Advances in the study of the mechanism of action of miR‑22 in liver lesions (Review)

Abstract

Globally, nearly 2 million deaths annually are attributed to the development of liver diseases, with liver cancer and cirrhosis being particularly prominent, which makes liver disease a significant global health concern. Cirrhosis is closely linked to the evolution of hepatitis, hepatic fibrosis and fatty liver. However, most liver diseases have an insidious onset, are challenging to treat and the prognosis and efficacy of current therapies are unsatisfactory, which can result in irreversible functional damage to the liver. Therefore, there is an urgent need to explore the molecular mechanisms underlying liver disease and identify new biomarkers and therapeutic targets. In previous years, microRNAs (miRs), a class of short non-coding RNAs comprising 17-25 nucleotides, have attracted attention for their roles in various types of liver diseases. Among them, miR-22 serves a unique role in mediating multiple pathway mechanisms and epigenetic modifications and can act both as an inhibitor of liver cancer and a metabolic blocker. Given its close association with the liver, several studies have reported that the differential expression of miR-22 regulates the metabolic process of liver cancer and is involved in the evolution of hepatic fibrosis and steatohepatitis, making it a potential target for early diagnosis and treatment. The present manuscript aimed to comprehensively review the key role of miR-22 in the evolution of liver diseases and offer valuable references and guidance for subsequent studies by identifying its specific mechanism of action and future development prospects.

Keywords: alcoholic fatty liver disease; hepatocellular carcinoma; liver fibrosis; microRNA-22; non-alcoholic fatty liver disease; viral hepatitis.

Figure 1.

Mechanism underlying miR-22 regulation of the occurrence and development of HCC. miR-22 is involved in the regulation of the occurrence and development of HCC. miR-22 mainly inhibits the proliferation, migration and invasion of HCC by decreasing the expression levels of CD147 and HDAC4 and participating in the immunomodulatory process by regulating Gal-9 and Th17, which ultimately serves a role in cancer inhibition. lncRNAs, such as DSCR8, NCK1-AS1 and MKLN1-AS, exhibit sponging effects on miR-22, thereby weakening the inhibitory effect on downstream cancer-promoting factors ARPC5, YARS and ETS1. In hepatitis virus-associated liver cancer, the negative regulation of miR-22 by TRERNA1 and EZH2 also weakens the inhibitory effect on HNRNPA1 and NRAS, which promotes the occurrence and development of liver cancer. Exogenous substances and metabolites, such as catalpol, butyrate and FXR, induce the expression of miR-22, which enhances the regulation of miR-22 on downstream factors MTA3 and CCNA2 and inhibits the progression of HCC. An arrow-headed line indicates promotion, whereas a bar-headed line signifies inhibition. The rectangular box represents the upstream component of miR-22, and the circular corner box represents the downstream component regulated by miR-22. Yellow represents the mechanism of hepatitis virus-associated liver cancer, blue represents the mechanism related to lncRNA, green represents the mechanism related to the induction of miR-22 by endogenous and exogenous substances, purple represents the mechanism related to immunity and pink represents the mechanism of miR-22 regulating the proliferation and migration of liver cancer without the influence of other substances. The dashed line box on the right shows the proliferation and migration of liver cancer cells and the dashed line box below shows the lysis and death of Tim3+ T cells. EZH2, enhancer of zeste homolog 2; TRERNA1, translation regulatory lncRNA 1; HBx, HBV-encoded X; DSCR8, down syndrome critical region 8; NCK1-AS1, NCK1 antisense RNA 1; MIAT, myocardial infarction-associated transcript; FXR, farnesoid X receptor; CDCA, chenodeoxycholic acid; HuR, human antigen R; HMGB1, high mobility group box 1; YWHAZ, tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein zeta; YARS, tyrosyl-tRNA synthetase; ARPC5, actin-related protein 2/3 complex subunit 5; SIRT1, sirtuin 1; ROS, reactive oxygen species; MKLN1-AS, muskelin 1 antisense RNA; ETS1, ETS proto-oncogene 1; CD147; HDAC4, histone deacetylase 4; CBL, casitas B-lineage lymphoma; MTA3, metastasis associated 1 family member 3; CCNA2, cyclin A2; CDKN1A, CDK inhibitor 1A; HNRNPA1, heterogeneous nuclear ribonucleoprotein A 1; NRAS proto-oncogene; ERα, estrogen receptor α; E2, estradiol; IL-1α, interleukin 1α; JARID2, jumonji AT rich interacting domain containing 2; Th17, T helper cell 17; Gal-9, galectin-9.

Figure 2.

Mechanism of action of miR-22 in fatty liver disease. miR-22 is involved in regulating the progression of fatty liver disease. Increased expression of miR-22 in liver tissue is observed with long-term alcohol intake, high-fat diet and diabetes. miR-22 targets and inhibits FGFR1, FGF21 and TET2, which contributes to hepatic steatosis and the progression of HCC. Moreover, T2 upregulates TCF7 by downregulating miR-22, which subsequently suppresses the expression of FBP1 and G6PC, and regulates glucose homeostasis in the liver. An arrow-headed line indicates promotion, whereas a bar-headed line signifies inhibition. The yellow box indicates miR-22. Other boxes of the same color represent important factors in the same pathway. The green and red dotted boxes represent important factors in their respective pathways. The black dotted box indicates HCC cell proliferation. FBP1, fructose 1–6 bisphosphatase; G6PC, glucose 6-phosphatase; miR, microRNA; TCF7, transcription factor 7; T2, 3,5-diiodine-L-thyronine; TET2, tet methylcytosine dioxygenase 2; FGF21, fibroblast growth factor 21; FGFR1, FGF21 receptor.

Figure 3.

Mechanism of miR-22 in liver fibrosis. miR-22 is involved in regulating the progression of liver fibrosis. The expression level of miR-22 is controlled by the hepatoprotective complex SCNPs and lncRNA Neat1. miR-22 targets and regulates the expression of fibrosis mediators TGFβR1, TGFβR2, COL3A1 and Cyth3 to mitigate the advancement of liver fibrosis. Inhibition of miR-22 can enhance the expression of AKT3 in the liver, stimulate the proliferation of LX-2 cells and the expression of fibrosis markers COL1A1 and α-SMA and accelerate liver fibrosis. An arrow-headed line indicates promotion, whereas a bar-headed line signifies inhibition. The yellow box indicates miR-22. Other boxes of the same color represent important factors in the same pathway. The black dotted box indicates the process of LX-2 cell proliferation. miR, microRNA; COL1A1, collagen type I a1 chain; a-SMA, a-smooth muscle actin; SCNPs, SIL-loaded chitosan nanoparticles; lncRNA, long non-coding RNA; COL3A1, collagen type III a1 chain; TGF-bR, TGF-b receptor; Cyth3, cytohesin 3; neat1, nuclear paraspeckle assembly transcript 1.