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Cancer Cell International
Published in: Cancer Cell International 1/2021

Open Access 01-12-2021 | Primary research

miR-190 promotes malignant transformation and progression of human urothelial cells through CDKN1B/p27 inhibition

Authors: Shirui Huang, Xiaohui Hua, Mengjiao Kuang, Junlan Zhu, Haiqi Mu, Zhongxian Tian, Xiaoqun Zheng, Qipeng Xie

Published in: Cancer Cell International | Issue 1/2021

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Abstract

Background

Although miR-190 has been reported to be related to human diseases, especially in the development and progression of cancer, its expression in human bladder cancer (BC) and potential contribution to BC remain unexplored.

Methods

RT-qPCR was used to verify the expression level of miR-190 and CDKN1B. Flow cytometry (FCM) assays were performed to detect cell cycle. Soft agar assay was used to measure anchorage-independent growth ability. Methylation-Specific PCR, Dual-luciferase reporter assay and Western blotting were used to elucidate the potential mechanisms involved.

Results

Our studies revealed that downregulation of the p27 (encoded by CDKN1B gene) protein is an important event related to miR-190, promoting the malignant transformation of bladder epithelial cells. miR-190 binds directly to CDKN1B 3’-UTR and destabilizes CDKN1B mRNA. Moreover, miR-190 downregulates TET1 by binding to the TET1 CDS region, which mediates hypermethylation of the CDKN1B promoter, thereby resulting in the downregulation of CDKN1B mRNA. These two aspects led to miR-190 inhibition of p27 protein expression in human BC cells. A more in-depth mechanistic study showed that c-Jun promotes the transcription of Talin2, the host gene of miR-190, thus upregulating the expression of miR-190 in human BC cells.

