Non‑coding RNAs: Role of miRNAs and lncRNAs in the regulation of autophagy in hepatocellular carcinoma (Review)

Abstract

The term autophagy describes a process that supports nutrient cycling and metabolic adaptation that is accomplished via multistep lysosomal degradation. These activities modulate cell, tissue and internal environment stability, and can also affect the occurrence and development of cancer. Previous studies have mostly described autophagy as having dual effects in cancer, serving to limit tumorigenesis in the early stages of cancer, but promoting tumor progression in certain types of cancer. There have been indications in recent years that microRNAs (miRNAs/miRs) and long non‑coding RNAs (lncRNAs), as types of non‑coding RNAs, play major roles in the occurrence, invasion, development and drug resistance of hepatocellular carcinoma (HCC) and in the migration of HCC cells by governing HCC cell autophagy. Therefore, understanding which miRNAs and lncRNAs play such roles and the relevant molecular mechanisms is critical. The present review highlights the significant functions of miRNAs and lncRNAs in the regulation of autophagy in HCC and the relevant mechanisms, aiming to provide novel insight into HCC therapeutics.

Keywords: autophagy; hepatocellular carcinoma; long non‑coding RNAs; microRNAs; non‑coding RNAs.

Figure 1.

Schematic diagram of the regulatory role of autophagy in promoting or inhibiting hepatocellular carcinoma. DAMPs, damage-associated molecular patterns.

Figure 2.

Pattern diagram of the autophagy process. Initiation: ULK complex (ULK1 or ULK2, ATG13, ATG101 and FIP200/RB1CC1) initiates phagocyte formation. Nucleation: ULK complex can actively regulate the activity of Ptdlns3k complex (Beclin1/BECN1, ATG14L, p150 and VPS34), and participate in the nucleation of the autophagosome prestructure together with this complex. Elongation: ATG9 acts synergistically with ATG2 and WIPI1/2; together with ATG5-ATG12-ATG16L1 complex and LC3 (in which ATG3/4/7/10 participates in the formation of ATG5-ATG12-ATG16L1 complex and the conversion of LC3 to LC3-II), ATG3/4/7/10 participates in the prolongation of autophagosome membrane and the formation of autophagosome. Closure: VSP37A, CHMP2A and VSP4 are involved in autophagosome closure. Fusion: VAMP7/8/9, SNAP29, STX17 and RAB7 are involved in the fusion of autophagosomes and lysosomes. Degradation: The resulting autophagy is degraded by hydrolase and lipase. ULK1/2, unc-51 like autophagy activating kinase 1 or 2; ATG, autophagy-related gene; FIP200, FAK family kinase-interacting protein of 200 kDa; LC3, microtubule-associated protein 1A/1B-light chain 3; VPS37A, vacuolar protein sorting 37 homolog A; CHMP2A, charged multivesicular body protein 2A; VPS4, vacuolar protein sorting 4; SNAP29, synaptosomal-associated protein 29; STX17, syntaxin 17; RAB7, RAS-related GTP-binding protein.

Figure 3.

Schematic diagram of the role of lncRNAs and miRNAs in autophagy in HCC. miR, microRNA; ATG2A, autophagy-related gene 2A; RAB1B, Ras-related protein Rab-1B; EZH2, enhancer of zeste homolog 2; NBR2, neighbor of BRCA1 gene 2; HIF-1α, hypoxia inducible factor 1α; MALAT1, metastasis-associated lung adenocarcinoma transcript 1; PVT1, plasmacytoma variant translocation 1; DANCR, differentiation antagonizing non-protein coding RNA; HCG11, HLA complex group 11; CCAT1, Colon cancer associated transcript 1; LINC00665, Long intergenic non-protein coding RNA 665; MAP4K3, mitogen activated protein kinase kinase kinase kinase 3; HULC, highly upregulated in liver cancer; VAMP2, vesicle-associated membrane protein-2; USP9X, ubiquitin-specific protease-9; ATG16L1, autophagy-related 16-like 1; RAB5A, RAB GTPase 5A; STMN1, stathmin 1; ATG4D, autophagy-related protein 4D; EZH2, enhancer 1 of zeste homolog 2; USP22, ubiquitin-specific peptidase 22; Sirt1, silent information regulator 1; NEAT1v1, nuclear enriched abundant transcript 1 variant 1; GABARAP, gamma-aminobutyric acid receptor-associated protein; SNHG1, small nucleolar RNA host gene 1; SLC3A2, solute carrier family 3 member 2; MALAT1, metastasis associated lung adenocarcinoma transcript 1; NEAT1, nuclear enriched abundant transcript 1; LINC00160, long intergenic non-protein coding rna 00160; PIK3R3, phosphoinositide-3-kinase regulatory subunit 3; SNHG16, small nucleolar RNA host gene 16; BANCR, BRAF-activated non-protein coding RNA; OLR1, oxidized low-density lipoprotein receptor 1; ZNF225, zinc finger protein225; MEG3, maternally expressed gene 3; BACH1, BTB domain and CNC homology 1; CCAT2, colon cancer-associated transcript 2; EGFR, epidermal growth factor receptor.