The role of circular RNA in therapeutic resistance of liver cancer_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

TANG Haocheng , HE Yutao , LIU Xin , TIAN Fangming , SHI Zhitian ,  WANG Lin

Second Ward of Hepatobiliary and Pancreatic Surgery, Second Affiliated Hospital of Kunming Medical University, Kunming 650000, P. R. China;

Corresponding?author：

WANG Lin, Email: wanglinfey@126.com

Keywords：

circular RNA; liver cancer; drug therapy; therapeutic resistance

DOI：

10.7507/1007-9424.202508058

Video：

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Objective To summarize the research status of circular RNAs (circRNAs) in resistance to targeted combined immunotherapy for hepatocellular carcinoma (HCC). Methods Relevant literatures at home and abroad were retrieved to review the regulatory role and molecular mechanisms of circRNAs in resistance to targeted combined immunotherapy for HCC. Results As non-coding RNAs with high stability and strong tissue specificity, circRNAs mediate resistance to targeted combined immunotherapy mainly through three core modes: sponging miRNAs, regulating protein stability, and encoding functional peptides. Conclusion CircRNAs interfere with proliferation and survival pathways and reshape the tumor microenvironment through diverse mechanisms, serving as core regulatory factors in resistance to targeted combined immunotherapy for HCC. CircRNAs are expected to become biomarkers for predicting HCC drug resistance and targets for therapeutic intervention, providing important support for breaking through the bottleneck of resistance to combined therapy.

