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The circINTS4/miR-146b/CARMA3 axis promotes tumorigenesis in bladder cancer

Cancer Gene Therapy (2019) | Download Citation

Abstract

Accumulating evidence shows that circular RNAs (circRNAs) function as microRNA sponges that regulate gene expression in the progression of human cancers. However, the roles of circRNAs and functional miRNA sponges in bladder cancer (BC) remain largely unknown. In the present study, we applied bioinformatics methods and hypothesised that miR-146b may target the 3′-untranslated region (UTR) of CARMA3 mRNA and circINTS4 may serve as a sponge for miR-146b in BC tumorigenesis. Expression of circINTS4 was significantly increased in miR-146b-downregulated BC tissues and cell lines compared to adjacent normal tissues. Furthermore, circINTS4 was found to control multiple pathological processes, including cell proliferation and migration, the cell cycle and apoptosis. Regarding the mechanism, circINTS4 directly bound to miR-146b to inhibit its activity of targeting the 3′-UTR of CARMA3 mRNA. In addition, circINTS4 could activate the NF-kB signalling pathway and suppress the P38 MAPK signalling pathway in a CARMA3-mediated manner in BC cells. In summary, the circINTS4/miR-146b/CARMA3 axis might serve as a promising therapeutic target for BC intervention.

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References

  1. 1.

    Antoni S, Ferlay J, Soerjomataram I, Znaor A, Jemal A, Bray F. Bladder cancer incidence and mortality: a global overview and recent trends. Eur Urol. 2017;71:96–108.

  2. 2.

    Rushton L, Hutchings SJ, Fortunato L, Young C, Evans GS, Brown T, et al. Occupational cancer burden in Great Britain. Br J Cancer. 2012;107(Suppl 1):S3–7.

  3. 3.

    Gakis G, Efstathiou J, Lerner SP, Cookson MS, Keegan KA, Guru KA, et al. ICUD-EAU International Consultation on Bladder Cancer 2012: radical cystectomy and bladder preservation for muscle-invasive urothelial carcinoma of the bladder. Eur Urol. 2013;63:45–57.

  4. 4.

    Babjuk M, Burger M, Zigeuner R, Shariat SF, van Rhijn BW, Comperat E, et al. EAU guidelines on non-muscle-invasive urothelial carcinoma of the bladder: update 2013. Eur Urol. 2013;64:639–53.

  5. 5.

    Bid HK. Words of wisdom. Re: markers predicting response to Bacillus Calmette-Guerin immunotherapy in high-risk bladder cancer patients: a systematic review. Eur Urol. 2012;61:846–7.

  6. 6.

    Pan D, Zhu Y, Zhou Z, Wang T, You H, Jiang C, et al. The CBM complex underwrites NF-kappaB activation to promote HER2-associated tumor malignancy. Mol Cancer Res. 2016;14:93–102.

  7. 7.

    McAllister-Lucas LM, Ruland J, Siu K, Jin X, Gu S, Kim DS, et al. CARMA3/Bcl10/MALT1-dependent NF-kappaB activation mediates angiotensin II-responsive inflammatory signaling in nonimmune cells. Proc Natl Acad Sci USA. 2007;104:139–44.

  8. 8.

    Zhang S, Pan D, Jia XM, Lin X, Zhao X. The CARMA3-BCL10-MALT1 (CBM) complex contributes to DNA damage-induced NF-kappaB activation and cell survival. Protein Cell. 2017;8:856–60.

  9. 9.

    Xia ZX, Li ZX, Zhang M, Sun LM, Zhang QF, Qiu XS. CARMA3 regulates the invasion, migration, and apoptosis of non-small cell lung cancer cells by activating NF-small ka, CyrillicB and suppressing the P38 MAPK signaling pathway. Exp Mol Pathol. 2016;100:353–60.

  10. 10.

    Grabiner BC, Blonska M, Lin PC, You Y, Wang D, Sun J, et al. CARMA3 deficiency abrogates G protein-coupled receptor-induced NF-{kappa}B activation. Genes Dev. 2007;21:984–96.

