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NOV is upregulated and promotes migration and invasion in bladder cancer

  • Research Article
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Tumor Biology

Abstract

NOV is pro-tumourigenic via epithelial-mesenchymal transition (EMT) in several malignancies but is not studied in bladder cancer (BCa). Whether NOV is responsible for bladder carcinogenesis and the underlying mechanism is unclear. Using immunohistochemical staining, we quantified expressions of NOV, pS6, Vimentin and E-cadherin in 66 bladder cancer and 10 normal bladder urothelium samples. EMT was profiled by EMT index (EMTi) calculated as the ratio of Vimentin to E-cadherin. In vitro and in vivo studies were carried out to profile the role of NOV in the tumourigenesis of BCa. NOV was upregulated in bladder cancer compared to normal tissue, and its expression was correlated to pS6 and EMTi. Expression of NOV was higher in recurrent and multiple tumours and was increased with progression of tumour grade. NOV expression was also higher in BCa cell lines. Silence of NOV attenuated EMT, decreased invasion and migration of BCa cells. Silence of NOV also inhibited xenograft tumour growth and decreased tumour EMT. NOV is pro-tumourigenic in bladder cancer especially in nonmuscle-invasive entities (NMIBC). NOV may promote carcinogenesis via promotion of EMT and association with increased mTOR activity.

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References

  1. Feng C, Guan M, Ding Q, Zhang Y, Jiang H, et al. Expression of pigment epithelium-derived factor in bladder tumour is correlated with interleukin-8 yet not with interleukin-1α. J Huazhong Univ Sci Technol [Med Sci]. 2011;31:21–5.

    Article  CAS  Google Scholar 

  2. Ferley J, Bray F, Pisani P, Parkin DM. Globalcan 2000: cancer incidence, mortality and prevalence world- wide, version 1.0 LARC Cancer Base No.5. Lyon: IARC Press; 2001.

    Google Scholar 

  3. Sylvester RJ, van der Meijden AP, Oosterlinck W, Witjes JA, Bouffioux C, et al. Predicting recurrence and progression in individual patients with stage Ta T1 bladder cancer using EORTC risk tables: a combined analysis of 2596 patients from seven EORTC trials. Eur Urol. 2006;49:466–5. discussion 475-467.

    Article  PubMed  Google Scholar 

  4. Messing EM. Urothelial tumors of the urinary tract. In: Walsh PC, Retik AB, Vaughan Jr ED, Wein AJ, editors. Campbell’s urology. 8th ed. Philadelphia: Saunders; 2002. p. 2750–1.

    Google Scholar 

  5. Messing EM. Urothelial tumors of the bladder. In: Wein AJ, Kavoussi LR, Novick AC, Partin AW, Peters CA, editors. Campbell-Walsh's urology. 9th ed. Philadelphia: Saunders; 2007. p. 17–2430.

    Google Scholar 

  6. Kalluri R, Weinberg RA. The basics of epithelial-mesenchymal transition. J Clin Invest. 2009;119:1420–8.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  7. Yun SJ, Kim WJ. Role of the epithelial-mesenchymal transition in bladder cancer: from prognosis to therapeutic target. Korean J Urol. 2013;54:645–50.

    Article  PubMed Central  PubMed  Google Scholar 

  8. Kleer CG, Zhang Y, Pan Q, Merajver SD. WISP3 (CCN6) is a secreted tumor-suppressor protein that modulates IGF signaling in inflammatory breast cancer. Neoplasia. 2004;6:179–85.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  9. Yu C, Le AT, Yeger H, Perbal B, Alman BA. NOV (CCN3) regulation in the growth plate and CCN family member expression in cartilage neoplasia. J Pathol. 2003;201:609–15.

    Article  CAS  PubMed  Google Scholar 

  10. Cui L, Xie R, Dang S, Zhang Q, Mao S, et al. NOV promoted the growth and migration of pancreatic cancer cells. Tumour Biol. 2013. doi:10.1007/s13277-013-1418-3.

