Research progress of circRNA translation in digestive system neoplasms_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

XU Xinxin , LU Yixun , GAO Jingwang , GAO Wenxing , LI Kai ,  CHEN Lin

Department of General Surgery, the First Medical Center of Chinese PLA General Hospital, Beijing 100853, P. R. China;

Corresponding?author：

CHEN Lin, Email: chenlinbj@sina.com

Keywords：

circular RNA; translation; digestive system neoplasm

DOI：

10.7507/1007-9424.202202029

Video：

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Objective By summarizing the latest research progress of circRNA translation mechanism and reviewing the research progress of circRNA translation in various digestive system tumors, this paper is aiming to forecast the clinical application prospect of circular RNA translation and provide ideas for the diagnosis and treatment of digestive system neoplasms. Method The literatures on the translation of circRNA and its role in digestive system neoplasms were searched and reviewed. Results As a member of the non-coding RNA family, circRNAs are generally considered to be difficult to encode proteins as translation templates. With the rapid development of bioinformatics, next-generation sequencing, proteomics and translation omics, it has been found that many kinds of circRNAs can encode proteins or peptides in a cap-independent manner and play a critical role in the development of digestive system neoplasms, including gastric cancer, liver cancer and colorectal cancer. Conclusions The translation function of circRNA plays an important role in the development and progression of digestive system tumors, and its translation products may become new diagnostic or therapeutic targets for digestive system tumors, with great clinical transformation potential.

Citation： XU Xinxin, LU Yixun, GAO Jingwang, GAO Wenxing, LI Kai, CHEN Lin. Research progress of circRNA translation in digestive system neoplasms. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2022, 29(9): 1234-1239. doi: 10.7507/1007-9424.202202029 Copy

