Theranostics 2017; 7(19):4777-4790. doi:10.7150/thno.21713

Research Paper

miR34a/GOLPH3 Axis abrogates Urothelial Bladder Cancer Chemoresistance via Reduced Cancer Stemness

Qing Zhang1*, Junlong Zhuang1*, Yongming Deng1*, Lin Yang1*, Wenmin Cao1, Wei Chen1, Tingsheng Lin1, Xiaoyu Lv1, Hang Yu1, Yanshi Xue1, Hongqian Guo1✉

1. Department of Urology, Drum Tower Hospital, Medical School of Nanjing University, Institute of Urology, Nanjing University, 321 Zhongshan Road, Nanjing 210008, Jiangsu, PR China
*These authors contributed equally to the work

Abstract

Rationale: Chemoresistance and subsequent recurrence of human urothelial bladder cancer (UBC) is partially driven by a subpopulation of tumor initiating cells, namely cancer stem cells (CSCs). However, the underlying molecular mechanism in chemotherapy-induced CSCs enrichment and following chemoresistance and recurrence remains largely unclear.

Methods: Gemcitabine and cisplatin (GC) chemoresistant cell lines (T24 GC 3rd and 5637 GC 3rd cells) and the chemo-sensitive UBC cell lines T24 and 5637 were established in vivo for the investigation of acquired resistance mechanisms. The role of miR34a/GOLPH3 axis in regulating UBC chemoresistance and recurrence was evaluated in cell and animal models. The expression levels of miR34a/GOLPH3 axis and CSCs markers were assayed in specimens of UBC. The association of GOLPH3 with clinicopathologic features and prognosis was analysed.

Results: RT-PCR and western blotting confirmed that the expression levels of miR34a were decreased and GOLPH3 were increased in GC chemoresistant UBC cell lines. Downregulation of miR34a resulted in the overexpression of GOLPH3, which is a target gene of miR34a confirmed by luciferase experiment. The ectopic expression of miR34a decreased the stem cell properties of chemoresistant UBC cells and re-sensitized these cells to GC treatment in vitro and in vivo. Moreover, miR34a/GOLPH3 axis has obvious clinical relevance with prognosis and recurrence in human UBC patients with standard GC chemotherapy.

Conclusion: Our results suggest that miR34a/GOLPH3 axis exert key role in CSCs involved UBC drug resistance and recurrence and warrant further development as a promising therapeutic approach in treating drug-resistant UBC.

Keywords: GOLPH3, miR-34a, Cancer stem cells, Urothelial bladder cancer, Drug-resistance

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How to cite this article:
Zhang Q, Zhuang J, Deng Y, Yang L, Cao W, Chen W, Lin T, Lv X, Yu H, Xue Y, Guo H. miR34a/GOLPH3 Axis abrogates Urothelial Bladder Cancer Chemoresistance via Reduced Cancer Stemness. Theranostics 2017; 7(19):4777-4790. doi:10.7150/thno.21713. Available from http://www.thno.org/v07p4777.htm