  11. Seront E, Pinto A, Bouzin C, Bertrand L, Machiels JP, et al. PTEN deficiency is associated with reduced sensitivity to mTOR inhibitor in human bladder cancer through the unhampered feedback loop driving PI3K/Akt activation. Br J Cancer. 2013;109:1586–92.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  12. Feng C, Wang P, Guan M, Jiang H, Wen H, et al. Urinary BLCA-4 is highly specific for detection of bladder cancer in Chinese Han population and is related to tumour invasiveness. Folia Biol (Praha). 2011;57:242–7.

    CAS  Google Scholar 

  13. Feng C, Wu Z, Guo T, Jiang H, Guan M, et al. BLCA-4 expression is related to MMP-9, VEGF, IL-1α and IL-8 in bladder cancer but not to PEDF, TNF-α or angiogenesis. Pathol Biol. 2012;60:e36–40.

    Article  CAS  PubMed  Google Scholar 

  14. Feng C-C, Ding Q, Zhang Y-F, Jiang H-W, Wen H, et al. Pigment epithelium-derived factor expression is down-regulated in bladder tumors and correlates with vascular endothelial growth factor and matrix metalloproteinase-9. Int Urol Nephrol. 2011;43:383–90.

    Article  CAS  PubMed  Google Scholar 

  15. Feng C-C, Wang P-H, Ding Q, Guan M, Zhang Y-F, et al. Expression of pigment epithelium-derived factor and tumor necrosis factor-α is correlated in bladder tumor and is related to tumor angiogenesis. Urol Oncol Semin Orig Investig. 2013;31:241–6.

    Article  Google Scholar 

  16. Mikaelian I, Malek M, Gadet R, Viallet J, Garcia A, et al. Genetic and pharmacologic inhibition of mTORC1 promotes EMT by a TGF-beta-independent mechanism. Cancer Res. 2013;73:6621–31.

    Article  CAS  PubMed  Google Scholar 

  17. Leal P, Garcia P, Sandoval A, Buchegger K, Weber H, et al. AKT/mTOR substrate P70S6K is frequently phosphorylated in gallbladder cancer tissue and cell lines. Onco Targets Ther. 2013;6:1373–84.

    PubMed Central  CAS  PubMed  Google Scholar 

  18. Maillard M, Cadot B, Ball RY, Sethia K, Edwards DR, et al. Differential expression of the ccn3 (nov) proto-oncogene in human prostate cell lines and tissues. Mol Pathol. 2001;54:275–80.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  19. Ding G, Feng C, Jiang H, Ding Q, Zhang L, et al. Combination of rapamycin, CI-1040, and 17-AAG inhibits metastatic capacity of prostate cancer via Slug inhibition. PLoS One. 2013;8:e77400.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  20. Gulhati P, Bowen KA, Liu J, Stevens PD, Rychahou PG, et al. mTORC1 and mTORC2 regulate EMT, motility, and metastasis of colorectal cancer via RhoA and Rac1 signaling pathways. Cancer Res. 2011;71:3246–56.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  21. Lamouille S, Derynck R. Cell size and invasion in TGF-beta-induced epithelial to mesenchymal transition is regulated by activation of the mTOR pathway. J Cell Biol. 2007;178:437–51.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  22. Wallin JJ, Guan J, Edgar KA, Zhou W, Francis R, et al. Active PI3K pathway causes an invasive phenotype which can be reversed or promoted by blocking the pathway at divergent nodes. PLoS One. 2012;7:e36402.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Urology, Changzheng Hospital, The Second Military Medical University, Shanghai, 200003, China

    Jie Chen, Yi Gao, Biyou Xu, Xingang Cui & Danfeng Xu

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  1. Jie Chen
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  2. Yi Gao
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  3. Biyou Xu
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  4. Xingang Cui
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  5. Danfeng Xu
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Corresponding authors

Correspondence to Xingang Cui or Danfeng Xu.

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Jie Chen and Yi Gao contributed equally.

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Chen, J., Gao, Y., Xu, B. et al. NOV is upregulated and promotes migration and invasion in bladder cancer. Tumor Biol. 35, 6749–6755 (2014). https://doi.org/10.1007/s13277-014-1919-8

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  • DOI: https://doi.org/10.1007/s13277-014-1919-8

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