor gene mutations

Molecular classifications defining new tumor subtypes has been recently refined using genetic and transcriptomic analyses of benign and malignant hepatocellular tumors. Here, we performed microRNA (miRNA) profiling in two series of fully annotated liver tumors to uncover associations between oncogene/tumors suppressors’ mutations, clinical and pathological features. Expression levels of 250 miRNAs in 46 benign and malignant hepatocellular tumors were compared to 4 normal liver samples using quantitative RT-PCR. miRNAs associated to genetic and clinical characteristics were validated in a second series of 43 liver tumor and 16 non-tumor samples. miRNAs profiling unsupervised analysis classified samples in unique clusters characterized by histological features (tumor/non-tumor P<0.001; benign/malignant tumors P<0.01, inflammatory adenoma and focal nodular hyperplasia P<0.01), clinical characteristics (HBV infection P<0.001; Alcohol consumption P<0.05) and oncogene/tumor suppressor gene mutations (ß-catenin P<0.01; HNF1α P<0.01). Our study identified and validated miR-224 over-expression in all tumors, miR-200c, miR-200, mir-21, miR-224, miR-10b and miR-222 specific deregulation in benign or malignant tumors. Moreover miR-96 was over-expressed in HBV tumors, miR-126* down regulated in alcohol related HCC. Down-regulations of miR-107 and miR-375 were specifically associated with HNF1α and ß-catenin gene mutations, respectively. miR-375 expression was highly correlated to that of ß-catenin targeted genes as miR-107 expression was correlated to that of HNF1α in a siRNA cell line model. Thus, it strongly suggests that ßcatenin and HNF1α could regulate miR-375 and miR-107 expression levels, respectively. Conclusion: Hepatocellular tumors may have distinct miRNAs expression fingerprint according to malignancy, risk factors and oncogene/tumor suppressor gene alterations. Dissecting these relationships provides new hypothesis to understand the functional impact of miRNAs deregulation in liver tumorigenesis and their promising use as diagnostic markers. in se rm -0 03 29 51 0, v er si on 1 3 N ov 2 00 9 Hepatocellular tumors miRNA profiling 3