Skip to main content

Advertisement

SpringerLink
Log in

miR-129-5p inhibits gemcitabine resistance and promotes cell apoptosis of bladder cancer cells by targeting Wnt5a

  • Urology - Original Paper
  • Published:
International Urology and Nephrology Aims and scope Submit manuscript

Abstract

Objectives

Gemcitabine resistance is a major obstacle for effective treatment of bladder cancer. This study was aimed to investigate the potential role of miR-129-5p in the development of gemcitabine resistance in bladder cancer cells and its underlying mechanism.

Methods

The IC50 for gemcitabine in 20 bladder cancer cells was first profiled from Genomics of Drug Sensitivity in Cancer. miR-129-5p level and gene mRNA expression were detected using quantitative real-time PCR (qRT-PCR). Cell viability, apoptosis, and gene protein level were assessed by MTT, flow cytometry, and Western blot, respectively. Regulatory relationship between Wnt5a and miR-129-5p was determined using luciferase reporter assay.

Results

We found that down-regulated miR-129-5p level contributed to gemcitabine resistance in bladder cancer cells and tissues. We also observed restoration of miR-129-5p could significantly increase cell sensitivity to gemcitabine and promote cell apoptosis. Mechanism analysis revealed that Wnt5a is a direct target gene of miR-129-5p and knock-down of Wnt5a reversed gemcitabine resistance.

Conclusions

Taken together, our findings indicate that miR-129-5p and Wnt5a may be novel therapeutic targets for overcoming gemcitabine resistance in bladder cancer treatment.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Meyers PA, Schwartz CL, Krailo M, Kleinerman ES, Betcher D, Bernstein ML, Conrad E, Ferguson W, Gebhardt M, Goorin AM, Harris MB, Healey J, Huvos A, Link M, Montebello J, Nadel H, Nieder M, Sato J, Siegal G, Weiner M, Wells R, Wold L, Womer R, Grier H (2005) Global cancer statistics. J Clin Oncol 23:2004–2011

    Article  CAS  PubMed  Google Scholar 

  2. Kirkali Z, Chan T, Manoharan M, Algaba F, Busch C, Cheng L, Kiemeney L, Kriegmair M, Montironi R, Murphy WM, Sesterhenn IA, Tachibana M, Weider J (2005) Bladder cancer: epidemiology, staging and grading, and diagnosis. Urology 66:4–34

    Article  PubMed  Google Scholar 

  3. Crinò L, Cappuzzo F (2002) Gemcitabine in non-small cell lung cancer. Expert Opin Pharmacother 3:745–753

    Article  PubMed  Google Scholar 

  4. Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S, Au HJ, Murawa P, Walde D, Wolff RA, Campos D, Lim R, Ding K, Clark G, Voskoglou-Nomikos T, Ptasynski M, Parulekar W, National Cancer Institute of Canada Clinical Trials Group (2007) Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 25:1960–1966

    Article  CAS  PubMed  Google Scholar 

  5. Chew HK, Doroshow JH, Frankel P, Margolin KA, Somlo G, Lenz HJ, Gordon M, Zhang W, Yang D, Russell C, Spicer D, Synold T, Bayer R, Hantel A, Stiff PJ, Tetef ML, Gandara DR, Albain KS (2009) Phase II studies of gemcitabine and cisplatin in heavily and minimally pretreated metastatic breast cancer. J Clin Oncol 27:2163–2169

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Pachon V, Garciaalfonso P, Iglesias L, Siso I, Abad G, Khosravi P, Diaz V, Perez-Manga G (2005) Gemcitabine plus continuous infusion of 5-FU for heavily pretreated advanced colorectal cancer patients. Phase I/II study. J Magn Magn Mater 323:2174–2178

    Google Scholar 

  7. von der Maase H, Hansen SW, Roberts JT, Dogliotti L, Oliver T, Moore MJ, Bodrogi I, Albers P, Knuth A, Lippert CM, Kerbrat P, Sanchez Rovira P, Wersall P, Cleall SP, Roychowdhury DF, Tomlin I, Visseren-Grul CM, Conte PF (2000) Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase III study. J Clin Oncol 18:3068–3077

    Article  PubMed  Google Scholar 

  8. Anghel RM, Gales LN, Trifanescu OG (2016) Outcome of urinary bladder cancer after combined therapies. J Med Life 9:153–159

    CAS  PubMed  PubMed Central  Google Scholar 

  9. von der Maase H, Sengelov L, Roberts JT, Ricci S, Dogliotti L, Oliver T, Moore MJ, Zimmermann A, Arning M (2005) Long-term survival results of a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer. J Clin Oncol 23:4602–4608