1.	Xiao MS, Ai Y, Wilusz JE. Biogenesis and functions of circular RNAs come into focus. Trends Cell Biol, 2020, 30(3): 226-240.
2.	Chen CY, Sarnow P. Initiation of protein synthesis by the eukaryotic translational apparatus on circular RNAs. Science, 1995, 268(5209): 415-417.
3.	Lei M, Zheng G, Ning Q, et al. Translation and functional roles of circular RNAs in human cancer. Mol Cancer, 2020, 19(1): 30. doi: 10.1186/s12943-020-1135-7.
4.	Kos A, Dijkema R, Arnberg AC, et al. The hepatitis delta (delta) virus possesses a circular RNA. Nature, 1986, 323(6088): 558-560.
5.	Sonenberg N, Hinnebusch AG. Regulation of translation initiation in eukaryotes: mechanisms and biological targets. Cell, 2009, 136(4): 731-745.
6.	Merrick WC, Pavitt GD. Protein synthesis initiation in eukaryotic cells. Cold Spring Harb Perspect Biol, 2018, 10(12): a033092. doi: 10.1101/cshperspect.a033092.
7.	Smith RCL, Kanellos G, Vlahov N, et al. Translation initiation in cancer at a glance. J Cell Sci, 2021, 134(1): jcs248476. doi: 10.1242/jcs.248476.
8.	Borden KLB, Volpon L. The diversity, plasticity, and adaptability of cap-dependent translation initiation and the associated machinery. RNA Biol, 2020, 17(9): 1239-1251.
9.	He L, Man C, Xiang S, et al. Circular RNAs′ cap-independent translation protein and its roles in carcinomas. Mol Cancer, 2021, 20(1): 119. doi: 10.1186/s12943-021-01417-4.
10.	Jang SK, Kr?usslich HG, Nicklin MJ, et al. A segment of the 5′ nontranslated region of encephalomyocarditis virus RNA directs internal entry of ribosomes during in vitro translation. J Virol, 1988, 62(8): 2636-2643.
11.	Lang KJ, Kappel A, Goodall GJ. Hypoxia-inducible factor-1alpha mRNA contains an internal ribosome entry site that allows efficient translation during normoxia and hypoxia. Mol Biol Cell, 2002, 13(5): 1792-1801.
12.	Shatsky IN, Dmitriev SE, Terenin IM, et al. Cap- and IRES-independent scanning mechanism of translation initiation as an alternative to the concept of cellular IRESs. Mol Cells, 2010, 30(4): 285-293.
13.	Chen X, Han P, Zhou T, et al. circRNADb: A comprehensive database for human circular RNAs with protein-coding annotations. Sci Rep, 2016, 6: 34985. doi: 10.1038/srep34985.
14.	Yang Y, Wang Z. IRES-mediated cap-independent translation, a path leading to hidden proteome. J Mol Cell Biol, 2019, 11(10): 911-919.
15.	Lamphear BJ, Kirchweger R, Skern T, et al. Mapping of functional domains in eukaryotic protein synthesis initiation factor 4G (eIF4G) with picornaviral proteases. Implications for cap-dependent and cap-independent translational initiation. J Biol Chem, 1995, 270(37): 21975-21983.
16.	Haizel SA, Bhardwaj U, Gonzalez RL, et al. 5′-UTR recruitment of the translation initiation factor eIF4GI or DAP5 drives cap-independent translation of a subset of human mRNAs. J Biol Chem, 2020, 295(33): 11693-11706.
17.	Huang W, Ling Y, Zhang S, et al. TransCirc: an interactive database for translatable circular RNAs based on multi-omics evidence. Nucleic Acids Res, 2021, 49(D1): D236-D242.
18.	Yang Y, Fan X, Mao M, et al. Extensive translation of circular RNAs driven by N 6-methyladenosine. Cell Res, 2017, 27(5): 626-641.
19.	Meyer KD, Patil DP, Zhou J, et al. 5′ UTR m(6)A promotes cap-independent translation. Cell, 2015, 163(4): 999. doi: 10.1016/j.cell.2015.10.012-1010.
20.	Abe N, Matsumoto K, Nishihara M, et al. Rolling circle translation of circular RNA in living human cells. Sci Rep, 2015, 5: 16435. doi: 10.1038/srep16435.
21.	Perriman R, Ares M. Circular mRNA can direct translation of extremely long repeating-sequence proteins in vivo . RNA, 1998, 4(9): 1047-1054.
22.	Liu Y, Li Z, Zhang M, et al. Rolling-translated EGFR variants sustain EGFR signaling and promote glioblastoma tumorigenicity. Neuro Oncol, 2021, 23(5): 743-756.
