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Journal of Experimental & Clinical Cancer Research
Published in: Journal of Experimental & Clinical Cancer Research 1/2019

Open Access 01-12-2019 | Research

USP13 functions as a tumor suppressor by blocking the NF-kB-mediated PTEN downregulation in human bladder cancer

Authors: Xiaojun Man, Chiyuan Piao, Xuyong Lin, Chuize Kong, Xiaolu Cui, Yuanjun Jiang

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2019

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Abstract

Background

USP13 has been reported to be involved in the tumorigenesis of human cancers, however, its functional role and regulatory mechanisms in bladder cancer (BC) remain unclear.

Methods

q-RT-PCR was performed to examine the expression of miR-130b-3p, miR-301b-3p and USP13 in BC tissue samples. Western blot, q-RT-PCR, bioinformatic analysis and dual-luciferase reporter assay were conducted to identify the regulatory function of miR-130b-3p/301b-3p for USP13. Co-immunoprecipitation assay was performed to assess the interaction between USP13 and PTEN protein. Cell-counting-kit 8, colony formation assay and transwell assay were performed to value the proliferative, migrative and invasive capacities of BC cells in vitro. Mouse xenograft model of BC cells was established to verify the function of USP13 in vivo. Immunohistochemistry was performed to identify the protein expression of USP13, NF-kB p65 or PTEN in clinical/xenograft tumor tissues.

Results

Our present study reveals that USP13 functions as a tumor suppressor by interacting with PTEN protein and increasing its expression in bladder cancer. We found that loss of USP13 led to the downregulation of PTEN and promoted proliferative, invasive and migrative capacities of bladder cancer cells. Furthermore, we discovered that USP13 was a common target of miR-130b-3p and miR-301b-3p, and the miR-130b/301b cluster, which could be transcriptionally upregulated by NF-kB. Our data demonstrated that NF-kB activation decreased expression level of USP13 and PTEN, and promoted the tumorigenesis phenotypes of BC cells. In addition, reintroduction of USP13 partially rescued PTEN expression as well as the oncogenesis trend caused by NF-kB.

