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Circular RNA hsa_circ_0009172 suppresses gastric cancer by regulation of microRNA-485-3p-mediated NTRK3

Cancer Gene Therapy volume 28, pages 1312–1324 (2021)Cite this article

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Abstract

Gastric cancer is the third leading cause of cancer-related death worldwide, with relapse and metastasis being major contributors to the mortality. Circular RNAs (circRNAs) have been at the center of several researches and some circRNAs have been indicated to be involved in gastric cancer as sponges. Nevertheless, the mechanism underlying the function of circRNA remains largely unclear. Therefore, this study was conducted with the main objective of screening the associated circRNA in gastric cancer and exploring its mechanism. Expression of hsa_circRNA_0009172 was validated in gastric cancer tissues and cell lines after the correlation between hsa_circRNA_0009172 and prognosis was determined. Moreover, the binding site between miR-485-3p and hsa_circRNA_0009172 or NTRK3 was verified using dual luciferase assay and RNA pull down. Function-gain and -loss experiments were performed for the purpose of detecting the effect of hsa_circRNA_0009172 in vivo and in vitro as well as its mechanism with microRNA (miRNA)-485-3p and NTRK3 in gastric cancer. The hsa_circRNA_0009172 expression was downregulated in gastric cancer tissues and cell lines, indicating a positive association with patient prognosis. Functionally, hsa_circ_0009172 overexpression inhibited proliferative, invasive and migrative potential of gastric cancer cells as well as epithelial-mesenchymal transition (EMT)-related proteins by sponging miR-485-3p to inhibit NTRK3, while miR-485-3p overexpression could reverse the inhibitory effect of hsa_circ_0009172 on gastric cancer. Furthermore, either up-regulation of hsa_circ_0009172 or down-regulation of miR-485-3p led to the suppression of xenograft tumor growth in nude mice. In conclusion, hsa_circ_0009172 serves as a tumor suppressor in gastric cancer by targeting miR-485-3p/NTRK3 axis.

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Fig. 1: hsa_circRNA_0009172/miR-485-3p/NTRK3 axis is associated with development of gastric cancer.
Fig. 2: hsa_circRNA_0009172 expression is related with poor prognosis of gastric cancer patients.
Fig. 3: Low hsa_circRNA_0009172 expression promotes malignant phenotypes of gastric cancer cells.
Fig. 4: hsa_circRNA_0009172 binds to miR-485-3p.
Fig. 5: miR-485-3p eliminates the suppression of hsa_circRNA_002178 to gastric cancer progression.
Fig. 6: hsa_circRNA_0009172 regulates NTRK3 expression through sponging miR-485-3p.
Fig. 7: hsa_circRNA_0009172 and miR-485-3p participates in tumor growth.

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Data availability

The datasets generated/analyzed during the current study are available.

References

  1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68:394–424.

    Article  Google Scholar 

  2. Thrumurthy SG, Chaudry MA, Chau I, Allum W. Does surgery have a role in managing incurable gastric cancer? Nat Rev Clin Oncol. 2015;12:676–82.

    Article  Google Scholar 

  3. Van Cutsem E, Sagaert X, Topal B, Haustermans K, Prenen H. Gastric cancer. Lancet. 2016;388:2654–64.

    Article  Google Scholar 

  4. Dongre A, Weinberg RA. New insights into the mechanisms of epithelial-mesenchymal transition and implications for cancer. Nat Rev Mol Cell Biol. 2019;20:69–84.

    Article  CAS  Google Scholar 

  5. Huang L, Wu RL, Xu AM. Epithelial-mesenchymal transition in gastric cancer. Am J Transl Res. 2015;7:2141–58.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Kristensen LS, Andersen MS, Stagsted LVW, Ebbesen KK, Hansen TB, Kjems J. The biogenesis, biology and characterization of circular RNAs. Nat Rev Genet. 2019;20:675–91.

    Article  CAS  Google Scholar 

  7. Shan C, Zhang Y, Hao X, Gao J, Chen X, Wang K. Biogenesis, functions and clinical significance of circRNAs in gastric cancer. Mol Cancer. 2019;18:136.

    Article  Google Scholar 

  8. Shang BQ, Li ML, Quan HY, Hou PF, Li ZW, Chu SF, et al. Functional roles of circular RNAs during epithelial-to-mesenchymal transition. Mol Cancer. 2019;18:138.

