Ubiquitin specific peptidase 19 is a prognostic biomarker and affect the proliferation and migration of clear cell renal cell carcinoma

Hu,Wenbing; Su,Yanfang; Fei,Xinxiong; Wang,Xudong; Zhang,Guanglin; Su,Chunyan; Du,Tianxing; Yang,Tao; Wang,Gangsheng; Tang,Ze; Zhang,Jierong

doi:10.3892/or.2020.7565

Ubiquitin specific peptidase 19 is a prognostic biomarker and affect the proliferation and migration of clear cell renal cell carcinoma

Authors:
- Wenbing Hu
- Yanfang Su
- Xinxiong Fei
- Xudong Wang
- Guanglin Zhang
- Chunyan Su
- Tianxing Du
- Tao Yang
- Gangsheng Wang
- Ze Tang
- Jierong Zhang
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Affiliations: Department of Oncology, Huangshi Central Hospital of Edong Healthcare, Affiliated Hospital of Hubei Polytechnic University, Huangshi, Hubei 435000, P.R. China, Medical Science Research Center, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430000, P.R. China
Published online on: March 26, 2020 https://doi.org/10.3892/or.2020.7565
Pages: 1964-1974
Copyright: © Hu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Ubiquitin specific peptidase 19 (USP19) is a member of the USP family and exhibits diverse roles in various biological processes, such as cell differentiation, cell cycle progression and apoptosis. There is limited knowledge regarding the role and impact of USP19 in cancer, particularly clear cell renal cell carcinoma (ccRCC). To examine the function of USP19 in ccRCC, The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus databases were examined to determine USP19 mRNA expression levels. USP19 mRNA levels were significantly lower in ccRCC tissues than in normal tissues. USP19 downregulation was associated with ccRCC progression and poor prognostic outcomes in TCGA cohort. Furthermore, the functional involvement of USP19 in ccRCC was examined using Cell Counting Kit‑8, soft agar, Transwell and wound healing assays in vitro following overexpression or knockdown of USP19 in the Caki‑1 cell line. USP19 overexpression inhibited ccRCC proliferation and migration, whereas USP19 knockdown promoted ccRCC proliferation and migration in vitro. Consistent with these results, it was further demonstrated that USP19 downregulation promoted tumor growth in vivo in a xenograft model. Mechanistically, it was found that USP19 exerted its inhibitory effect on ccRCC proliferation and migration by suppressing the activation of ERK. Collectively, the present findings identified a role for USP19 as a tumor suppressor in ccRCC and demonstrated that USP19 is a potential prognostic biomarker that could be applied in ccRCC therapy.