  11. 11.

    Jiang T, Grabiner B, Zhu Y, Jiang C, Li H, You Y, et al. CARMA3 is crucial for EGFR-Induced activation of NF-kappaB and tumor progression. Cancer Res. 2011;71:2183–92.

  12. 12.

    Jiang C, Zhou Z, Quan Y, Zhang S, Wang T, Zhao X, et al. CARMA3 is a host factor regulating the balance of inflammatory and antiviral responses against viral infection. Cell Rep. 2016;14:2389–401.

  13. 13.

    Xie C, Han Y, Fu L, Li Q, Qiu X, Wang E. Overexpression of CARMA3 is associated with advanced tumor stage, cell cycle progression, and cisplatin resistance in human epithelial ovarian cancer. Tumour Biol. 2014;35:7957–64.

  14. 14.

    Ning S, Li X. Non-coding RNA resources. Adv Exp Med Biol. 2018;1094:1–7.

  15. 15.

    Di Mauro V, Barandalla-Sobrados M, Catalucci D. The noncoding-RNA landscape in cardiovascular health and disease. Noncoding RNA Res. 2018;3:12–9.

  16. 16.

    Li Y, Liang Y, Zhu Y, Zhang Y, Bei Y. Noncoding RNAs in cardiac hypertrophy. J Cardiovasc Transl Res. 2018;11:439–49.

  17. 17.

    Huang F, Yi J, Zhou T, Gong X, Jiang H, Yao X. Toward understanding non-coding rna roles in intracranial aneurysms and subarachnoid hemorrhage. Transl Neurosci. 2017;8:54–64.

  18. 18.

    Sun X, Malhotra A. Noncoding RNAs (ncRNA) in hepato cancer: a review. J Environ Pathol Toxicol Oncol. 2018;37:15–25.

  19. 19.

    Memczak S, Jens M, Elefsinioti A, Torti F, Krueger J, Rybak A, et al. Circular RNAs are a large class of animal RNAs with regulatory potency. Nature. 2013;495:333–8.

  20. 20.

    Gao JL, Chen G, He HQ, Wang J. CircRNA as a new field in human disease research. Zhongguo Zhong Yao Za Zhi. 2018;43:457–62.

  21. 21.

    Zhang Y, Liang W, Zhang P, Chen J, Qian H, Zhang X, et al. Circular RNAs: emerging cancer biomarkers and targets. J Exp Clin Cancer Res. 2017;36:152.

  22. 22.

    Qian L, Yu S, Chen Z, Meng Z, Huang S, Wang P. The emerging role of circRNAs and their clinical significance in human cancers. Biochim Biophys Acta. 2018;1870:247–60.

  23. 23.

    Zhao T, Miao Z, Wang Z, Xu Y, Wu J, Liu X, et al. CARMA3 overexpression accelerates cell proliferation and inhibits paclitaxel-induced apoptosis through NF-kappaB regulation in breast cancer cells. Tumour Biol. 2013;34:3041–7.

  24. 24.

    Li Z, Qu L, Dong Q, Huang B, Li H, Tang Z, et al. Overexpression of CARMA3 in non-small-cell lung cancer is linked for tumor progression. PLoS ONE 2012;7:e36903.

  25. 25.

    Wu GL, Yuan JL, Huang XD, Rong JF, Zhang LX, Liu YP, et al. Evaluating the expression of CARMA3 as a prognostic tumor marker in renal cell carcinoma. Tumour Biol. 2013;34:3431–5.

  26. 26.

    Miao Z, Zhao T, Wang Z, Xu Y, Song Y, Wu J, et al. CARMA3 is overexpressed in colon cancer and regulates NF-kappaB activity and cyclin D1 expression. Biochem Biophys Res Commun. 2012;425:781–87.

  27. 27.

    Jung HJ, Suh Y. Circulating miRNAs in ageing and ageing-related diseases. J Genet Genom. 2014;41:465–72.

  28. 28.

    Takasaki S. Roles of microRNAs in cancers and development. Methods Mol Biol. 2015;1218:375–413.