    Article  CAS  PubMed  Google Scholar 

  10. Filipowicz W, Bhattacharyya SN, Sonenberg N (2008) Mechanisms of post-transcriptional regulation by microRNAs: are the answers in sight? Nat Rev Genet 9:102–114

    Article  CAS  PubMed  Google Scholar 

  11. Bartel DP (2009) MicroRNAs: target recognition and regulatory functions. Cell 136:215–233

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Lu X, Ma J, Chu J, Shao Q, Zhang Y, Lu G, Li J, Huang X, Li W, Li Y, Ling Y, Zhao T (2017) MiR-129-5p sensitizes the response of Her-2 positive breast cancer to trastuzumab by reducing Rps6. Cell Physiol Biochem 44:2346–2356

    Article  CAS  PubMed  Google Scholar 

  13. Ma Z, Cai H, Zhang Y, Chang L, Cui Y (2017) MiR-129-5p inhibits non-small cell lung cancer cell stemness and chemoresistance through targeting DLK1. Biochem Biophys Res Commun 490:309–316

    Article  CAS  PubMed  Google Scholar 

  14. Wu Q, Yang Z, Xia L, Nie Y, Wu K, Shi Y, Fan D (2014) Methylation of miR-129-5p CpG island modulates multi-drug resistance in gastric cancer by targeting ABC transporters. Oncotarget 5:11552–11563

    PubMed  PubMed Central  Google Scholar 

  15. Zhang P, Li J, Song Y, Wang X (2017) MiR-129-5p inhibits proliferation and invasion of chondrosarcoma cells by regulating SOX4/Wnt/β-catenin signaling pathway. Cell Physiol Biochem 42:242–253

    Article  CAS  PubMed  Google Scholar 

  16. Wang Q, Yu J (2018) MiR-129-5p suppresses gastric cancer cell invasion and proliferation by inhibiting COL1A1. Biochem Cell Biol 96:19–25

    Article  CAS  PubMed  Google Scholar 

  17. Geng Z, Xu F, Zhang Y (2016) MiR-129-5p-mediated Beclin-1 suppression inhibits endothelial cell autophagy in atherosclerosis. Am J Transl Res 8:1886–1894

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Duan L, Hao X, Liu Z, Zhang Y, Zhang G (2014) MiR-129-5p is down-regulated and involved in the growth, apoptosis and migration of medullary thyroid carcinoma cells through targeting RET. FEBS Lett 588:1644–1651

    Article  CAS  PubMed  Google Scholar 

  19. Yang J, Li T, Gao C, Lv X, Liu K, Song H, Xing Y, Xi T (2014) FOXO1 3′UTR functions as a ceRNA in repressing the metastases of breast cancer cells via regulating miRNA activity. FEBS Lett 588:3218–3224

    Article  CAS  PubMed  Google Scholar 

  20. Fan P, Liu L, Yin Y, Zhao Z, Zhang Y, Amponsah PS, Xiao X, Bauer N, Abukiwan A, Nwaeburu CC, Gladkich J, Gao C, Schemmer P, Gross W, Herr I (2016) MicroRNA-101-3p reverses gemcitabine resistance by inhibition of ribonucleotide reductase M1 in pancreatic cancer. Cancer Lett 373:130–137

    Article  CAS  PubMed  Google Scholar 

  21. Wang H, Li Q, Niu X, Wang G, Zheng S, Fu G, Wang Z (2017) miR-143 inhibits bladder cancer cell proliferation and enhances their sensitivity to gemcitabine by repressing IGF-1R signaling. Oncol Lett 13:435–440

    Article  CAS  PubMed  Google Scholar 

  22. Wu ZH, Tao ZH, Zhang J, Li T, Ni C, Xie J, Zhang JF, Hu XC (2016) MiRNA-21 induces epithelial to mesenchymal transition and gemcitabine resistance via the PTEN/AKT pathway in breast cancer. Tumour Biol 37:7245–7254

    Article  CAS  PubMed  Google Scholar 

  23. Kikuchi A, Yamamoto H, Sato A, Matsumoto S (2012) Wnt5a: its signalling, functions and implication in diseases. Acta Physiol 204:17–33

    Article  CAS  Google Scholar 

  24. McDonald SL, Silver A (2009) The opposing roles of Wnt-5a in cancer. Br J Cancer 101:209–214

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Bo H, Zhang S, Gao L, Chen Y, Zhang J, Chang X, Zhu M (2013) Upregulation of Wnt5a promotes epithelial-to-mesenchymal transition and metastasis of pancreatic cancer cells. BMC Cancer 13:496

