Tumor Biology

, Volume 36, Issue 11, pp 8839–8844 | Cite as

RETRACTED ARTICLE: Regulation of metastasis of bladder cancer cells through the WNT signaling pathway

  • Yiheng Du
  • Yongchuan Wang
  • Fei Zhang
  • Wenbo Wu
  • Wei Wang
  • Hao Li
  • Shujie Xia
  • Haitao LiuEmail author
Research Article


Bladder cancer (BC) is the most popular malignant urinary cancer, with the highest incidence and mortality of all genitourinary system tumors worldwide. To date, the molecular regulation of the metastasis of BC remains ill defined. Here, we examined the levels of matrix metallopeptidase 9 (MMP9) and nuclear β-catenin in the BC specimen. We used lithium chloride (LiCl) to inhibit cytosol β-catenin phosphorylation and degradation to increase nuclear β-catenin levels in BC cells. We used IWP-2 to enhance cytosol β-catenin phosphorylation and degradation to decrease nuclear β-catenin levels in BC cells. We examined MMP9 levels in these experimental settings by quantitative reverse transcription-PCR (RT-qPCR), Western blot, and ELISA. The cell invasiveness was evaluated by Transwell cell assay. We found significantly higher levels of MMP9 and nuclear β-catenin in human BC specimen with metastasis, compared to those without metastasis. Moreover, a strong correlation was detected between MMP9 and nuclear β-catenin. LiCl significantly increased nuclear β-catenin, resulting in MMP9 activation in BC cells. IWP-2 significantly decreased nuclear β-catenin, resulting in MMP9 inhibition in BC cells. MMP9 regulated cell invasiveness. Together, these data suggest that the WNT signaling pathway regulates metastasis of BC through activation of MMP9. Therapies targeting the WNT signaling pathway may be a promising treatment for BC.


Bladder cancer (BC) WNT signaling MMP9 β-Catenin 



This work was financially supported by the Shanghai Jiao Tong University Medical and Engineering Collaborative Research Fund Project (YG2012MS45).