Conclusions

In this study, we found that miR-190 plays an important role in the development of BC. Taken together, these findings indicate that miR-190 may promote the malignant transformation of human urothelial cells by downregulating CDKN1B, which strengthens our understanding of miR-190 in regulating BC cell transformation.
Literature
1.
2.
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(6):394–424.CrossRefPubMed
3.
Sjödahl G, Lauss M, Lövgren K, Chebil G, Gudjonsson S, Veerla S, Patschan O, Aine M, Fernö M. Ringnér MJ. A molecular taxonomy for urothelial carcinoma. 2012.
4.
Damrauer JS, Hoadley KA, Chism DD, Fan C, Tiganelli CJ, Wobker SE, Yeh JJ, Milowsky MI, Iyer G, Parker JS, et al. Intrinsic subtypes of high-grade bladder cancer reflect the hallmarks of breast cancer biology. Proc Natl Acad Sci USA. 2014;111(8):3110–5.PubMedCrossRefPubMedCentral
5.
Matarazzo S, Melocchi L, Rezzola S, Grillo E, Maccarinelli F, Giacomini A, Turati M, Taranto S, Zammataro L, Cerasuolo M, et al: Long Pentraxin-3 Follows and Modulates Bladder Cancer Progression. Cancers. 2019;11:9.
6.
Choi W, Czerniak B, Ochoa A, Su X, Siefker-Radtke A, Dinney C, McConkey DJ. Intrinsic basal and luminal subtypes of muscle-invasive bladder cancer. Nat Rev Urol. 2014;11(7):400–10.PubMedCrossRef
7.
Acharya A, Berry DC, Zhang H, Jiang Y, Jones BT, Hammer RE, Graff JM, Mendell JT. miR-26 suppresses adipocyte progenitor differentiation and fat production by targeting Fbxl19. Genes Dev. 2019;33(19–20):1367–1380.
8.
Mukohyama J, Isobe T, Hu Q, Hayashi T, Watanabe T, Maeda M, Yanagi H, Qian X, Yamashita K, Minami H, et al. miR-221 targets QKI to enhance the tumorigenic capacity of human colorectal cancer stem cells. Cancer Res. 2019;79(20):5151–8.PubMedPubMedCentralCrossRef
9.
Yu Y, Yin W, Yu ZH, Zhou YJ, Chi JR, Ge J, Cao XC. miR-190 enhances endocrine therapy sensitivity by regulating SOX9 expression in breast cancer. J Exp Clin Cancer Res. 2019;38(1):22.PubMedPubMedCentralCrossRef
10.
Beezhold K, Liu J, Kan H, Meighan T, Castranova V, Shi X, Chen F. miR-190-mediated downregulation of PHLPP contributes to arsenic-induced Akt activation and carcinogenesis. Toxicol Sci. 2011;123(2):411–20.PubMedPubMedCentralCrossRef
11.
Yu Y, Zhang D, Huang H, Li J, Zhang M, Wan Y, Gao J, Huang C. NF-κB1 p50 promotes p53 protein translation through miR-190 downregulation of PHLPP1. Oncogene. 2014;33(8):996–1005.PubMedCrossRef
12.
Xiong Y, Wu S, Yu H, Wu J, Wang Y, Li H, Huang H, Zhang H. miR-190 promotes HCC proliferation and metastasis by targeting PHLPP1. Exp Cell Res. 2018;371(1):185–95.PubMedCrossRef
13.
Yu Y, Luo W, Yang ZJ, Chi JR, Li YR, Ding Y, Ge J, Wang X, Cao XC. miR-190 suppresses breast cancer metastasis by regulation of TGF-beta-induced epithelial-mesenchymal transition. Mol Cancer. 2018;17(1):70.PubMedPubMedCentralCrossRef
14.
Jia WZ, Yu T, An Q, Yang H, Zhang Z, Liu X, Xiao G. MicroRNA-190 regulates FOXP2 genes in human gastric cancer. Onco Targets Ther. 2016;9:3643–51.PubMedPubMedCentral
15.
Jia D, Li S, Li D, Xue H, Yang D, Liu Y. Mining TCGA database for genes of prognostic value in glioblastoma microenvironment. Aging. 2018;10(4):592–605.PubMedPubMedCentralCrossRef
16.
Polyak K, Lee MH, Erdjument-Bromage H, Koff A, Roberts JM, Tempst P, Massagué J. Cloning of p27Kip1, a cyclin-dependent kinase inhibitor and a potential mediator of extracellular antimitogenic signals. Cell. 1994;78(1):59–66.PubMedCrossRef
17.
Wong N, Wang X. miRDB: an online resource for microRNA target prediction and functional annotations. Nucleic Acids Res. 2015;43(Database issue):D146–52.PubMedCrossRef
18.