Conclusion

We reported a potential regulatory loop that the NF-kB-induced miR-130b/301b overexpression decreased USP13 expression and subsequently resulted in the downregulation of PTEN protein and promoted tumorigenesis of bladder cancer. Moreover, NF-kB-mediated PTEN downregulation is very likely to facilitate the full activation of NF-kB.
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Literature
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(6):394–424.CrossRefPubMed
2.
Ferlay J, Colombet M, Soerjomataram I, et al. Cancer incidence and mortality patterns in Europe: estimates for 40 countries and 25 major cancers in 2018. Eur J Cancer. 2018;103:356–87.PubMed
3.
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(1):96–108.PubMed
4.
Wu XR. Urothelial tumorigenesis: a tale of divergent pathways. Nat Rev Cancer. 2005;5(9):713–25.PubMed
5.
Dinney CP, McConkey DJ, Millikan RE, et al. Focus on bladder cancer. Cancer Cell. 2004;6(2):111–6.PubMed
6.
Bellmunt J, Powles T, Vogelzang NJ. A review on the evolution of PD-1/PD-L1 immunotherapy for bladder cancer: the future is now. Cancer Treat Rev. 2017;54:58–67.PubMed
7.
Powles T, Eder JP, Fine GD, et al. MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer. Nature. 2014;515(7528):558–62.PubMed
8.
Chen DS, Irving BA, Hodi FS. Molecular pathways: next-generation immunotherapy--inhibiting programmed death-ligand 1 and programmed death-1. Clin Cancer Res. 2012;18(24):6580–7.PubMed
9.
Maehama T, Dixon JE. The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate. J Biol Chem. 1998;273(22):13375–8.PubMed
10.
Li J, Yen C, Liaw D, et al. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science. 1997;275(5308):1943–7.PubMed
11.
Steck PA, Pershouse MA, Jasser SA, et al. Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers. Nat Genet. 1997;15(4):356–62.PubMed
12.
Tsuruta H, Kishimoto H, Sasaki T, et al. Hyperplasia and carcinomas in Pten-deficient mice and reduced PTEN protein in human bladder cancer patients. Cancer Res. 2006;66(17):8389–96.PubMed
13.
Tanaka M, Koul D, Davies MA, Liebert M, Steck PA, Grossman HB. MMAC1/PTEN inhibits cell growth and induces chemosensitivity to doxorubicin in human bladder cancer cells. Oncogene. 2000;19(47):5406–12.PubMed
14.
Chaux A, Compérat E, Varinot J, et al. High levels of phosphatase and tensin homolog expression are associated with tumor progression, tumor recurrence, and systemic metastases in pT1 urothelial carcinoma of the bladder: a tissue microarray study of 156 patients treated by transurethral resection. Urology. 2013;81(1):116–22.PubMed
15.
Wang DS, Rieger-Christ K, Latini JM, et al. Molecular analysis of PTEN and MXI1 in primary bladder carcinoma. Int J Cancer. 2000;88(4):620–5.PubMed
16.
17.
Wang X, Jiang X. Post-translational regulation of PTEN. Oncogene. 2008;27(41):5454–63.PubMed
18.
Fata JE, Debnath S, Jenkins EC, Fournier MV. Nongenomic mechanisms of PTEN regulation. Int J Cell Biol. 2012;2012:379685.PubMedPubMedCentral
19.
Trotman LC, Wang X, Alimonti A, et al. Ubiquitination regulates PTEN nuclear import and tumor suppression. Cell. 2007;128(1):141–56.PubMedPubMedCentral
20.
Song MS, Salmena L, Carracedo A, et al. The deubiquitinylation and localization of PTEN are regulated by a HAUSP-PML network. Nature. 2008;455(7214):813–7.PubMedPubMedCentral
21.
Wilkinson KD. Regulation of ubiquitin-dependent processes by deubiquitinating enzymes. FASEB J. 1997;11(14):1245–56.PubMed
22.
Zhang J, Zhang P, Wei Y, et al. Deubiquitylation and stabilization of PTEN by USP13. Nat Cell Biol. 2013;15(12):1486–94.PubMedPubMedCentral
23.
Karin M, Lin A. NF-kappaB at the crossroads of life and death. Nat Immunol. 2002;3(3):221–7.PubMed
24.
Cui X, Kong C, Zhu Y, et al. miR-130b, an onco-miRNA in bladder cancer, is directly regulated by NF-κB and sustains NF-κB activation by decreasing Cylindromatosis expression. Oncotarget. 2016;7(30):48547–61.PubMedPubMedCentral
25.
