Micro-RNA profiling in hepatocellular tumors

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Micro RNAs (miRNAs) are small non-coding RNAs that regulate gene expression. Many studies show that they are implicated in essential physiological functions and particularly in tumors ⁴⁶. Specific alterations of miRNA expression have been identified directly involved in carcinogenesis. Indeed, miRNAs could act as oncogenes or tumor suppressors. In addition, some miRNAs deregulations seem to be associated to specific tumors subtypes, suggesting that they could be used as tumor biomarker. Recently, 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 ⁴⁷. 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; benign/malignant tumors, inflammatory adenoma and focal nodular hyperplasia), clinical characteristics (HBV infection and alcohol consumption) and oncogene/tumor suppressor gene mutations (ß-catenin and HNF1a). 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 5 (Figure 3). 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 HNF1a 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 HNF1a in a siRNA cell line model. Thus, strongly suggesting that ß-catenin and HNF1a could regulate miR-375 and miR-107 expression levels, respectively. All together, 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 ⁴⁷.

Several other studies have also identified a relationship between miRNA deregulation and the phenotype of HCC^{48-56, 57 , 58 , 59-62}. Despite different clinical features of the tumors, various risk factors, techniques and strategies used to normalized data, several miRNA altered in their expression have been recurrently found in the different studies. These observations indicate that miRNA profiling may be robust biomarkers to classify tumors. Recently the expression of miR-122 ⁶³, miR-221 ⁵¹ and miR26 ⁵⁸ were found to be associated with a poor prognosis in human HCC. All together, 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.