23.	Yang Y, Gao X, Zhang M, et al. Novel role of FBXW7 circular RNA in repressing glioma tumorigenesis. J Natl Cancer Inst, 2018, 110(3): 304-315.
24.	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.
25.	Pamudurti NR, Bartok O, Jens M, et al. Translation of circRNAs. Mol Cell, 2017, 66(1): 9-21.
26.	Jiang T, Xia Y, Lv J, et al. A novel protein encoded by circMAPK1 inhibits progression of gastric cancer by suppressing activation of MAPK signaling. Mol Cancer, 2021, 20(1): 66. doi: 10.1186/s12943-021-01358-y.
27.	Zhang Y, Jiang J, Zhang J, et al. CircDIDO1 inhibits gastric cancer progression by encoding a novel DIDO1-529aa protein and regulating PRDX2 protein stability. Mol Cancer, 2021, 20(1): 101. doi: 10.1186/s12943-021-01390-y.
28.	Peng Y, Xu Y, Zhang X, et al. A novel protein AXIN1-295aa encoded by circAXIN1 activates the Wnt/β-catenin signaling pathway to promote gastric cancer progression. Mol Cancer, 2021, 20(1): 158. doi: 10.1186/s12943-021-01457-w.
29.	Liang WC, Wong CW, Liang PP, et al. Translation of the circular RNA circβ-catenin promotes liver cancer cell growth through activation of the Wnt pathway. Genome Biol, 2019, 20(1): 84. doi: 10.1186/s13059-019-1685-4.
30.	Li Y, Chen B, Zhao J, et al. HNRNPL circularizes ARHGAP35 to produce an oncogenic protein. Adv Sci (Weinh), 2021, 8(13): 2001701. doi: 10.1002/advs.202001701.
31.	Li P, Song R, Yin F, et al. circMRPS35 promotes malignant progression and cisplatin resistance in hepatocellular carcinoma. Mol Ther, 2022, 30(1): 431-447.
32.	Li H, Lan T, Liu H, et al. IL-6-induced cGGNBP2 encodes a protein to promote cell growth and metastasis in intrahepatic cholangiocarcinoma. Hepatology, 2021, Online ahead of print. doi: 10.1002/hep.32232.
33.	Zheng X, Chen L, Zhou Y, et al. A novel protein encoded by a circular RNA circPPP1R12A promotes tumor pathogenesis and metastasis of colon cancer via Hippo-YAP signaling. Mol Cancer, 2019, 18(1): 47. doi: 10.1186/s12943-019-1010-6.
34.	Pan Z, Cai J, Lin J, et al. A novel protein encoded by circFNDC3B inhibits tumor progression and EMT through regulating Snail in colon cancer. Mol Cancer, 2020, 19(1): 71. doi: 10.1186/s12943-020-01179-5.
35.	Zhi X, Zhang J, Cheng Z, et al. circLgr4 drives colorectal tumorigenesis and invasion through Lgr4-targeting peptide. Int J Cancer, 2019, Epub 2021 Nov 25. doi: 10.1002/ijc.32549.
36.	Liang ZX, Liu HS, Xiong L, et al. A novel NF-κB regulator encoded by circPLCE1 inhibits colorectal carcinoma progression by promoting RPS3 ubiquitin-dependent degradation. Mol Cancer, 2021, 20(1): 103. doi: 10.1186/s12943-021-01404-9.
37.	Wang L, Zhou J, Zhang C, et al. A novel tumour suppressor protein encoded by circMAPK14 inhibits progression and metastasis of colorectal cancer by competitively binding to MKK6. Clin Transl Med, 2021, 11(10): e613. doi: 10.1002/ctm2.613.
38.	Wang J, Pan W. The biological role of the collagen alpha-3 (Ⅵ) chain and its cleaved C5 domain fragment endotrophin in cancer. Onco Targets Ther, 2020, 13: 5779-5793.
39.	Zhang C, Zhou X, Geng X, et al. Circular RNA hsa_circ_0006401 promotes proliferation and metastasis in colorectal carcinoma. Cell Death Dis, 2021, 12(5): 443. doi: 10.1038/s41419-021-03714-8.
40.	Nigro JM, Cho KR, Fearon ER, et al. Scrambled exons. Cell, 1991, 64(3): 607-613.
41.	Wen SY, Qadir J, Yang BB. Circular RNA translation: novel protein isoforms and clinical significance. Trends Mol Med, 2022, Online ahead of print. doi: 10.1016/j.molmed.2022.03.003.
42.	Qu L, Yi Z, Shen Y, et al. Circular RNA vaccines against SARS-CoV-2 and emerging variants. Cell, 2022, Online ahead of print. doi: 10.1016/j.cell.2022.03.044.