Conflicts of interest



  1. 1.
    Gray PJ, Shipley WU, Efstathiou JA, Zietman AL. Recent advances and the emerging role for chemoradiation in nonmuscle invasive bladder cancer. Curr Opin Urol. 2013;23:429–34.CrossRefPubMedGoogle Scholar
  2. 2.
    Kaplan AL, Litwin MS, Chamie K. The future of bladder cancer care in the USA. Nat Rev Urol. 2014;11:59–62.CrossRefPubMedGoogle Scholar
  3. 3.
    Noon AP, Catto JW. Bladder cancer in 2012: challenging current paradigms. Nat Rev Urol. 2013;10:67–8.CrossRefPubMedGoogle Scholar
  4. 4.
    Payton S. Bladder cancer: biomarker panel predicts recurrence after radical cystectomy. Nat Rev Urol. 2013;10:309.CrossRefPubMedGoogle Scholar
  5. 5.
    Tan MY, Mu XY, Liu B, Wang Y, Bao ED, Qiu JX, et al. Sumo-specific protease 2 suppresses cell migration and invasion through inhibiting the expression of MMP13 in bladder cancer cells. Cell Physiol Biochem. 2013;32:542–8.CrossRefPubMedGoogle Scholar
  6. 6.
    Kanno T, Gotoh A, Fujita Y, Nakano T, Nishizaki T. A(3) adenosine receptor mediates apoptosis in 5637 human bladder cancer cells by G(q) protein/PKC-dependent AIF upregulation. Cell Physiol Biochem. 2012;30:1159–68.CrossRefPubMedGoogle Scholar
  7. 7.
    Ao N, Liu Y, Feng H, Bian X, Li Z, Gu B, et al. Ubiquitin-specific peptidase USP22 negatively regulates the STAT signaling pathway by deubiquitinating SIRT1. Cell Physiol Biochem. 2014;33:1863–75.CrossRefPubMedGoogle Scholar
  8. 8.
    Guo C, Hou GQ, Li XD, Xia X, Liu DX, Huang DY, et al. Quercetin triggers apoptosis of lipopolysaccharide (LPS)-induced osteoclasts and inhibits bone resorption in RAW264.7 cells. Cell Physiol Biochem. 2012;30:123–36.CrossRefPubMedGoogle Scholar
  9. 9.
    Li Q, Li M, Wang YL, Fauzee NJ, Yang Y, Pan J, et al. RNA interference of PARG could inhibit the metastatic potency of colon carcinoma cells via PI3-kinase/AKT pathway. Cell Physiol Biochem. 2012;29:361–72.CrossRefPubMedGoogle Scholar
  10. 10.
    Prins PA, Perati PR, Kon V, Guo Z, Ramesh A, Linton MF, et al. Benzo[a]pyrene potentiates the pathogenesis of abdominal aortic aneurysms in apolipoprotein E knockout mice. Cell Physiol Biochem. 2012;29:121–30.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Song H, Pan D, Sun W, Gu C, Zhang Y, Zhao P, et al. SiRNA directed against annexin II receptor inhibits angiogenesis via suppressing MMP2 and MMP9 expression. Cell Physiol Biochem. 2015;35:875–84.CrossRefPubMedGoogle Scholar
  12. 12.
    Wang R, Ke ZF, Wang F, Zhang WH, Wang YF, Li SH, et al. GOLPH3 overexpression is closely correlated with poor prognosis in human non-small cell lung cancer and mediates its metastasis through upregulating MMP-2 and MMP-9. Cell Physiol Biochem. 2015;35:969–82.CrossRefPubMedGoogle Scholar
  13. 13.
    Ahmad R, Shihab PK, Jasem S, Behbehani K. FSL-1 induces MMP-9 production through TLR-2 and NF-kappaB /AP-1 signaling pathways in monocytic THP-1 cells. Cell Physiol Biochem. 2014;34:929–42.CrossRefPubMedGoogle Scholar
  14. 14.
    Yang CQ, Li W, Li SQ, Li J, Li YW, Kong SX, et al. MCP-1 stimulates MMP-9 expression via ERK 1/2 and p38 MAPK signaling pathways in human aortic smooth muscle cells. Cell Physiol Biochem. 2014;34:266–76.CrossRefPubMedGoogle Scholar
  15. 15.
    Lee DK, Park EJ, Kim EK, Jin J, Kim JS, Shin IJ, et al. Atorvastatin and simvastatin, but not pravastatin, up-regulate LPS-induced MMP-9 expression in macrophages by regulating phosphorylation of ERK and CREB. Cell Physiol Biochem. 2012;30:499–511.CrossRefPubMedGoogle Scholar
  16. 16.
    Bai Y, Wang L, Li Y, Liu S, Li J, Wang H, et al. High ambient glucose levels modulates the production of MMP-9 and alpha5(IV) collagen by cultured podocytes. Cell Physiol Biochem. 2006;17:57–68.CrossRefPubMedGoogle Scholar
  17. 17.
    Polakis P. Wnt signaling in cancer. Cold Spring Harb Perspect Biol. 2012;4.Google Scholar
  18. 18.