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Zhang A, He S, Sun X, Ding L, Bao X, Wang N (2014) Wnt5a promotes migration of human osteosarcoma cells by triggering a phosphatidylinositol-3 kinase/Akt signals. Cancer Cell Int 14:15

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Takiguchi G, Nishita M, Kurita K, Kakeji Y, Minami Y (2016) Wnt5a-Ror2 signaling in mesenchymal stem cells promotes proliferation of gastric cancer cells by activating CXCL16-CXCR6 axis. Cancer Sci 107:290–297

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Wang B, Tang Z, Gong H, Zhu L, Liu X (2017) Wnt5a promotes epithelial-to-mesenchymal transition and metastasis in non-small-cell lung cancer. Biosci Rep. https://doi.org/10.1042/BSR20171092

    Article  PubMed  PubMed Central  Google Scholar 

  29. Cao Y, Wang X, Xu C, Gao Z, Zhou H, Wang Y, Cao R, Liu T, Liu T (2016) 4-HPR impairs bladder cancer cell migration and invasion by interfering with the Wnt5a/JNK and Wnt5a/MMP-2 signaling pathways. Oncol Lett 12:1833–1839

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Säfholm A, Tuomela J, Rosenkvist J, Dejmek J, Härkönen P, Andersson T (2008) The Wnt-5a-derived hexapeptide Foxy-5 inhibits breast cancer metastasis in vivo by targeting cell motility. Clin Cancer Res 14:6556–6563

    Article  CAS  PubMed  Google Scholar 

  31. Prasad CP, Chaurasiya SK, Guilmain W, Andersson T (2016) WNT5A signaling impairs breast cancer cell migration and invasion via mechanisms independent of the epithelial-mesenchymal transition. J Exp Clin Cancer Res 35:144

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Cheng R, Sun B, Liu Z, Zhao X, Qi L, Li Y, Gu Q (2014) Wnt5a suppresses colon cancer by inhibiting cell proliferation and epithelial-mesenchymal transition. J Cell Physiol 229:1908–1917

    Article  CAS  PubMed  Google Scholar 

  33. Oishi I, Suzuki H, Onishi N, Takada R, Kani S, Ohkawara B, Koshida I, Suzuki K, Yamada G, Schwabe GC, Mundlos S, Shibuya H, Takada S, Minami Y (2003) The receptor tyrosine kinase Ror2 is involved in non-canonical Wnt5a/JNK signalling pathway. Genes Cells 8:645–654

    Article  CAS  PubMed  Google Scholar 

  34. Ishitani T, Kishida S, Hyodo-Miura J, Ueno N, Yasuda J, Waterman M, Shibuya H, Moon RT, Ninomiya-Tsuji J, Matsumoto K (2003) The TAK1-NLK mitogen-activated protein kinase cascade functions in the Wnt-5a/Ca(2+) pathway to antagonize Wnt/beta-catenin signaling. Mol Cell Biol 23:131–139

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Topol L, Jiang X, Choi H, Garrett-Beal L, Carolan PJ, Yang Y (2003) Wnt-5a inhibits the canonical Wnt pathway by promoting GSK-3-independent beta-catenin degradation. J Cell Biol 162:899–908

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Asem MS, Buechler S, Wates RB, Miller DL, Sharon SM (2016) Wnt5a signaling in cancer. Cancers 8:79

    Article  CAS  PubMed Central  Google Scholar 

  37. Hung TH, Hsu SC, Cheng CY, Choo KB, Tseng CP, Chen TC, Lan YW, Huang TT, Lai HC, Chen CM, Chong KY (2014) Wnt5A regulates ABCB1 expression in multidrug-resistant cancer cells through activation of the non-canonical PKA/β-catenin pathway. Oncotarget 5:12273–12290

    PubMed  PubMed Central  Google Scholar 

Download references

Author information

Author notes

  1. Jingyi Cao and Qichao Wang contributed equally to this work.

Authors and Affiliations

  1. Department of Urology, Xuzhou Cancer Hospital, Xuzhou, 221005, Jiangsu, People’s Republic of China

    Jingyi Cao, Qichao Wang, Gang Wu, Shasha Li & Qian Wang

Authors
  1. Jingyi Cao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Qichao Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Gang Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Shasha Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Qian Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Gang Wu or Qian Wang.

Ethics declarations

Conflict of interest

The authors declare that they have no competing interests.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Cao, J., Wang, Q., Wu, G. et al. miR-129-5p inhibits gemcitabine resistance and promotes cell apoptosis of bladder cancer cells by targeting Wnt5a. Int Urol Nephrol 50, 1811–1819 (2018). https://doi.org/10.1007/s11255-018-1959-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11255-018-1959-x

Keywords

Search

Navigation