Little things with significant impact: miRNAs in hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) has developed into one of the most lethal, aggressive, and malignant cancers worldwide. Although HCC treatment has improved in recent years, the incidence and lethality of HCC continue to increase yearly. Therefore, an in-depth study of the pathogenesis of HCC and the search for more reliable therapeutic targets are crucial to improving the survival quality of HCC patients. Currently, miRNAs have become one of the hotspots in life science research, which are widely present in living organisms and are non-coding RNAs involved in regulating gene expression. MiRNAs exert their biological roles by suppressing the expression of downstream genes and are engaged in various HCC-related processes, including proliferation, apoptosis, invasion, and metastasis. In addition, the expression status of miRNAs is related to the drug resistance mechanism of HCC, which has important implications for the systemic treatment of HCC. This paper reviews the regulatory role of miRNAs in the pathogenesis of HCC and the clinical applications of miRNAs in HCC in recent years.

Keywords: autophagy; ferroptosis; hepatocellular carcinoma; metabolic reprogramming; microRNA; tumor microenvironment.

Figure 1

Dysregulated miRNAs regulate HCC progression by affecting blood vessels in tumors in 3 ways. (A) Sp1 maintains a high miR-130b-3p expression state by binding to the miR-130b-3p-promoter, while miR-130b-3p activates the PI3K/AKT/mTOR pathway by inhibiting HOXA5 expression, thereby stimulating HCC cells to induce angiogenesis. Exo-miR-210 is secreted by HCC cells into endothelial cells to promote angiogenesis by inhibiting SMAD4 and STAT6 expression. (B) MiR-101 can inhibit VM formation by targeting multiple molecules in CAFs and HCC cells and downregulating their expression. (C) Exo-miR-638 is delivered by HCC cells into endothelial cells and down-regulated their expression by targeting VE-Cad and ZO-1. Similarly, Exo-miR-103 was secreted into endothelial cells by HCC cells and suppressed the expression of VE-Cad, p120, and ZO-1. In addition, miR-103 in HCC cells also inhibited the expression of p120. They confer a strong metastatic potential to HCC cells by increasing the permeability of blood vessels.

Figure 2

Mechanisms by which miRNAs in HCC drive the interconversion between M1-like and M2-like TAMs. We can conclude that miRNAs dynamically promote the conversion between M1-like and M2-like TAMs. MiR-21 can inhibit STAT1 and NF-κB activation, and Exo-miR-452-5p can target TIMP3 and down-regulate its expression. Both contribute to HCC cellular immune escape by inhibiting M1 polarization of TAMs and inducing M2 polarization of TAMs, respectively, thereby promoting HCC progression. In addition, miR-99b delivered to TAMs and miR-206 in TAMs induced M1 polarization of TAMs by enhancing NF-κB activity; meanwhile, miR-99b also inhibited M2 polarization of TAMs. Together, they confer TAMs immune surveillance and the ability to kill tumor cells to suppress HCC.

Figure 3

The mechanism by which miRNAs in HCC induce the activation of NFs into CAFs. NFs usually remain resting in normal cells, and when tumors occur in vivo, HCC cells transfer miRNAs to NFs via paracrine secretion. MiRNAs in NFs induce the conversion of NFs into CAFs by activating cancer-related signaling pathways, and activated fibroblasts further promote the malignant behavior of HCC cells by secreting IL-6 and IL-8.

Figure 4

Mechanisms by which chemotherapeutic drugs induce autophagy and miRNAs inhibit autophagy from enhancing the sensitivity of HCC cells to chemotherapeutic drugs. Autophagy may shield HCC cells from the toxic effects of chemotherapeutic drug-induced death, promote HCC survival, and induce drug resistance in a wide range of HCC cells. MiRNAs may act as autophagy inhibitors to reverse the resistance of HCC cells to chemotherapeutic drugs by inhibiting the autophagic process in HCC cells, thereby promoting HCC cell apoptosis.

Figure 5

MiRNAs are involved in regulating the mechanism of aerobic glycolysis in HCC. MiRNAs act as essential regulators in the Warburg effect by down-regulating the expression levels of oncogenes or oncogenes or participating in cancer-related pathways, thereby directly or indirectly regulating critical enzymes in glycolysis and ultimately regulating the Warburg effect in HCC. In addition, intermediates in glycolysis can also enter other metabolic processes and synthesize biomolecules that contribute to adapting HCC cells to the harsh microenvironment and gain advantages in growth.