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1	Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA and Jemal A: Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 68:394–424. 2018. View Article : Google Scholar
2	Rini BI, Campbell SC and Escudier B: Renal cell carcinoma. Lancet. 373:1119–1132. 2009. View Article : Google Scholar
3	Delahunt B, Bethwaite PB and Nacey JN: Outcome prediction for renal cell carcinoma: Evaluation of prognostic factors for tumors divided according to histological subtype. Pathology. 39:459–465. 2007. View Article : Google Scholar
4	Lin YF, Chou JL, Chang JS, Chiu IJ, Chiu HW and Lin YF: Dysregulation of the miR-25-IMPA2 axis promotes metastatic progression in clear cell renal cell carcinoma. EBioMedicine. 45:220–230. 2019. View Article : Google Scholar :
5	Afriansyah A, Hamid AR, Mochtar CA and Umbas R: Targeted therapy for metastatic renal cell carcinoma. Acta Med Indones. 48:335–347. 2016.
6	Husnjak K and Dikic I: Ubiquitin-binding proteins: Decoders of ubiquitin-mediated cellular functions. Annu Rev Biochem. 81:291–322. 2012. View Article : Google Scholar
7	Harada K, Kato M and Nakamura N: USP19-mediated deubiquitination facilitates the stabilization of HRD1 ubiquitin ligase. Int J Mol Sci. 17(pii): E18292016. View Article : Google Scholar
8	Fraile JM, Quesada V, Rodríguez D, Freije JM and López-Otín C: Deubiquitinases in cancer: New functions and therapeutic options. Oncogene. 31:2373–2388. 2012. View Article : Google Scholar
9	Hu M, Li P, Li M, Li W, Yao T, Wu JW, Gu W, Cohen RE and Shi Y: Crystal structure of a UBP-family deubiquitinating enzyme in isolation and in complex with ubiquitin aldehyde. Cell. 111:1041–1054. 2002. View Article : Google Scholar
10	Hassink GC, Zhao B, Sompallae R, Altun M, Gastaldello S, Zinin NV, Masucci MG and Lindsten K: The ER-resident ubiquitin-specific protease 19 participates in the UPR and rescues ERAD substrates. EMBO Rep. 10:755–761. 2009. View Article : Google Scholar :
11	Jin S, Tian S, Chen Y, Zhang C, Xie W, Xia X, Cui J and Wang RF: USP19 modulates autophagy and antiviral immune responses by deubiquitinating Beclin-1. EMBO J. 35:866–880. 2016. View Article : Google Scholar :
12	Gierisch ME, Pedot G, Walser F, Lopez-Garcia LA, Jaaks P, Niggli FK and Schäfer BW: USP19 deubiquitinates EWS-FLI1 to regulate Ewing sarcoma growth. Sci Rep. 9:9512019. View Article : Google Scholar :
13	Shahriyari L, Abdel-Rahman M and Cebulla C: BAP1 expression is prognostic in breast and uveal melanoma but not colon cancer and is highly positively correlated with RBM15B and USP19. PLoS One. 14:e02115072019. View Article : Google Scholar :
14	Eikrem O, Beisland C, Hjelle K, Flatberg A, Scherer A, Landolt L, Skogstrand T, Leh S, Beisvag V and Marti HP: Transcriptome sequencing (RNAseq) enables utilization of Formalin-fixed, paraffin-embedded biopsies with clear cell renal cell carcinoma for exploration of disease biology and biomarker development. PLoS One. 11:e01497432016. View Article : Google Scholar :
15	Yao X, Tan J, Lim KJ, Koh J, Ooi WF, Li Z, Huang D, Xing M, Chan YS, Qu JZ, et al: VHL deficiency drives enhancer activation of oncogenes in clear cell renal cell carcinoma. Cancer Discov. 7:1284–1305. 2017. View Article : Google Scholar
16	R Core Team: R: A language and environment for statistical computing. R Foundation for Statistical Computing; Vienna: 2104
17	Love MI, Huber W and Anders S: Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 15:5502014. View Article : Google Scholar :
18	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar
19	National Research Council (US) Committee for the Update of the Guide for the Care and Use of Laboratory Animals, . Guide for the Care and Use of Laboratory Animals, 8th edition. National Academies Press (US); Washington, DC: 2011
20	Macè A, Kutalik Z and Valsesia A: Copy number variation. Methods Mol Biol. 1793:231–258. 2018. View Article : Google Scholar
21	Zińczuk J, Zaręba K, Guzińska-Ustymowicz K1, Kędra B Kemona A and Pryczynicz A: Expression of chosen cell cycle and proliferation markers in pancreatic intraepithelial neoplasia. Prz Gastroenterol. 13:118–126. 2018.
