A large set of miRNAs is dysregulated since the earliest steps of human hepatocellular carcinoma development

Hepatocellular carcinoma (HCC) mostly results from a stepwise process characterized by the development of premalignant lesions, such as low- (LGDN) or high-grade (HGDN) dysplastic nodules in a cirrhotic setting. MicroRNAs (miRNAs) are small noncoding RNAs involved in post-transcriptional regulation of gene expression than can act as oncogenes or tumor suppressors. Whether and which miRNAs are involved in the early stages of HCC development remains elusive. Here, small RNA sequencing was applied to profile miRNA expression in 55 samples (cirrhotic nodules, CNs), LGDNs, HGDNs, early HCCs (eHCCs) and small progressed HCCs (pHCCs), obtained from 17 patients bearing HCCs of different etiology. A miRNA expression signature of 62 miRNAs distinguishing pHCCs from matched CNs was identified. Interestingly, 52 of these miRNAs discriminated CNs from LGDNs/HGDNs, regardless of the etiology, and remained modified along the tumorigenic process. Functional analysis of the predicted mRNA targets of deregulated miRNAs identified common modifications between early and late stages of HCC development likely involved in the stepwise process of HCC development. Our results demonstrate that miRNAs deregulation takes place very early in human liver carcinogenesis, implying their critical role in the tumorigenic process. The identification of miRNAs discriminating cirrhotic from neoplastic nodules may have relevant translational implications for early diagnosis.