Agarwal V, Bell GW, Nam JW, Bartel DP. Predicting effective microRNA target sites in mammalian mRNAs. Elife. 2015;4:78.
19.
Jin H, Sun W, Zhang Y, Yan H, Liufu H, Wang S, Chen C, Gu J, Hua X, Zhou L. MicroRNA-411 downregulation enhances tumor growth by upregulating MLLT11 expression in human bladder cancer. Mol Ther Nucleic Acids. 2018;11:312–22.PubMedPubMedCentralCrossRef
20.
Yan H, Ren S, Lin Q, Yu Y, Chen C, Hua X, Jin H, Lu Y, Zhang H, Xie Q. Inhibition of UBE2N-dependent CDK6 protein degradation by miR-934 promotes human bladder cancer cell growth. FASEB J. 2019;33(11):12112–23.PubMedCrossRef
21.
Xie Q, Chen C, Li H, Xu J, Wu L, Yu Y, Ren S, Li H, Hua X, Yan H. miR-3687 overexpression promotes bladder cancer cell growth by inhibiting the negative effect of FOXP1 on cyclin E2 transcription. Mol Ther. 2019;27(5):1028–38.PubMedPubMedCentralCrossRef
22.
Sun W, Li S, Yu Y, Jin H, Xie Q, Hua X, Wang S, Tian Z, Zhang H, Jiang G, et al. MicroRNA-3648 is upregulated to suppress TCF21, resulting in promotion of invasion and metastasis of human bladder cancer. Mol Ther Nucleic Acids. 2019;16:519–30.PubMedPubMedCentralCrossRef
23.
Zhu J, Tian Z, Li Y, Hua X, Zhang D, Li J, Jin H, Xu J, Chen W, Niu B, et al. ATG7 promotes bladder cancer invasion via autophagy-mediated increased ARHGDIB mRNA stability. Adv Sci (Weinh). 2019;6(8):1801927.CrossRef
24.
Xie Q, Guo X, Gu J, Zhang L, Jin H, Huang H, Li J, Huang C. p85alpha promotes nucleolin transcription and subsequently enhances EGFR mRNA stability and EGF-induced malignant cellular transformation. Oncotarget. 2016; 7(13):16636–16649.
25.
DiGiovanni J, Rho O, Xian W, Beltran L. Role of the epidermal growth factor receptor and transforming growth factor alpha in mouse skin carcinogenesis. Prog Clin Biol Res. 1994;387:113–38.PubMed
26.
Fabian MR, Sonenberg N, Filipowicz W. Regulation of mRNA translation and stability by microRNAs. Annu Rev Biochem. 2010;79:351–79.PubMedCrossRef
27.
28.
Li LC, Dahiya R. MethPrimer: designing primers for methylation PCRs. Bioinformatics. 2002;18(11):1427–31.PubMedCrossRef
29.
Shilatifard A. Chromatin modifications by methylation and ubiquitination: implications in the regulation of gene expression. Annu Rev Biochem. 2006;75:243–69.PubMedCrossRef
30.
Christman JK. 5-Azacytidine and 5-aza-2′-deoxycytidine as inhibitors of DNA methylation: mechanistic studies and their implications for cancer therapy. Oncogene. 2002;21(35):5483–95.PubMedCrossRef
31.
32.
Tahiliani M, Koh KP, Shen Y, Pastor WA, Bandukwala H, Brudno Y, Agarwal S, Iyer LM, Liu DR, Aravind L. Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science. 2009;324(5929):930–5.PubMedPubMedCentralCrossRef
33.
Lorsbach R, Moore J, Mathew S, Raimondi S, Mukatira S, Downing J. TET1, a member of a novel protein family, is fused to MLL in acute myeloid leukemia containing the t (10; 11)(q22; q23). Leukemia. 2003;17(3):637–641.
34.
Xu Y, Xu C, Kato A, Tempel W, Abreu JG, Bian C, Hu Y, Hu D, Zhao B, Cerovina T. Tet3 CXXC domain and dioxygenase activity cooperatively regulate key genes for Xenopus eye and neural development. Cell. 2012;151(6):1200–13.PubMedPubMedCentralCrossRef
35.
Griffiths-Jones S, Saini HK, van Dongen S, Enright AJ. miRBase: tools for microRNA genomics. Nucleic Acids Res. 2008;36(Database issue):D154–8.PubMed
36.
Cramer EM, Shao Y, Wang Y, Yuan Y. miR-190 is upregulated in Epstein–Barr Virus type I latency and modulates cellular mRNAs involved in cell survival and viral reactivation. Virology. 2014;464:184–95.PubMedCrossRef
37.
