The Underlying Mechanisms of Noncoding RNAs in the Chemoresistance of Hepatocellular Carcinoma

Abstract

Hepatocellular carcinoma (HCC) is one of the most lethal human malignancies. Chemotherapeutic agents, such as sorafenib and lenvatinib, can improve the outcomes of HCC patients. Nevertheless, chemoresistance has become a major hurdle in the effective treatment of HCC. Noncoding RNAs (ncRNAs), including mircoRNAs (miRNAs), long ncRNAs (lncRNAs), and circular RNAs (circRNAs), have been demonstrated to participate in the onset and progression of HCC. Moreover, multiple lines of evidence have indicated that ncRNAs also play a pivotal role in HCC drug resistance. ncRNAs can regulate drug efflux and metabolism, glucose metabolism, cellular death pathways, and malignant characteristics in HCC. A deeper understanding of the molecular mechanisms responsible for ncRNA-mediated drug resistance in HCC will provide new opportunities for improving the treatment of HCC. In this review, we summarize recent findings on the molecular mechanisms by which ncRNAs regulate HCC chemoresistance, as well as their potential clinical implications in overcoming HCC chemoresistance.

Keywords: chemoresistance; circular RNAs; hepatocellular carcinoma; long noncoding RNAs; microRNAs.

Graphical abstract

Figure 1

ncRNAs Affect Drug Efflux and Nrf2-Dependent Drug Metabolism in HCC Cells Various miRNAs and lncRNAs can regulate intracellular drug concentrations in HCC cells by targeting drug efflux pumps. Several miRNAs and lncRNAs dominate the expression of drug efflux pumps and metabolizing enzymes in HCC cells through the Nrf2 signaling pathway. miR-215 inhibits the expression of DHFR and TS, which are important targets of chemotherapeutic agents. miRNAs and lncRNAs also orchestrate the survival and proliferation of HCC cells by regulating the JAK/STAT signaling pathway. ABC transporter, ATP-binding cassette transporter; YAP1, Yes-associated protein 1; Keap1, Kelch-like ECH-associated protein 1; Nrf2, nuclear factor-erythroid 2-related factor 2; ROS, reactive oxygen species; DHFR, dihydrofolate reductase; TS, thymidylate synthase; IGF-1, insulin-like growth factor-1; IGF-1R, type 1 insulin-like growth factor receptor; JAK, Janus kinase; STAT, signal transducer and activator of transcription.

Figure 2

ncRNAs Regulate Cell Death Pathways to Influence HCC Chemoresistance Multiple miRNAs and lncRNAs act as mediators of the autophagic process in HCC cells by regulating the PI3K/Akt signaling pathway. They also control the expression of key autophagy-related proteins, including Sirt1, LC3, and ATGs. Several miRNAs and lncRNAs participate in FAS-mediated extrinsic apoptosis in HCC cells by targeting FASLG, caspase-8, and caspase-3. miRNAs and lncRNAs are also involved in mitochondria-mediated intrinsic apoptosis by modulating the NF-κB and p53 signaling pathways. In addition, miR-125b and miR-122 can suppress glucose metabolism and thus regulate HCC cell growth and apoptosis. RTK, receptor tyrosine kinase; RASAL1, RAS protein activator like-1; PTEN, phosphatase and tensin homolog; PI3K, phosphoinositide 3-kinase; Akt, protein kinase B; mTOR, mammalian target of rapamycin; ULK1, unc-51-like kinase 1; ATG, autophagy-related gene; ATG16L1, ATG16-like 1; Sirt1, silent information regulator 1; LC3, microtubule-associated protein 1 light chain 3; TP53INP1, tumor protein 53-induced nuclear protein 1; NF-κB, nuclear factor-B; IKBKB, inhibitor of NF-κB kinase β; FASLG, FAS ligand; FADD, FAS-associating protein with death domain; Bcl-2, B cell lymphoma-2; Bax, Bcl-2-associated X protein; Bid, Bcl-2-interacting domain death agonist; tBid, truncated Bid; GLUT, glucose transporter; HK II, hexokinase II; G6P, glucose-6-phosphate; PEP, phosphoenolpyruvate; PKM2, pyruvate kinase M2; TCA, tricarboxylic acid.

Figure 3

ncRNAs Modulate the EMT Program in HCC Cells ncRNAs can interfere with the Wnt/β-catenin, TGF-β/SMAD, and Notch signaling cascades to regulate the expression of EMT-inducing transcription factors (Twist1 and Snail) in HCC cells. Specifically, miR-106a directly targets Twist1 to restrict the EMT process in HCC cells. miR-383 can restrain the EIF5A2-mediated EMT program in HCC cells. GSK3β, glycogen synthase kinase 3β; EIF5A2, eukaryotic translation initiation factor 5A2; EMT, epithelial-mesenchymal transition; TGF-β, transforming growth factor-β; TGF-βR, TGF-β receptor; SMAD, small mothers against decapentaplegic homolog; NICD, the intracellular domain of Notch.

Figure 4

Schematic Illustration of ncRNA-Based Therapeutic Strategies in Drug-Resistant HCC Cells Antisense oligonucleotides, small molecule inhibitors, and miRNA sponges can be employed to suppress the expression of oncogenic ncRNAs, thus reversing HCC chemoresistance. Nanoparticle-encapsulated ncRNAs, chemically modified ncRNAs, or exogenous ncRNA mimics can be delivered to inhibit the expression of their target genes that mediate drug resistance in HCC cells. GalNAc, N-acetylgalactosamine; siRNA, small interfering RNA.