    Polakis P. The many ways of Wnt in cancer. Curr Opin Genet Dev. 2007;17:45–51.CrossRefPubMedGoogle Scholar
  19. 19.
    Reya T, Clevers H. Wnt signalling in stem cells and cancer. Nature. 2005;434:843–50.CrossRefPubMedGoogle Scholar
  20. 20.
    Barker N, Clevers H. Catenins, Wnt signaling and cancer. Bioessays. 2000;22:961–5.CrossRefPubMedGoogle Scholar
  21. 21.
    Lin R, Feng J, Dong S, Pan R, Zhuang H, Ding Z. Regulation of autophagy of prostate cancer cells by beta-catenin signaling. Cell Physiol Biochem. 2015;35:926–32.CrossRefPubMedGoogle Scholar
  22. 22.
    Gu S, Honisch S, Kounenidakis M, Alkahtani S, Alarifi S, Alevizopoulos K, et al. Membrane androgen receptor down-regulates c-src-activity and beta-catenin transcription and triggers GSK-3beta-phosphorylation in colon tumor cells. Cell Physiol Biochem. 2014;34:1402–12.CrossRefPubMedGoogle Scholar
  23. 23.
    Jiang HL, Xu D, Yu H, Ma X, Lin GF, Ma DY, et al. DAX-1 inhibits hepatocellular carcinoma proliferation by inhibiting beta-catenin transcriptional activity. Cell Physiol Biochem. 2014;34:734–42.CrossRefPubMedGoogle Scholar
  24. 24.
    Tan M, Gong H, Zeng Y, Tao L, Wang J, Jiang J, et al. Downregulation of homeodomain-interacting protein kinase-2 contributes to bladder cancer metastasis by regulating Wnt signaling. J Cell Biochem. 2014;115:1762–7.CrossRefPubMedGoogle Scholar
  25. 25.
    Varol N, Konac E, Onen IH, Gurocak S, Alp E, Yilmaz A, et al. The epigenetically regulated effects of Wnt antagonists on the expression of genes in the apoptosis pathway in human bladder cancer cell line (T24). DNA Cell Biol. 2014;33:408–17.CrossRefPubMedGoogle Scholar
  26. 26.
    Fan Y, Shen B, Tan M, Mu X, Qin Y, Zhang F, et al. Long non-coding RNA UCA1 increases chemoresistance of bladder cancer cells by regulating Wnt signaling. FEBS J. 2014;281:1750–8.CrossRefPubMedGoogle Scholar
  27. 27.
    Guo Y, Ying L, Tian Y, Yang P, Zhu Y, Wang Z, et al. miR-144 downregulation increases bladder cancer cell proliferation by targeting EZH2 and regulating Wnt signaling. FEBS J. 2013;280:4531–8.CrossRefPubMedGoogle Scholar
  28. 28.
    Wang X, Wang H, Bu R, Fei X, Zhao C, Song Y. Methylation and aberrant expression of the Wnt antagonist secreted frizzled-related protein 1 in bladder cancer. Oncol lett. 2012;4:334–8.PubMedPubMedCentralGoogle Scholar
  29. 29.
    Tang Y, Simoneau AR, Liao WX, Yi G, Hope C, Liu F, et al. WIF1, a Wnt pathway inhibitor, regulates SKP2 and c-myc expression leading to G1 arrest and growth inhibition of human invasive urinary bladder cancer cells. Mol Cancer Ther. 2009;8:458–68.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Urakami S, Shiina H, Enokida H, Kawakami T, Kawamoto K, Hirata H, et al. Combination analysis of hypermethylated Wnt-antagonist family genes as a novel epigenetic biomarker panel for bladder cancer detection. Clin Cancer Res. 2006;12:2109–16.CrossRefPubMedGoogle Scholar
  31. 31.
    Urakami S, Shiina H, Enokida H, Kawakami T, Tokizane T, Ogishima T, et al. Epigenetic inactivation of Wnt inhibitory factor-1 plays an important role in bladder cancer through aberrant canonical Wnt/beta-catenin signaling pathway. Clin Cancer Res. 2006;12:383–91.CrossRefPubMedGoogle Scholar
  32. 32.
    Wissmann C, Wild PJ, Kaiser S, Roepcke S, Stoehr R, Woenckhaus M, et al. WIF1, a component of the Wnt pathway, is down-regulated in prostate, breast, lung, and bladder cancer. J Pathol. 2003;201:204–12.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Yiheng Du
    • 1
  • Yongchuan Wang
    • 2
  • Fei Zhang
    • 1
  • Wenbo Wu
    • 1
  • Wei Wang
    • 1
  • Hao Li
    • 1
  • Shujie Xia
    • 1
  • Haitao Liu
    • 1
    Email author
  1. 1.Department of Urology, Shanghai First People’s HospitalShanghai Jiao Tong UniversityShanghaiChina
  2. 2.Department of UrologyWeifang Hospital of Chinese Traditional MedicineWeifangChina

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