  29. 29.

    Danan M, Schwartz S, Edelheit S, Sorek R. Transcriptome-wide discovery of circular RNAs in Archaea. Nucleic Acids Res. 2012;40:3131–42.

  30. 30.

    Lukiw WJ. Circular RNA (circRNA) in Alzheimer’s dissease (AD). Front Genet. 2013;4:307.

  31. 31.

    Ashwal-Fluss R, Meyer M, Pamudurti NR, Ivanov A, Bartok O, Hanan M, et al. circRNA biogenesis competes with pre-mRNA splicing. Mol Cell. 2014;56:55–66.

  32. 32.

    Salzman J, Chen RE, Olsen MN, Wang PL, Brown PO. Cell-type specific features of circular RNA expression. PLoS Genet. 2013;9:e1003777.

  33. 33.

    Jeck WR, Sorrentino JA, Wang K, Slevin MK, Burd CE, Liu J, et al. Circular RNAs are abundant, conserved, and associated with ALU repeats. RNA. 2013;19:141–57.

  34. 34.

    Zhang Y, Zhang XO, Chen T, Xiang JF, Yin QF, Xing YH, et al. Circular intronic long noncoding RNAs. Mol Cell. 2013;51:792–806.

  35. 35.

    Taulli R, Loretelli C, Pandolfi PP. From pseudo-ceRNAs to circ-ceRNAs: a tale of cross-talk and competition. Nat Struct Mol Biol. 2013;20:541–43.

  36. 36.

    Li Z, Huang C, Bao C, Chen L, Lin M, Wang X, et al. Exon-intron circular RNAs regulate transcription in the nucleus. Nat Struct Mol Biol. 2015;22:256–64.

  37. 37.

    Han Z, Zhang Y, Sun Y, Chen J, Chang C, Wang X, et al. ERbeta-mediated alteration of circATP2B1 and miR-204-3p signaling promotes invasion of clear cell renal cell carcinoma. Cancer Res. 2018;78:2550–63.

  38. 38.

    Chen Z, Duan X. hsa_circ_0000177-miR-638-FZD7-Wnt signaling cascade contributes to the malignant behaviors in glioma. DNA Cell Biol. 2018;37:791–97.

  39. 39.

    Li F, Ma K, Sun M, Shi S. Identification of the tumor-suppressive function of circular RNA ITCH in glioma cells through sponging miR-214 and promoting linear ITCH expression. Am J Transl Res. 2018;10:1373–86.

  40. 40.

    Fang G, Ye BL, Hu BR, Ruan XJ, Shi YX. CircRNA_100290 promotes colorectal cancer progression through miR-516b-induced downregulation of FZD4 expression and Wnt/beta-catenin signaling. Biochem Biophys Res Commun. 2018;504:184–9.

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Acknowledgements

This work was supported by National Natural Science Fund [Grant No. 81672525], the Project of Liaoning Distinguished Professor (Grant No. [2012]145), Liaoning Natural Science Fund [Grant No. 201602830], Shenyang Plan Project of Science and Technology (Grant No. F17-230-9-08) and Shenyang Clinical Medicine Research Center (Grant No. [2017]76), and China Medical University’s 2017 discipline promotion programme (Grant No. 2017XK08) and China Medical University’s 2018 discipline promotion programme. Funding agency did not participate in the design of the study and collection, analysis and interpretation of data, and in writing the manuscript.

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  1. Department of Urology, The First Hospital of China Medical University, Shenyang, Liaoning, 110001, China

    • Xiaotong Zhang
    • , Xi Liu
    • , Zhifei Jing
    • , Jianbin Bi
    • , Zeliang Li
    • , Xiankui Liu
    • , Jun Li
    • , Zhenhua Li
    • , Zhe Zhang
    •  & Chuize Kong

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The authors declare that they have no conflict of interest.

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Correspondence to Zhenhua Li or Zhe Zhang or Chuize Kong.

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DOI

https://doi.org/10.1038/s41417-019-0085-y