miRNAs affect the development of hepatocellular carcinoma via dysregulation of their biogenesis and expression

Abstract

The pathogenesis of hepatocellular carcinoma (HCC) is not fully understood, which has affected the early diagnosis and treatment of HCC and the survival time of patients. MicroRNAs (miRNAs) are a class of evolutionarily conserved small, non-coding RNAs, which regulate the expression of various genes post-transcriptionally. Emerging evidence indicates that the key enzymes involved in the miRNA biosynthesis pathway and some tumor-specific miRNAs are widely deregulated or upregulated in HCC and closely associated with the occurrence and development of various cancers, including HCC. Early studies have shown that miRNAs have critical roles in HCC progression by targeting many critical protein-coding genes, thereby contributing to the promotion of cell proliferation; the avoidance of apoptosis, inducing via angiogenesis; and the activation of invasion and metastasis pathways. Experimental data indicate that discovery of increasing numbers of aberrantly expressed miRNAs has opened up a new field for investigating the molecular mechanism of HCC progression. In this review, we describe the current knowledge about the roles and validated targets of miRNAs in the above pathways that are known to be hallmarks of HCC, and we also describe the influence of genetic variations in miRNA biosynthesis and genes.

Figure 1

Schematic representation of the biogenesis pathway of microRNAs and the aberrant expression of key enzymes involved in this pathway in HCC. First, miRNAs are transcribed by RNA pol II/III from the miRNA coding gene to pri-miRNAs, and soon afterwards microprocessor complex recognizes pri-miRNA to generate pre-miRNA. XPO-5 with its cofactor RAN-GTP mediates the nuclear export of pre-miRNA. Finally, the RLC loading complex assists in the binding of mature miRNA to RISC to mediate gene silencing. However, in HCC, the expression of some key enzymes involved in this pathway appears to be aberrant, and this aberrant expression results in an abnormal microRNA biogenesis pathway (shown in A/B/C/D/E).

Figure 2

Deregulated miRNAs in HCC affect cell cycle. These miRNAs impact cell cycle progression by targeting cell growth regulators. The green miRNAs may promote the HCC cell cycle, and the red miRNAs may inhibit the HCC cell cycle.

Figure 3

Deregulated miRNAs in invasion and metastasis. The expression of many miRNAs involved in HCC cell invasion and metastasis are altered and affect RAS-, RHO-, and EMT-related signaling pathways. The green miRNAs may inhibit HCC cell invasion and metastasis, and the red miRNAs may promote HCC cell invasion and metastasis.