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1. Bray F, Laversanne M, Sung H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 2024, 74(3): 229-263.
2. Ringelhan M, Pfister D, O'Connor T, et al. The immunology of hepatocellular carcinoma. Nat Immunol, 2018, 19(3): 222-232.
3. Park JW, Chen M, Colombo M, et al. Global patterns of hepatocellular carcinoma management from diagnosis to death: the BRIDGE Study. Liver Int, 2015, 35(9): 2155-2166.
4. Forner A, Reig M, Bruix J. Hepatocellular carcinoma. Lancet, 2018, 391(10127): 1301-1314.
5. Huang A, Yang XR, Chung WY, et al. Targeted therapy for hepatocellular carcinoma. Signal Transduct Target Ther, 2020, 5(1): 146. doi: 10.1038/s41392-020-00264-x.
6. Ladd AD, Duarte S, Sahin I, et al. Mechanisms of drug resistance in HCC. Hepatology, 2024, 79(4): 926-940.
7. Yan H, Bu P. Non-coding RNA in cancer. Essays Biochem, 2021, 65(4): 625-639.
8. Lu JC, Zhang PF, Huang XY, et al. Amplification of spatially isolated adenosine pathway by tumor-macrophage interaction induces anti-PD1 resistance in hepatocellular carcinoma. J Hematol Oncol, 2021, 14(1): 200. doi: 10.1186/s13045-021-01207-x.
9. Kristensen LS, Andersen MS, Stagsted LVW, et al. The biogenesis, biology and characterization of circular RNAs. Nat Rev Genet, 2019, 20(11): 675-691.
10. Chen LL. The biogenesis and emerging roles of circular RNAs. Nat Rev Mol Cell Biol, 2016, 17(4): 205-211.
11. Zhang XO, Dong R, Zhang Y, et al. Diverse alternative back-splicing and alternative splicing landscape of circular RNAs. Genome Res, 2016, 26(9): 1277-1287.
12. Gao Y, Wang J, Zheng Y, et al. Comprehensive identification of internal structure and alternative splicing events in circular RNAs. Nat Commun, 2016, 7: 12060. doi: 10.1038/ncomms12060.
13. Suzuki H, Zuo Y, Wang J, et al. Characterization of RNase R-digested cellular RNA source that consists of lariat and circular RNAs from pre-mRNA splicing. Nucleic Acids Res, 2006, 34(8): e63. doi: 10.1093/nar/gkl151.
14. Fabian MR, Sonenberg N, Filipowicz W. Regulation of mRNA translation and stability by microRNAs. Annu Rev Biochem, 2010, 79: 351-379.
15. Salmena L, Poliseno L, Tay Y, et al. A ceRNA hypothesis: the Rosetta Stone of a hidden RNA language? Cell, 2011, 146(3): 353-358.
16. Memczak S, Jens M, Elefsinioti A, et al. Circular RNAs are a large class of animal RNAs with regulatory potency. Nature, 2013, 495(7441): 333-338.
17. Hansen TB, Jensen TI, Clausen BH, et al. Natural RNA circles function as efficient microRNA sponges. Nature, 2013, 495(7441): 384-388.
18. Ashwal-Fluss R, Meyer M, Pamudurti NR, et al. circRNA biogenesis competes with pre-mRNA splicing. Mol Cell, 2014, 56(1): 55-66.
19. Legnini I, Di Timoteo G, Rossi F, et al. Circ-ZNF609 is a circular RNA that can be translated and functions in myogenesis. Mol Cell, 2017, 66(1): 22-37.
20. Chen CY, Sarnow P. Initiation of protein synthesis by the eukaryotic translational apparatus on circular RNAs. Science, 1995, 268(5209): 415-417.
21. Li JH, Liu S, Zhou H, et al. starBase v2.0: decoding miRNA-ceRNA, miRNA-ncRNA and protein-RNA interaction networks from large-scale CLIP-Seq data. Nucleic Acids Res, 2014, 42(Database issue): D92-97.
22. Chen Y, Yang F, Fang E, et al. Circular RNA circAGO2 drives cancer progression through facilitating HuR-repressed functions of AGO2-miRNA complexes. Cell Death Differ, 2019, 26(7): 1346-1364.
23. Yang Q, Du WW, Wu N, et al. A circular RNA promotes tumorigenesis by inducing c-myc nuclear translocation. Cell Death Differ, 2017, 24(9): 1609-1620.
24. Nan A, Chen L, Zhang N, et al. Circular RNA circNOL10 inhibits lung cancer development by promoting SCLM1-mediated transcriptional regulation of the humanin polypeptide family. Adv Sci (Weinh), 2018, 6(2): 1800654. doi: 10.1002/advs.201800654.
25. Du WW, Yang W, Liu E, et al. Foxo3 circular RNA retards cell cycle progression via forming ternary complexes with p21 and CDK2. Nucleic Acids Res, 2016, 44(6): 2846-2858.
26. Du WW, Fang L, Yang W, et al. Induction of tumor apoptosis through a circular RNA enhancing Foxo3 activity. Cell Death Differ, 2017, 24(2): 357-370.
27. Sun S, Wang W, Luo X, et al. Circular RNA circ-ADD3 inhibits hepatocellular carcinoma metastasis through facilitating EZH2 degradation via CDK1-mediated ubiquitination. Am J Cancer Res, 2019, 9(8): 1695-1707.
28. Liu B, Yang G, Wang X, et al. CircBACH1 (hsa_circ_0061395) promotes hepatocellular carcinoma growth by regulating p27 repression via HuR. J Cell Physiol, 2020, 235(10): 6929-6941.
29. Jie M, Wu Y, Gao M, et al. CircMRPS35 suppresses gastric cancer progression via recruiting KAT7 to govern histone modification. Mol Cancer, 2020, 19(1): 56. doi: 10.1186/s12943-020-01160-2.
30. Liu Y, Dong Y, Zhao L, et al. Circular RNA-MTO1 suppresses breast cancer cell viability and reverses monastrol resistance through regulating the TRAF4/Eg5 axis. Int J Oncol, 2018, 53(4): 1752-1762.
31. Li Y, Zheng Q, Bao C, et al. Circular RNA is enriched and stable in exosomes: a promising biomarker for cancer diagnosis. Cell Res, 2015, 25(8): 981-984.
32. Dai X, Chen C, Yang Q, et al. Exosomal circRNA_100284 from arsenite-transformed cells, via microRNA-217 regulation of EZH2, is involved in the malignant transformation of human hepatic cells by accelerating the cell cycle and promoting cell proliferation. Cell Death Dis, 2018, 9(5): 454. doi: 10.1038/s41419-018-0485-1.
33. Finn RS, Qin S, Ikeda M, et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med, 2020, 382(20): 1894-1905.
34. Hu X, Zhu H, Shen Y, et al. The role of non-coding RNAs in the sorafenib resistance of hepatocellular carcinoma. Front Oncol, 2021, 11: 696705. doi: 10.3389/fonc.2021.696705.
35. Wu MY, Tang YP, Liu JJ, et al. Global transcriptomic study of circRNAs expression profile in sorafenib resistant hepatocellular carcinoma cells. J Cancer, 2020, 11(10): 2993-3001.
36. Kashyap D, Garg VK, Goel N. Intrinsic and extrinsic pathways of apoptosis: role in cancer development and prognosis. Adv Protein Chem Struct Biol, 2021, 125: 73-120.
37. Monger A, Boonmuen N, Suksen K, et al. Inhibition of topoisomerase IIα and induction of apoptosis in gastric cancer cells by 19-triisopropyl andrographolide. Asian Pac J Cancer Prev, 2017, 18(10): 2845-2851.
38. Yang Z, Liu Y, Shi C, et al. Suppression of PTEN/AKT signaling decreases the expression of TUBB3 and TOP2A with subsequent inhibition of cell growth and induction of apoptosis in human breast cancer MCF-7 cells via ATP and caspase-3 signaling pathways. Oncol Rep, 2017, 37(2): 1011-1019.
39. Ruan Y, Chen T, Zheng L, et al. cDCBLD2 mediates sorafenib resistance in hepatocellular carcinoma by sponging miR-345-5p binding to the TOP2A coding sequence. Int J Biol Sci, 2023, 19(14): 4608-4626.
40. Li X, Yin X, Bao H, et al. Circular RNA ITCH increases sorafenib-sensitivity in hepatocellular carcinoma via sequestering miR-20b-5p and modulating the downstream PTEN-PI3K/Akt pathway. Mol Cell Probes, 2023, 67: 101877. doi: 10.1016/j.mcp.2022.101877.
41. Zhang X, Wang W, Mo S, et al. DEAD-Box helicase 17 circRNA (circDDX17) reduces sorafenib resistance and tumorigenesis in hepatocellular carcinoma. Dig Dis Sci, 2024, 69(6): 2096-2108.
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