    Article  Google Scholar 

  9. Tian M, Chen R, Li T, Xiao B. Reduced expression of circRNA hsa_circ_0003159 in gastric cancer and its clinical significance. J Clin Lab Anal. 2018;32:e22281.

    Article  Google Scholar 

  10. Zhang Y, Liu H, Li W, Yu J, Li J, Shen Z, et al. CircRNA_100269 is downregulated in gastric cancer and suppresses tumor cell growth by targeting miR-630. Aging (Albany NY). 2017;9:1585–94.

    Article  CAS  Google Scholar 

  11. Zhang J, Liu H, Hou L, Wang G, Zhang R, Huang Y, et al. Circular RNA_LARP4 inhibits cell proliferation and invasion of gastric cancer by sponging miR-424-5p and regulating LATS1 expression. Mol Cancer. 2017;16:151.

    Article  Google Scholar 

  12. Lamouille S, Subramanyam D, Blelloch R, Derynck R. Regulation of epithelial-mesenchymal and mesenchymal-epithelial transitions by microRNAs. Curr Opin Cell Biol. 2013;25:200–7.

    Article  CAS  Google Scholar 

  13. Song S, Ajani JA. The role of microRNAs in cancers of the upper gastrointestinal tract. Nat Rev Gastroenterol Hepatol. 2013;10:109–18.

    Article  CAS  Google Scholar 

  14. Lou C, Xiao M, Cheng S, Lu X, Jia S, Ren Y, et al. MiR-485-3p and miR-485-5p suppress breast cancer cell metastasis by inhibiting PGC-1alpha expression. Cell Death Dis. 2016;7:e2159.

    Article  CAS  Google Scholar 

  15. Muinos-Gimeno M, Guidi M, Kagerbauer B, Martin-Santos R, Navines R, Alonso P, et al. Allele variants in functional MicroRNA target sites of the neurotrophin-3 receptor gene (NTRK3) as susceptibility factors for anxiety disorders. Hum Mutat. 2009;30:1062–71.

    Article  CAS  Google Scholar 

  16. Wood LD, Calhoun ES, Silliman N, Ptak J, Szabo S, Powell SM, et al. Somatic mutations of GUCY2F, EPHA3, and NTRK3 in human cancers. Hum Mutat. 2006;27:1060–1.

    Article  Google Scholar 

  17. Shi E, Chmielecki J, Tang CM, Wang K, Heinrich MC, Kang G, et al. FGFR1 and NTRK3 actionable alterations in “Wild-Type” gastrointestinal stromal tumors. J Transl Med. 2016;14:339.

    Article  Google Scholar 

  18. Bu JY, Lv WZ, Liao YF, Xiao XY, Lv BJ. Long non-coding RNA LINC00978 promotes cell proliferation and tumorigenesis via regulating microRNA-497/NTRK3 axis in gastric cancer. Int J Biol Macromol. 2019;123:1106–14.

    Article  CAS  Google Scholar 

  19. Luo Y, Kaz AM, Kanngurn S, Welsch P, Morris SM, Wang J, et al. NTRK3 is a potential tumor suppressor gene commonly inactivated by epigenetic mechanisms in colorectal cancer. PLoS Genet. 2013;9:e1003552.

    Article  CAS  Google Scholar 

  20. Xiong D, Sheng Y, Ding S, Chen J, Tan X, Zeng T, et al. LINC00052 regulates the expression of NTRK3 by miR-128 and miR-485-3p to strengthen HCC cells invasion and migration. Oncotarget. 2016;7:47593–608.

    Article  Google Scholar 

  21. Padmanabhan N, Ushijima T, Tan P. How to stomach an epigenetic insult: the gastric cancer epigenome. Nat Rev Gastroenterol Hepatol. 2017;14:467–78.

    Article  Google Scholar 

  22. Bang YJ, Van Cutsem E, Feyereislova A, Chung HC, Shen L, Sawaki A, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet. 2010;376:687–97.

    Article  CAS  Google Scholar 

  23. Tang W, Fu K, Sun H, Rong D, Wang H, Cao H. CircRNA microarray profiling identifies a novel circulating biomarker for detection of gastric cancer. Mol Cancer. 2018;17:137.

    Article  Google Scholar 

  24. Yin Y, Long J, He Q, Li Y, Liao Y, He P, et al. Emerging roles of circRNA in formation and progression of cancer. J Cancer. 2019;10:5015–21.

