The Roles Of MicroRNAs In Human Hepatocellular Carcinoma

MicroRNAs (miRNAs) are important gene expression regulators, which are often deregulated in cancers. In this study, we analyzed the microRNAs profiles of 78 matched cancer / noncanerous liver tissues from HCC patients and 10 normal liver tissues and found that 84 microRNAs were differentially expressed among hepatocellular carcinoma (HCC), corresponding non-cancerous liver tissues (N) and normal liver tissues (NL). 69 out of the 84 microRNAs were differentially expressed between HCC and non-cancerous liver tissues. Then, by a support vector machine (SVM) and leave-one-out cross-validation prediction models, 89.70% HCC and noncancerous liver sample could be classified correctly. For non-cancerous versus normal liver samples, we found 27 microRNAs differentially expressed and 97.7% of samples could be grouped correctly by the SVM and leave-one-out cross-validation prediction models. For HCC versus normal, we found 55 differentially expressed microRNAs and all the samples could be classified correctly by the prediction models. Interestingly, out of the 84 microRNAs with deregulated expressions, 10 microRNAs were differentially expressed among all three groups (HCC, N and NL). Then the expressions of eight differentially expressed microRNAs were validated by real time RT PCR. Moreover, some of these differentially expressed microRNAs were related to the clinical factors of HCC patients. For example, hsa-miR-296, hsa-miR-122a and hsa-miR-93 were related to liver cirrhosis, hepatitis B virus infection and metathesis of HCC, respectively. Most importantly, Kaplan-Meier estimates and the log-rank test showed that high expression of hsa-miR-125b was correlated with good survival of HCC patients (hazard ratio, 1.787, 95% confidence interval, 1.020-3.133, p=0.043). The transfection assay showed that over-expression of miR-125b in liver cancer cell line could obviously suppress the cell growth and phosporylation of Akt. The investigation on the function of hsa-miR-93 indicated that hsa-miR-93 could promote the growth of liver cancer cells by accelerating G1/S transition.Besides, CCND1 (cyclin D1) related microRNAs were determined by using the CCND1 over-expressed transgenic mouse model. Among of these microRNAs, hsa-miR-200b and hsa-miR-365 were also deregulated in human HCC tissues. Then we found both hsa-miR-200b and hsa-miR-365 could promote liver cancer cells growth by regulating cell cycle. This experiment suggested that the genes with well known function perhaps provided a clue to the research on the function of microRNAs in HCC.In conclusion, we have demonstrated the diagnostic miRNA profile for HCC, and for the first time, identified the miR-125b with predictive significance for HCC prognosis. Beside, some microRNAs affected the growth of liver cancer cells by different mechanisms which contributed to the progress of HCC.