Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2020, 164(2):196-202 | DOI: 10.5507/bp.2019.031

Downregulation of CIP2A inhibits cancer cell proliferation and vascularization in renal clear cell carcinoma

Hui Gao, Yuqiao Li, Tao Lin, Yan Cheng, Yunbo Ma
Department of Urology, Liaocheng People's Hospital, Liaocheng City, Shandong Province, P. R. China, 252000

Background: CIP2A has been proved to play a role as an oncogene in various types of malignancies while its functionality in renal clear cell carcinoma has not been investigated. Our study aimed to investigate the role of CIP2A in renal clear cell carcinoma and to explore the possible mechanisms.

Methods: A total of 80 patients with renal clear cell carcinoma and 32 healthy people were included in the study. Expression of CIP2A was detected by qRT-PCR. CIP2A silencing renal clear cell carcinoma cell line was established. Its effects on cell proliferation and migration were verified by CCK-8 assay and Transwell cell assay, respectively. The effects of CIP2A overexpression on AKT and VEGF were investigated.

Results: CIP2A expression level was increased in tumor tissues compared to adjacent healthy tissues. Serum levels of CIP2A protein were higher in cancer patients than in healthy controls, and serum levels of CIP2A protein were increased with increased stage of primary tumor. Serum CIP2A protein can be used to accurately predict renal clear cell carcinoma and its prognosis. CIP2A siRNA silencing inhibited tumor cell proliferation, and treatment with Akt activator reduced this inhibitory effect. CIP2A siRNA silencing decreased the expression level of VEGF and phosphorylation levels of AKT in renal clear cell carcinoma cells, while AKT activator treatment showed no significant effects on CIP2A expression.

Conclusion: Downregulation of CIP2A can inhibit cancer cell proliferation and vascularization in renal clear cell carcinoma through inactivation of the Akt pathway and its downstream VEGF.

Keywords: renal clear cell carcinoma, CIP2A, AKT, VEGF

Received: October 30, 2018; Revised: June 26, 2019; Accepted: June 26, 2019; Prepublished online: August 21, 2019; Published: June 18, 2020  Show citation

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Gao, H., Li, Y., Lin, T., Cheng, Y., & Ma, Y. (2020). Downregulation of CIP2A inhibits cancer cell proliferation and vascularization in renal clear cell carcinoma. Biomedical papers, 164(2), 196-202. doi: 10.5507/bp.2019.031
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    References

