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

• Published in: Theranostics 2017, Vol.7 (12), p.3053-3067
• Main Authors: Zhuang, Junlong, Shen, Lan, Yang, Lin, Huang, Xiaojing, Lu, Qun, Cui, Yangyan, Zheng, Xi, Zhao, Xiaozhi, Zhang, Dianzheng, Huang, Ruimin, Guo, Hongqian, Yan, Jun
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - pharmacology; Cell Line, Tumor; Deoxycytidine - analogs & derivatives; Deoxycytidine - pharmacology; Disease Models, Animal; Drug Resistance; Humans; Male; Mice, Nude; MicroRNAs - metabolism; Neoplastic Stem Cells - physiology; Nuclear Factor 90 Proteins - metabolism; Research Paper; RNA, Long Noncoding - metabolism; Signal Transduction; Transforming Growth Factor beta1 - metabolism; Urinary Bladder Neoplasms - pathology
• ISSN: 1838-7640; 1838-7640
• DOI: 10.7150/thno.19542

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 . 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.