A Large Set of miRNAs Is Dysregulated from the Earliest Steps of Human Hepatocellular Carcinoma Development

Abstract

Hepatocellular carcinoma (HCC) typically results from a stepwise process characterized by the development of premalignant lesions, such as low- or high-grade dysplastic nodules (LGDNs and HGDNs, respectively), in a cirrhotic setting. MicroRNAs (miRNAs) are small noncoding RNAs involved in post-transcriptional regulation of gene expression that 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, and small progressed HCCs, obtained from 17 patients bearing HCCs of different etiologies. An miRNA expression signature of 62 miRNAs distinguishing small progressed HCCs from matched CNs was identified. Interestingly, 52 of these miRNAs discriminated CNs from LGDNs/HGDNs, regardless of etiology, and remained modified along the tumorigenic process. Functional analysis of the predicted mRNA targets of deregulated miRNAs identified common modifications between the early and late stages of HCC development likely involved in the stepwise process of HCC development. Our results demonstrate that miRNA deregulation happens very early in HCC in humans, implying their crucial role in the tumorigenic process. The identification of miRNAs discriminating CNs from neoplastic nodules may have relevant translational implications in early diagnosis.

A genome-wide microRNA screen identifies regulators of tetraploid cell proliferation

“…, 2017 ). Interestingly, small-RNA sequencing has revealed several miRNAs that are highly overexpressed in patient hepatocellular carcinoma (HCC) samples relative to cirrhotic nodules, including miR-24-3p with a more than sevenfold increase in expression ( Sulas, Di Tommaso, Novello, et al. , 2018 ).…”

Diagnostic and prognostic roles of circulating miRNA-223-3p in hepatitis B virus–related hepatocellular carcinoma

“…It is well recognized that these small non-coding RNAs involve in post-transcriptional regulation of gene expression and many cellular processes such as growth, angiogenesis, differentiation and metastasis [6]. Recent data have demonstrated that miRNA deregulation are already detectable in premalignant lesions including low-grade or high-grade dysplastic nodules, indicative of their contribution in early stages of HCC development [14]. Moreover, deregulated miRNAs are shown to be pivotal modulators in tumor progression and aggressiveness, in which they act as oncogenes or tumor suppressors [7].…”

The combination of coffee compounds attenuates early fibrosis-associated hepatocarcinogenesis in mice: involvement of miRNA profile modulation

“…While miRNAs are directly implicated in physiological processes in the liver, including postnatal growth, regeneration and functioning, their abnormal expression is pivotal in different stages of fibrosis/cirrhosis-associated hepatocarcinogenesis in humans, contributing to sustained cell proliferation, epithelial mesenchymal transition, invasion, metastasis, angiogenesis, and drug resistance hallmarks [8]. In chemically-induced rodent models of fibrosis and hepatocarcinogenesis, the importance of miRNA deregulation is also reported [6,72]. Especially, the DEN/CCl4 approach used recapitulated some miRNomic features of the corresponding human disease, as the downregulation of miR-144-3p and miR-376a-3p, eliciting the translational value of the present short/medium term bioassay.…”

“…Most HCC cases (70 -90%) arise in the setting of liver fibrosis/cirrhosis, mainly caused by chronic hepatitis B (HBV) and C (HCV) virus infections, alcoholic liver disease and non-alcoholic fatty liver disease (NAFLD) [3,4]. This malignancy emerges due to the accumulation of multiple molecular alterations, including the deregulation of microRNA (miRNA) expression [5,6]. miRNAs are noncoding, singlestranded molecules of ~22 nucleotides that constitute a class of gene regulators [7].…”