Theranostics 2017; 7(12):3053-3067. doi:10.7150/thno.19542

Research Paper

TGFβ1 Promotes Gemcitabine Resistance through Regulating the LncRNA-LET/NF90/miR-145 Signaling Axis in Bladder Cancer

Junlong Zhuang1*, Lan Shen2*, Lin Yang1, Xiaojing Huang2, Qun Lu1, Yangyan Cui2, Xi Zheng1, Xiaozhi Zhao1, Dianzheng Zhang3, Ruimin Huang4, Hongqian Guo1✉, Jun Yan2✉

1. Department of Urology, Drum Tower Hospital, Medical School of Nanjing University, Institute of Urology, Nanjing University, Nanjing, Jiangsu, China;
2. State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animals for Disease Study, Model Animal Research Center, Nanjing University, Nanjing 210061, Jiangsu, China;
3. Department of Biochemistry and Molecular Biology, Philadelphia College of Osteopathic Medicine, Philadelphia, PA 19131, USA;
4. Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
* These authors contributed equally to this work.

Abstract

High tumor recurrence is frequently observed in patients with urinary bladder cancers (UBCs), with the need for biomarkers of prognosis and drug response. Chemoresistance and subsequent recurrence of cancers are driven by a subpopulation of tumor initiating cells, namely cancer stem-like cells (CSCs). However, the underlying molecular mechanism in chemotherapy-induced CSCs enrichment remains largely unclear. In this study, we found that during gemcitabine treatment lncRNA-Low Expression in Tumor (lncRNA-LET) was downregulated in chemoresistant UBC, accompanied with the enrichment of CSC population. Knockdown of lncRNA-LET increased UBC cell stemness, whereas forced expression of lncRNA-LET delayed gemcitabine-induced tumor recurrence. Furthermore, lncRNA-LET was directly repressed by gemcitabine treatment-induced overactivation of TGFβ/SMAD signaling through SMAD binding element (SBE) in the lncRNA-LET promoter. Consequently, reduced lncRNA-LET increased the NF90 protein stability, which in turn repressed biogenesis of miR-145 and subsequently resulted in accumulation of CSCs evidenced by the elevated levels of stemness markers HMGA2 and KLF4. Treatment of gemcitabine resistant xenografts with LY2157299, a clinically relevant specific inhibitor of TGFβRI, sensitized them to gemcitabine and significantly reduced tumorigenecity in vivo. Notably, overexpression of TGFβ1, combined with decreased levels of lncRNA-LET and miR-145 predicted poor prognosis in UBC patients. Collectively, we proved that the dysregulated lncRNA-LET/NF90/miR-145 axis by gemcitabine-induced TGFβ1 promotes UBC chemoresistance through enhancing cancer cell stemness. The combined changes in TGFβ1/lncRNA-LET/miR-145 provide novel molecular prognostic markers in UBC outcome. Therefore, targeting this axis could be a promising therapeutic approach in treating UBC patients.

Keywords: tumor recurrence, cancer stem-like cells, lncRNA-LET, miRNA biogenesis, bladder cancer.

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How to cite this article:
Zhuang J, Shen L, Yang L, Huang X, Lu Q, Cui Y, Zheng X, Zhao X, Zhang D, Huang R, Guo H, Yan J. TGFβ1 Promotes Gemcitabine Resistance through Regulating the LncRNA-LET/NF90/miR-145 Signaling Axis in Bladder Cancer. Theranostics 2017; 7(12):3053-3067. doi:10.7150/thno.19542. Available from http://www.thno.org/v07p3053.htm