Hamilton MP, Rajapakshe K, Hartig SM, et al. Identification of a pan-cancer oncogenic microRNA superfamily anchored by a central core seed motif. Nat Commun. 2013;4:2730.PubMed
26.
Grimson A, Farh KK, Johnston WK, Garrett-Engele P, Lim LP, Bartel DP. MicroRNA targeting specificity in mammals: determinants beyond seed pairing. Mol Cell. 2007;27(1):91–105.PubMedPubMedCentral
27.
Wang X. Improving microRNA target prediction by modeling with unambiguously identified microRNA-target pairs from CLIP-ligation studies. Bioinformatics. 2016;32(9):1316–22.PubMedPubMedCentral
28.
Kim S, Domon-Dell C, Kang J, Chung DH, Freund JN, Evers BM. Down-regulation of the tumor suppressor PTEN by the tumor necrosis factor-alpha/nuclear factor-kappaB (NF-kappaB)-inducing kinase/NF-kappaB pathway is linked to a default IkappaB-alpha autoregulatory loop. J Biol Chem. 2004;279(6):4285–91.PubMed
29.
Li JH, Liu S, Zhou H, Qu LH, Yang JH. starBase v2.0: decoding miRNA-ceRNA, miRNA-ncRNA and protein-RNA interaction networks from large-scale CLIP-Seq data. Nucleic Acids Res. 2014;42(Database issue):D92–7.PubMed
30.
Chandrashekar DS, Bashel B, SAH B, et al. UALCAN: a portal for facilitating tumor subgroup gene expression and survival analyses. Neoplasia. 2017;19(8):649–58.PubMedPubMedCentral
31.
Earl J, Rico D, Carrillo-de-Santa-Pau E, Rodríguez-Santiago B, Méndez-Pertuz M, Auer H, Gómez G, Grossman HB, Pisano DG, Schulz WA, et al. The UBC-40 urothelial bladder Cancer cell line index: a genomic resource for functional studies. BMC Genomics. 2015;16:403.PubMedPubMedCentral
32.
Myers MP, Stolarov JP, Eng C, et al. P-TEN, the tumor suppressor from human chromosome 10q23, is a dual-specificity phosphatase. Proc Natl Acad Sci U S A. 1997;94(17):9052–7.PubMedPubMedCentral
33.
Liu J, Xia H, Kim M, et al. Beclin1 controls the levels of p53 by regulating the deubiquitination activity of USP10 and USP13. Cell. 2011;147(1):223–34.PubMedPubMedCentral
34.
Zhao X, Fiske B, Kawakami A, Li J, Fisher DE. Regulation of MITF stability by the USP13 deubiquitinase. Nat Commun. 2011;2:414.PubMed
35.
36.
Li Y, Luo K, Yin Y, et al. USP13 regulates the RAP80-BRCA1 complex dependent DNA damage response. Nat Commun. 2017;8:15752.PubMedPubMedCentral
37.
Vasudevan KM, Gurumurthy S, Rangnekar VM. Suppression of PTEN expression by NF-kappa B prevents apoptosis. Mol Cell Biol. 2004;24(3):1007–21.PubMedPubMedCentral
38.
Peng H, Chen Y, Gong P, et al. Higher methylation intensity induced by EBV LMP1 via NF-κB/DNMT3b signaling contributes to silencing of PTEN gene. Oncotarget. 2016;7(26):40025–37.PubMedPubMedCentral
39.
Oliva-González C, Uresti-Rivera EE, Galicia-Cruz OG, Jasso-Robles FI, Gandolfi AJ, Escudero-Lourdes C. The tumor suppressor phosphatase and tensin homolog protein (PTEN) is negatively regulated by NF-κb p50 homodimers and involves histone 3 methylation/deacetylation in UROtsa cells chronically exposed to monomethylarsonous acid. Toxicol Lett. 2017;280:92–8.PubMed
40.
Mayo MW, Madrid LV, Westerheide SD, et al. PTEN blocks tumor necrosis factor-induced NF-kappa B-dependent transcription by inhibiting the transactivation potential of the p65 subunit. J Biol Chem. 2002;277(13):11116–25.PubMed
41.
Koul D, Yao Y, Abbruzzese JL, Yung WK, Reddy SA. Tumor suppressor MMAC/PTEN inhibits cytokine-induced NFkappaB activation without interfering with the IkappaB degradation pathway. J Biol Chem. 2001;276(14):11402–8.PubMed
42.
Gustin JA, Maehama T, Dixon JE, Donner DB. The PTEN tumor suppressor protein inhibits tumor necrosis factor-induced nuclear factor kappa B activity. J Biol Chem. 2001;276(29):27740–4.PubMed
Metadata
Title
USP13 functions as a tumor suppressor by blocking the NF-kB-mediated PTEN downregulation in human bladder cancer
Authors
Xiaojun Man
Chiyuan Piao
Xuyong Lin
Chuize Kong
Xiaolu Cui
Yuanjun Jiang
Publication date
01-12-2019
Publisher
BioMed Central
Published in
Journal of Experimental & Clinical Cancer Research / Issue 1/2019
Electronic ISSN: 1756-9966
DOI
https://doi.org/10.1186/s13046-019-1262-4

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