    1. Muglia VF, Prando A. Renal cell carcinoma: histological classification and correlation with imaging findings. Radiol Bras 2015;48(3):166-74. Go to original source... Go to PubMed...
    2. Hsieh JJ, Purdue MP, Signoretti S, Swanton C, Albiges L, Schmidinger M, Heng DY, Larkin J, Ficarra V. Renal cell carcinoma. Nat Rev Dis Primers 2017;3:17009. Go to original source... Go to PubMed...
    3. Rini BI, Campbell SC, Escudier B. Renal cell carcinoma. Lancet 2009;373(9669):1119-32. Go to original source... Go to PubMed...
    4. Randall JM, Millard F, Kurzrock R. Molecular aberrations, targeted therapy, and renal cell carcinoma: current state-of-the-art. Cancer and Metastasis Rev 2014;33(4):1109-24. Go to original source... Go to PubMed...
    5. Sato Y, Yoshizato T, Shiraishi Y, Maekawa S, Okuno Y, Kamura T, Shimamura T, Sato-Otsubo A, Nagae G, Suzuki H, Nagata Y, Yoshida K, Kon A, Suzuki Y, Chiba K, Tanaka H, Niida A, Fujimoto A, Tsunoda T, Morikawa T, Maeda D, Kume H, Sugano S, Fukayama M, Aburatani H, Sanada M, Miyano S, Homma Y, Ogawa S. Integrated molecular analysis of clear-cell renal cell carcinoma. Nat Genet 2013;45(8):860-7. Go to original source... Go to PubMed...
    6. Duns G, van den Berg E, van Duivenbode I, Osinga J, Hollema H, Hofstra RM, Kok K. Histone methyltransferase gene SETD2 is a novel tumor suppressor gene in clear cell renal cell carcinoma. Cancer Res 2010;0008-5472. CAN-10-0120. Go to original source... Go to PubMed...
    7. Gossage L, Murtaza M, Slatter AF, Lichtenstein CP, Warren A, Haynes B, Marass F, Roberts I, Shanahan SJ, Claas A, Dunham A, May AP, Rosenfeld N, Forshew T, Eisen T. Clinical and pathological impact of VHL, PBRM1, BAP1, SETD2, KDM6A, and JARID1c in clear cell renal cell carcinoma. Genes Chromosomes Cancer 2014;53(1):38-51. Go to original source... Go to PubMed...
    8. Liu H, Qiu H, Song Y, Liu Y, Wang H, Lu M, Deng M, Gu Y, Yin J, Luo K, Zhang Z, Jia X, Zheng G, He Z. Cip2a promotes cell cycle progression in triple-negative breast cancer cells by regulating the expression and nuclear export of p27Kip1. Oncogene 2017;36(14):1952. Go to original source... Go to PubMed...
    9. Dong QZ, Wang Y, Dong XJ, Li ZX, Tang ZP, Cui QZ, Wang EH. CIP2A is overexpressed in non-small cell lung cancer and correlates with poor prognosis. Ann Surg Oncol 2011;18(3):857-65. Go to original source... Go to PubMed...
    10. Li W, Ge Z, Liu C, Liu Z, Bjorkholm M, Jia J, Xu D. CIP2A is overexpressed in gastric cancer and its depletion leads to impaired clonogenicity, senescence, or differentiation of tumor cells. Clin Cancer Res 2008;14(12):3722-8. Go to original source... Go to PubMed...
    11. Ren J, Li W, Yan L, Jiao W, Tian S, Li D, Tang Y, Gu G, Liu H, Xu Z. Expression of CIP2A in renal cell carcinomas correlates with tumour invasion, metastasis and patients' survival. Br J Cancer 2011;105(12):1905. Go to original source... Go to PubMed...
    12. Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S, Grunwald V, Thompson JA, Figlin RA, Hollaender N, Urbanowitz G, Berg WJ, Kay A, Lebwohl D, Ravaud A, RECORD-1 Study Group. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet 2008;372(9637):449-56. Go to original source... Go to PubMed...
    13. Hori SS, Gambhir SS. Mathematical model identifies blood biomarker-based early cancer detection strategies and limitations. Sci Transl Med 2011;3(109):109ra116. Go to original source... Go to PubMed...
    14. Li X, Liu R, Yang J, Sun L, Zhang L, Jiang Z, Puri P, Gurley EC, Lai G, Tang Y, Huang Z, Pandak WM, Hylemon PB, Zhou H. The role of long noncoding RNA H19 in gender disparity of cholestatic liver injury in multidrug resistance 2 gene knockout mice. Hepatology 2017;66(3):869-84. Go to original source... Go to PubMed...
    15. Bianchessi V, Badi I, Bertolotti M, Nigro P, D'Alessandra Y, Capogrossi MC, Zanobini M, Pompilio G, Raucci A, Lauri A. The mitochondrial lncRNA ASncmtRNA-2 is induced in aging and replicative senescence in Endothelial Cells. J Mol Cell Cardiol 2015;81:62-70. Go to original source... Go to PubMed...
    16. Lu L, Xu H, Luo F, Liu X, Lu X, Yang Q, Xue J, Chen C, Shi L, Liu Q. Epigenetic silencing of miR-218 by the lncRNA CCAT1, acting via BMI1, promotes an altered cell cycle transition in the malignant transformation of HBE cells induced by cigarette smoke extract. Toxicol Appl Pharmacol 2016;304:30-41. Go to original source...
    17. Soares do Amaral N, Cruz e Melo N, de Melo Maia B, Malagoli Rocha R. Noncoding RNA profiles in tobacco-and alcohol-associated diseases. Genes 2016;8(1):6. Go to original source... Go to PubMed...
    18. Lei N, Peng B, ZhANG JY. CIP2A regulates cell proliferation via the AKT signaling pathway in human lung cancer. Oncol Rep 2014;32(4):1689-94. Go to original source... Go to PubMed...
    19. Chen KF, Liu CY, Lin YC, Yu HC, Liu TH, Hou DR, Chen PJ, Cheng AL. CIP2A mediates effects of bortezomib on phospho-Akt and apoptosis in hepatocellular carcinoma cells. Oncogene 2010;29(47):6257. Go to original source... Go to PubMed...
    20. Lin YC, Chen KC, Chen CC, Cheng AL, Chen KF. CIP2A-mediated Akt activation plays a role in bortezomib-induced apoptosis in head and neck squamous cell carcinoma cells. Oral Oncol 2012;48(7):585-93. Go to original source... Go to PubMed...
    21. Huang Y, Mao Y, Li H, Shen G, Nan G. Knockdown of Nrf2 inhibits angiogenesis by downregulating VEGF expression through PI3K/Akt signaling pathway in cerebral microvascular endothelial cells under hypoxic conditions. Biochem Cell Biol 2018;96(4):475-82. doi: 10.1139/bcb-2017-0291 Go to original source... Go to PubMed...
    22. Grun D, Adhikary G, Eckert RL. VEGF-A acts via neuropilin-1 to enhance epidermal cancer stem cell survival and formation of aggressive and highly vascularized tumors. Oncogene 2016; 35(33):4379. Go to original source... Go to PubMed...
    23. Gao F, Xu T, Wang X, Zhong S, Chen S, Zhang M, Zhang X, Shen Y, Wang X, Xu C, Shen Z. CIP2A mediates fibronectin-induced bladder cancer cell proliferation by stabilizing β-catenin. J Exp Clin Cancer Res 2017;36(1):70. Go to original source... Go to PubMed...

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