New Insights into the Role of miR-29a in Hepatocellular Carcinoma: Implications in Mechanisms and Theragnostics

Abstract

Hepatocellular carcinoma (HCC) remains one of the most lethal human cancer globally. For advanced HCC, curable plan for advanced HCC is yet to be established, and the prognosis remains poor. The detail mechanisms underlying the progression of HCC tumorigenicity and the corruption of tumor microenvironment (TME) is complex and inconclusive. A growing body of studies demonstrate microRNAs (miRs) are important regulators in the tumorigenicity and TME development. Notably, mounting evidences indicate miR-29a play a crucial role in exerting hepatoprotective effect on various types of stress and involved in the progression of HCC, which elucidates their potential theragnostic implications. In this review, we reviewed the advanced insights into the detail mechanisms by which miR-29a dictates carcinogenesis, epigenetic program, and metabolic adaptation, and implicated in the sponging activity of competitive endogenous RNAs (ceRNA) and the TME components in the scenario of HCC. Furthermore, we highlighted its clinical significance in diagnosis and prognosis, as well as the emerging therapeutics centered on the activation of miR-29a.

Keywords: angiogenesis; carcinogenesis; competitive endogenous RNAs; diagnosis; epigenetics; fibrosis; hepatocellular carcinoma; immunomodulation; metabolic adaptation; metastasis; miR-29a; therapeutics; tumor microenvironment.

Figure 1

Genetic properties and biological functions of miR-29. (A) Schematic illustration of the miR-29a family members. (B) The enrichment analysis of miR-29 targets in Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways was conducted by ENCORI (The Encyclopedia of RNA Interactomes). The histogram demonstrates number of miR-29a-targeted genes involved in particular KEGG pathway terms. The log10(p-value) of each KEGG terms is expressed by a heatmap.

Figure 2

miR-29a and HCC carcinogenesis. Graphic illustration of miR-29a signaling pathway on carcinogenic factors. The PubMed identifier (PMID) of references of interest are indicated above the corresponding genes.

Figure 3

miR-29a as an epigenetic modifier. Graphic illustration of miR-29a signaling pathway on epigenetics in the context of tumor growth and metastasis. The PMID of references of interest are indicated above the corresponding genes.

Figure 4

Role and mechanism of miR-29a in metabolic adaptation. Graphic illustration of miR-29a signaling pathway on metabolic adaptation in the context of tumor growth and metastasis. The PMID of references of interest are indicated above the corresponding genes.

Figure 5

ceRNA acts as miR-29a sponge to positively promote HCC progression. Graphic illustration of ceRNAs-mediated suppression of miR-29a and its downstream signaling pathway involved in tumor growth and metastasis. The PMID of references of interest are indicated above the corresponding genes.

Figure 6

miR-29a as a regulator of tumor microenvironment. Graphic illustration of miR-29a signaling pathway on factors contributing to the corruption of tumor microenvironment. The PMID of references of interest are indicated above the corresponding genes. The PMID of references of interest are indicated above the corresponding genes.

Figure 7

miR-29a targets in the progression and tumor microenvironment of HCC. Proposed model depicting targets of miR-29a involved in the molecular mechanisms and the formation of tumor microenvironment of HCC, including epigenetics, HBV dissemination, apoptosis, proliferation, metabolic regulation, competing endogenous RNAs (ceRNA), fibrosis, metastasis, angiogenesis, and immunomodulation. Targeted genes upon interacting with miR-29a conferring tumor-suppressing (green) or tumor-promoting (red) effect are summarized.