1. Xiao MS, Ai Y, Wilusz JE. Biogenesis and functions of circular RNAs come into focus. Trends Cell Biol, 2020, 30(3): 226-240.
2. Chen CY, Sarnow P. Initiation of protein synthesis by the eukaryotic translational apparatus on circular RNAs. Science, 1995, 268(5209): 415-417.
3. Lei M, Zheng G, Ning Q, et al. Translation and functional roles of circular RNAs in human cancer. Mol Cancer, 2020, 19(1): 30. doi: 10.1186/s12943-020-1135-7.
4. Kos A, Dijkema R, Arnberg AC, et al. The hepatitis delta (delta) virus possesses a circular RNA. Nature, 1986, 323(6088): 558-560.
5. Sonenberg N, Hinnebusch AG. Regulation of translation initiation in eukaryotes: mechanisms and biological targets. Cell, 2009, 136(4): 731-745.
6. Merrick WC, Pavitt GD. Protein synthesis initiation in eukaryotic cells. Cold Spring Harb Perspect Biol, 2018, 10(12): a033092. doi: 10.1101/cshperspect.a033092.
7. Smith RCL, Kanellos G, Vlahov N, et al. Translation initiation in cancer at a glance. J Cell Sci, 2021, 134(1): jcs248476. doi: 10.1242/jcs.248476.
8. Borden KLB, Volpon L. The diversity, plasticity, and adaptability of cap-dependent translation initiation and the associated machinery. RNA Biol, 2020, 17(9): 1239-1251.
9. He L, Man C, Xiang S, et al. Circular RNAs′ cap-independent translation protein and its roles in carcinomas. Mol Cancer, 2021, 20(1): 119. doi: 10.1186/s12943-021-01417-4.
10. Jang SK, Kr?usslich HG, Nicklin MJ, et al. A segment of the 5′ nontranslated region of encephalomyocarditis virus RNA directs internal entry of ribosomes during in vitro translation. J Virol, 1988, 62(8): 2636-2643.
11. Lang KJ, Kappel A, Goodall GJ. Hypoxia-inducible factor-1alpha mRNA contains an internal ribosome entry site that allows efficient translation during normoxia and hypoxia. Mol Biol Cell, 2002, 13(5): 1792-1801.
12. Shatsky IN, Dmitriev SE, Terenin IM, et al. Cap- and IRES-independent scanning mechanism of translation initiation as an alternative to the concept of cellular IRESs. Mol Cells, 2010, 30(4): 285-293.
13. Chen X, Han P, Zhou T, et al. circRNADb: A comprehensive database for human circular RNAs with protein-coding annotations. Sci Rep, 2016, 6: 34985. doi: 10.1038/srep34985.
14. Yang Y, Wang Z. IRES-mediated cap-independent translation, a path leading to hidden proteome. J Mol Cell Biol, 2019, 11(10): 911-919.
15. Lamphear BJ, Kirchweger R, Skern T, et al. Mapping of functional domains in eukaryotic protein synthesis initiation factor 4G (eIF4G) with picornaviral proteases. Implications for cap-dependent and cap-independent translational initiation. J Biol Chem, 1995, 270(37): 21975-21983.
16. Haizel SA, Bhardwaj U, Gonzalez RL, et al. 5′-UTR recruitment of the translation initiation factor eIF4GI or DAP5 drives cap-independent translation of a subset of human mRNAs. J Biol Chem, 2020, 295(33): 11693-11706.
17. Huang W, Ling Y, Zhang S, et al. TransCirc: an interactive database for translatable circular RNAs based on multi-omics evidence. Nucleic Acids Res, 2021, 49(D1): D236-D242.
18. Yang Y, Fan X, Mao M, et al. Extensive translation of circular RNAs driven by N 6-methyladenosine. Cell Res, 2017, 27(5): 626-641.
19. Meyer KD, Patil DP, Zhou J, et al. 5′ UTR m(6)A promotes cap-independent translation. Cell, 2015, 163(4): 999. doi: 10.1016/j.cell.2015.10.012-1010.
20. Abe N, Matsumoto K, Nishihara M, et al. Rolling circle translation of circular RNA in living human cells. Sci Rep, 2015, 5: 16435. doi: 10.1038/srep16435.
21. Perriman R, Ares M. Circular mRNA can direct translation of extremely long repeating-sequence proteins in vivo . RNA, 1998, 4(9): 1047-1054.
22. Liu Y, Li Z, Zhang M, et al. Rolling-translated EGFR variants sustain EGFR signaling and promote glioblastoma tumorigenicity. Neuro Oncol, 2021, 23(5): 743-756.