22	Sarsik B, Doganavsargil B, Simsir A, Yazici A, Pehlivanoglu B, Cal C and Sen S: P21 and p27 immunoexpression in upper urinary tract urothelial carcinomas. Pathol Oncol Res. 22:839–845. 2016. View Article : Google Scholar
23	Egeblad M and Werb Z: New functions for the matrix metalloproteinases in cancer progression. Nat Rev Cancer. 2:161–174. 2002. View Article : Google Scholar
24	Björklund M and Koivunen E: Gelatinase-mediated migration and invasion of cancer cells. Biochim Biophys Acta. 1755:37–69. 2005.
25	Wang D, Wang D, Wang N, Long Z and Ren X: Long Non-coding RNA BANCR promotes endometrial cancer cell proliferation and invasion by regulating MMP2 and MMP1 via ERK/MAPK signaling pathway. Cell Physiol Biochem. 40:644–656. 2016. View Article : Google Scholar
26	Tian XQ, Guo FF, Sun DF, Wang YC, Yang L, Chen SL, Hong J and Fang JY: Downregulation of ZNF278 arrests the cell cycle and decreases the proliferation of colorectal cancer cells via inhibition of the ERK/MAPK pathway. Oncol Rep. 38:3685–3692. 2017.
27	He W, Ju D, Jie Z, Zhang A, Xing X and Yang Q: Aberrant CpG-methylation affects genes expression predicting survival in lung adenocarcinoma. Cancer Med. 7:5716–5726. 2018. View Article : Google Scholar :
28	Schuijers J, Manteiga JC, Weintraub AS, Day DS, Zamudio AV, Hnisz D, Lee TI and Young RA: Transcriptional dysregulation of MYC reveals common enhancer-docking mechanism. Cell Rep. 23:349–360. 2018. View Article : Google Scholar :
29	Gu X, Coates PJ, Boldrup L, Wang L, Krejci A, Hupp T, Fahraeus R, Norberg-Spaak L, Sgaramella N, Wilms T and Nylander K: Copy number variation: A prognostic marker for young patients with squamous cell carcinoma of the oral tongue. J Oral Pathol Med. 48:24–30. 2019. View Article : Google Scholar
30	Wee Y, Wang T, Liu Y, Li X and Zhao M: A pan-cancer study of copy number gain and up-regulation in human oncogenes. Life Sci. 211:206–214. 2018. View Article : Google Scholar
31	Wang L, Zhao H, Xu Y, Li J, Deng C, Deng Y, Bai J, Li X, Xiao Y and Zhang Y: Systematic identification of lincRNA-based prognostic biomarkers by integrating lincRNA expression and copy number variation in lung adenocarcinoma. Int J Cancer. 144:1723–1734. 2019. View Article : Google Scholar
32	Duan X, Jiang B, Yang J, Zhou L, Tian B and Mao X: FOXP3 inhibits MYC expression via regulating miR-198 and influences cell viability, proliferation and cell apoptosis in HepG2. Cancer Med. 7:6182–6192. 2018. View Article : Google Scholar :
33	He J, Yu L, Wang CM and Zhou XF: MiR-1275 promotes non-small cell lung cancer cell proliferation and metastasis by regulating LZTS3 expression. Eur Rev Med Pharmacol Sci. 22:2680–2687. 2018.
34	Chen Y, Zhang L, Liu L, Sun S, Zhao X, Wang Y, Zhang Y, Du J and Gu L: Rasip1 is a RUNX1 target gene and promotes migration of NSCLC cells. Cancer Manag Res. 10:4537–4552. 2018. View Article : Google Scholar :
35	Wang Y, Zheng C, Li T, Zhang R, Wang Y, Zhang J, He Q, Sun Z and Wang X: Long noncoding RNA Z38 promotes cell proliferation and metastasis and inhibits cell apoptosis in human gastric cancer. Oncol Lett. 16:6051–6058. 2018.
36	Lu Y, Bedard N, Chevalier S and Wing SS: Identification of distinctive patterns of USP19-mediated growth regulation in normal and malignant cells. PLoS One. 6:e159362011. View Article : Google Scholar :
37	Bao H, Guo CG, Qiu PC, Zhang XL, Dong Q and Wang YK: Long non-coding RNA Igf2as controls hepatocellular carcinoma progression through the ERK/MAPK signaling pathway. Oncol Lett. 14:2831–2837. 2017. View Article : Google Scholar :
38	Li B, Liu YH, Sun AG, Huan LC, Li HD and Liu DM: MiR-130b functions as a tumor promoter in glioma via regulation of ERK/MAPK pathway. Eur Rev Med Pharmacol Sci. 21:2840–2846. 2017.
39	Wu M, Tu HQ, Chang Y, Tan B, Wang G, Zhou J, Wang L, Mu R and Zhang WN: USP19 deubiquitinates HDAC1/2 to regulate DNA damage repair and control chromosomal stability. Oncotarget. 8:2197–2208. 2017.
40	Liu Q, Zhao S, Su PF and Yu S: Gene and isoform expression signatures associated with tumor stage in kidney renal clear cell carcinoma. BMC Syst Biol. 7 (Suppl 5):S72013. View Article : Google Scholar