    Article  CAS  Google Scholar 

  25. Vo JN, Cieslik M, Zhang Y, Shukla S, Xiao L, Zhang Y, et al. The Landscape of Circular RNA in. Cancer Cell. 2019;176:869–81 e13.

    CAS  Google Scholar 

  26. Fang X, Wen J, Sun M, Yuan Y, Xu Q. CircRNAs and its relationship with gastric cancer. J Cancer. 2019;10:6105–13.

    Article  CAS  Google Scholar 

  27. Peng Z, Wang CX, Fang EH, Wang GB, Tong Q. Role of epithelial-mesenchymal transition in gastric cancer initiation and progression. World J Gastroenterol. 2014;20:5403–10.

    Article  CAS  Google Scholar 

  28. Naeli P, Pourhanifeh MH, Karimzadeh MR, Shabaninejad Z, Movahedpour A, Tarrahimofrad H, et al. Circular RNAs and gastrointestinal cancers: Epigenetic regulators with a prognostic and therapeutic role. Crit Rev Oncol Hematol. 2020;145:102854.

    Article  Google Scholar 

  29. Liu H, Liu Y, Bian Z, Zhang J, Zhang R, Chen X, et al. Circular RNA YAP1 inhibits the proliferation and invasion of gastric cancer cells by regulating the miR-367-5p/p27 (Kip1) axis. Mol Cancer. 2018;17:151.

    Article  CAS  Google Scholar 

  30. Deng G, Mou T, He J, Chen D, Lv D, Liu H, et al. Circular RNA circRHOBTB3 acts as a sponge for miR-654-3p inhibiting gastric cancer growth. J Exp Clin Cancer Res. 2020;39:1.

    Article  CAS  Google Scholar 

  31. Wang J, Zhang H, Zhou X, Wang T, Zhang J, Zhu W, et al. Five serum-based miRNAs were identified as potential diagnostic biomarkers in gastric cardia adenocarcinoma. Cancer Biomark. 2018;23:193–203.

    Article  CAS  Google Scholar 

  32. Dai D, Tan Y, Guo L, Tang A, Zhao Y. Identification of exosomal miRNA biomarkers for diagnosis of papillary thyroid cancer by small RNA sequencing. Eur J Endocrinol. 2020;182:111–21.

    Article  CAS  Google Scholar 

  33. Cocco E, Scaltriti M, Drilon A. NTRK fusion-positive cancers and TRK inhibitor therapy. Nat Rev Clin Oncol. 2018;15:731–47.

    Article  CAS  Google Scholar 

  34. Wada R, Arai H, Kure S, Peng WX, Naito Z. “Wild type” GIST: Clinicopathological features and clinical practice. Pathol Int. 2016;66:431–7.

    Article  CAS  Google Scholar 

  35. Kubo T, Kuroda Y, Shimizu H, Kokubu A, Okada N, Hosoda F, et al. Resequencing and copy number analysis of the human tyrosine kinase gene family in poorly differentiated gastric cancer. Carcinogenesis. 2009;30:1857–64.

    Article  CAS  Google Scholar 

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Acknowledgements

We would like to give our sincere appreciation to the reviewers for their helpful comments on this article.

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Authors and Affiliations

  1. Department of Oncology, The First Affiliated Hospital, College of Medicine Xi’an Jiaotong University, Xi’an, 710061, PR China

    Hao Wang & Suxia Han

  2. Department of Radiation Oncology, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, 450000, PR China

    Hao Wang, Nan Wang, Xiaoli Zheng, Chengcheng Fan, Xue Li & Ke Ye

  3. Centers of Radiotherapy Oncology, Shaanxi Provincial Tumor Hospital, Xi’an, 710068, PR China

    Lei Wu

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Contributions

Hao Wang, Nan Wang, Xiaoli Zheng, Lei Wu, Chengcheng Fan, Xue Li, Ke Ye, and Suxia Han designed the study. Hao Wang, Nan Wang, and Xiaoli Zheng collated the data, carried out data analyses, and produced the initial draft of the manuscript. Lei Wu, Chengcheng Fan, Xue Li, Ke Ye, and Suxia Han contributed to drafting the manuscript. All authors have read and approved the final submitted manuscript.

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Correspondence to Suxia Han.

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Wang, H., Wang, N., Zheng, X. et al. Circular RNA hsa_circ_0009172 suppresses gastric cancer by regulation of microRNA-485-3p-mediated NTRK3. Cancer Gene Ther 28, 1312–1324 (2021). https://doi.org/10.1038/s41417-020-00280-7

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