23. Yang Y, Gao X, Zhang M, et al. Novel role of FBXW7 circular RNA in repressing glioma tumorigenesis. J Natl Cancer Inst, 2018, 110(3): 304-315.
24. 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.
25. Pamudurti NR, Bartok O, Jens M, et al. Translation of circRNAs. Mol Cell, 2017, 66(1): 9-21.
26. Jiang T, Xia Y, Lv J, et al. A novel protein encoded by circMAPK1 inhibits progression of gastric cancer by suppressing activation of MAPK signaling. Mol Cancer, 2021, 20(1): 66. doi: 10.1186/s12943-021-01358-y.
27. Zhang Y, Jiang J, Zhang J, et al. CircDIDO1 inhibits gastric cancer progression by encoding a novel DIDO1-529aa protein and regulating PRDX2 protein stability. Mol Cancer, 2021, 20(1): 101. doi: 10.1186/s12943-021-01390-y.
28. Peng Y, Xu Y, Zhang X, et al. A novel protein AXIN1-295aa encoded by circAXIN1 activates the Wnt/β-catenin signaling pathway to promote gastric cancer progression. Mol Cancer, 2021, 20(1): 158. doi: 10.1186/s12943-021-01457-w.
29. Liang WC, Wong CW, Liang PP, et al. Translation of the circular RNA circβ-catenin promotes liver cancer cell growth through activation of the Wnt pathway. Genome Biol, 2019, 20(1): 84. doi: 10.1186/s13059-019-1685-4.
30. Li Y, Chen B, Zhao J, et al. HNRNPL circularizes ARHGAP35 to produce an oncogenic protein. Adv Sci (Weinh), 2021, 8(13): 2001701. doi: 10.1002/advs.202001701.
31. Li P, Song R, Yin F, et al. circMRPS35 promotes malignant progression and cisplatin resistance in hepatocellular carcinoma. Mol Ther, 2022, 30(1): 431-447.
32. Li H, Lan T, Liu H, et al. IL-6-induced cGGNBP2 encodes a protein to promote cell growth and metastasis in intrahepatic cholangiocarcinoma. Hepatology, 2021, Online ahead of print. doi: 10.1002/hep.32232.
33. Zheng X, Chen L, Zhou Y, et al. A novel protein encoded by a circular RNA circPPP1R12A promotes tumor pathogenesis and metastasis of colon cancer via Hippo-YAP signaling. Mol Cancer, 2019, 18(1): 47. doi: 10.1186/s12943-019-1010-6.
34. Pan Z, Cai J, Lin J, et al. A novel protein encoded by circFNDC3B inhibits tumor progression and EMT through regulating Snail in colon cancer. Mol Cancer, 2020, 19(1): 71. doi: 10.1186/s12943-020-01179-5.
35. Zhi X, Zhang J, Cheng Z, et al. circLgr4 drives colorectal tumorigenesis and invasion through Lgr4-targeting peptide. Int J Cancer, 2019, Epub 2021 Nov 25. doi: 10.1002/ijc.32549.
36. Liang ZX, Liu HS, Xiong L, et al. A novel NF-κB regulator encoded by circPLCE1 inhibits colorectal carcinoma progression by promoting RPS3 ubiquitin-dependent degradation. Mol Cancer, 2021, 20(1): 103. doi: 10.1186/s12943-021-01404-9.
37. Wang L, Zhou J, Zhang C, et al. A novel tumour suppressor protein encoded by circMAPK14 inhibits progression and metastasis of colorectal cancer by competitively binding to MKK6. Clin Transl Med, 2021, 11(10): e613. doi: 10.1002/ctm2.613.
38. Wang J, Pan W. The biological role of the collagen alpha-3 (Ⅵ) chain and its cleaved C5 domain fragment endotrophin in cancer. Onco Targets Ther, 2020, 13: 5779-5793.
39. Zhang C, Zhou X, Geng X, et al. Circular RNA hsa_circ_0006401 promotes proliferation and metastasis in colorectal carcinoma. Cell Death Dis, 2021, 12(5): 443. doi: 10.1038/s41419-021-03714-8.
40. Nigro JM, Cho KR, Fearon ER, et al. Scrambled exons. Cell, 1991, 64(3): 607-613.
41. Wen SY, Qadir J, Yang BB. Circular RNA translation: novel protein isoforms and clinical significance. Trends Mol Med, 2022, Online ahead of print. doi: 10.1016/j.molmed.2022.03.003.
42. Qu L, Yi Z, Shen Y, et al. Circular RNA vaccines against SARS-CoV-2 and emerging variants. Cell, 2022, Online ahead of print. doi: 10.1016/j.cell.2022.03.044.

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Research progress of circRNA translation in digestive system neoplasms

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