Liang J, Zubovitz J, Petrocelli T, Kotchetkov R, Connor MK, Han K, Lee JH, Ciarallo S, Catzavelos C, Beniston R, et al. PKB/Akt phosphorylates p27, impairs nuclear import of p27 and opposes p27-mediated G1 arrest. Nat Med. 2002;8(10):1153–60.PubMedCrossRef
38.
Yoon H, Kim M, Jang K, Shin M, Besser A, Xiao X, Zhao D, Wander SA, Briegel K, Morey L, et al. p27 transcriptionally coregulates cJun to drive programs of tumor progression. Proc Natl Acad Sci U S A. 2019;116(14):7005–14.PubMedPubMedCentralCrossRef
39.
Catzavelos C, Tsao M-S, DeBoer G, Bhattacharya N, Shepherd FA, Slingerland JM. Reduced expression of the cell cycle inhibitor p27Kip1 in non-small cell lung carcinoma: a prognostic factor independent of Ras. Can Res. 1999;59(3):684–8.
40.
Tamura N, Dong Y, Sui L, Tai Y, Sugimoto K, Nagahata S, Tokuda M. Cyclin-dependent kinase inhibitor p27 is related to cell proliferation and prognosis in laryngeal squamous cell carcinomas. The Journal of Laryngology Otology. 2001;115(5):400–6.PubMedCrossRef
41.
Ciaparrone M, Yamamoto H, Yao Y, Sgambato A, Cattoretti G, Tomita N, Monden T, Rotterdam H, Weinstein IB. Localization and expression of p27KIP1 in multistage colorectal carcinogenesis. Cancer research. 1998;58(1):114–22.PubMed
42.
Korkolopoulou P, Vassilopoulos I, Konstantinidou AE, Zorzos H, Patsouris E, Agapitos E, Davaris P. The combined evaluation of p27Kip1 and Ki-67 expression provides independent information on overall survival of ovarian carcinoma patients. Gynecol Oncol. 2002;85(3):404–14.PubMedCrossRef
43.
Yang W, Shen J, Wu M, Arsura M, FitzGerald M, Suldan Z, Kim DW, Hofmann CS, Pianetti S, Romieu-Mourez R, et al. Repression of transcription of the p27(Kip1) cyclin-dependent kinase inhibitor gene by c-Myc. Oncogene. 2001;20(14):1688–702.PubMedCrossRef
44.
Göpfert U, Kullmann M, Hengst L. Cell cycle-dependent translation of p27 involves a responsive element in its 5′-UTR that overlaps with a uORF. Human molecular genetics. 2003;12(14):1767–79.PubMedCrossRef
45.
Connor MK, Kotchetkov R, Cariou S, Resch A, Lupetti R, Beniston RG, Melchior F, Hengst L, Slingerland JM. CRM1/Ran-mediated nuclear export of p27Kip1 involves a nuclear export signal and links p27 export and proteolysis. Molecular biology of the cell. 2003;14(1):201–13.PubMedPubMedCentralCrossRef
46.
Nakayama KI, Nakayama K. Ubiquitin ligases: cell-cycle control and cancer. Nat Rev Cancer. 2006;6(5):369–81.PubMedCrossRef
47.
Santiago M, Antunes C, Guedes M, Iacovino M, Kyba M, Reik W, Sousa N, Pinto L, Branco MR, Marques CJ. Tet3 regulates cellular identity and DNA methylation in neural progenitor cells. Cell Mol Life Sci. 2020;77(14):2871–83.PubMedCrossRef
48.
Angel P, Karin M. The role of Jun, Fos and the AP-1 complex in cell-proliferation and transformation. Biochim Biophys Acta. 1991;1072(2–3):129–57.PubMed
49.
Schreiber M, Kolbus A, Piu F, Szabowski A, Mohle-Steinlein U, Tian J. Control of cell cycle progression by c-Jun is p53 dependent. Genes Dev. 1999;13(5):607–19.PubMedPubMedCentralCrossRef
50.
Chen SY, Cai C, Fisher CJ, Zheng Z, Omwancha J, Hsieh CL, Shemshedini L. c-Jun enhancement of androgen receptor transactivation is associated with prostate cancer cell proliferation. Oncogene. 2006;25(54):7212–23.PubMedCrossRef
Metadata
Title
miR-190 promotes malignant transformation and progression of human urothelial cells through CDKN1B/p27 inhibition
Authors
Shirui Huang
Xiaohui Hua
Mengjiao Kuang
Junlan Zhu
Haiqi Mu
Zhongxian Tian
Xiaoqun Zheng
Qipeng Xie
Publication date
01-12-2021
Publisher
BioMed Central
Published in
Cancer Cell International / Issue 1/2021
Electronic ISSN: 1475-2867
DOI
https://doi.org/10.1186/s12935-021-01937-5

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