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TGF beta 1 Promotes Gemcitabine Resistance through Regulating the LncRNA-LET/NF90/miR-145 Signaling Axis in Bladder Cancer

文献类型：期刊论文

作者Zhuang, Junlong3; Shen, Lan4,5; Yang, Lin3; Huang, Xiaojing4,5; Lu, Qun3; Cui, Yangyan4,5; Zheng, Xi3; Zhao, Xiaozhi3; Zhang, Dianzheng2; Huang, Ruimin1
刊名THERANOSTICS
出版日期2017
卷号7期号:12页码:3053-3067
关键词tumor recurrence cancer stem-like cells lncRNA-LET miRNA biogenesis bladder cancer
ISSN号1838-7640
DOI10.7150/thno.19542
文献子类Article
英文摘要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 TGF beta/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 TGF beta RI, sensitized them to gemcitabine and significantly reduced tumorigenecity in vivo. Notably, overexpression of TGF beta 1, 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 TGF beta 1 promotes UBC chemoresistance through enhancing cancer cell stemness. The combined changes in TGF beta 1/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.
WOS关键词LONG NONCODING RNA ; GROWTH-FACTOR-BETA ; EPITHELIAL-MESENCHYMAL TRANSITION ; TUMOR-INITIATING CELLS ; I KINASE INHIBITOR ; PANCREATIC DUCTAL ADENOCARCINOMA ; STEM-CELLS ; BREAST-CANCER ; DOWN-REGULATION ; GASTRIC-CANCER
资助项目National Natural Science Foundation of China[81372168] ; National Natural Science Foundation of China[81572519] ; National Natural Science Foundation of China[81672873] ; Natural Science Foundation for Universities in Jiangsu Province[BK20151396] ; Wu Jieping Medical Foundation[320.6750.16051] ; "Personalized Medicines-Molecular Signature-based Drug Discovery and Development", Strategic Priority Research Program of the Chinese Academy of Sciences[XDA 12020108] ; Institutes for Drug Discovery and Development, Chinese Academy of Sciences[CASIMM0120163010] ; One Hundred Talent Program of Chinese Academy of Sciences[00000000]
WOS研究方向Research & Experimental Medicine
语种英语
WOS记录号WOS:000406037800007
出版者IVYSPRING INT PUBL
源URL[http://119.78.100.183/handle/2S10ELR8/275708]  
专题分子影像中心（筹）
通讯作者Guo, Hongqian; Yan, Jun
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China
2.Philadelphia Coll Osteopath Med, Dept Biochem & Mol Biol, Philadelphia, PA 19131 USA;
3.Nanjing Univ, Inst Urol, Med Sch, Dept Urol,Drum Tower Hosp, Nanjing, Jiangsu, Peoples R China;
4.Nanjing Univ, Model Anim Res Ctr, MOE Key Lab Model Anim Dis Study, Nanjing 210061, Jiangsu, Peoples R China;
5.Nanjing Univ, Model Anim Res Ctr, State Key Lab Pharmaceut Biotechnol, Nanjing 210061, Jiangsu, Peoples R China;
推荐引用方式
GB/T 7714		 Zhuang, Junlong,Shen, Lan,Yang, Lin,et al. TGF beta 1 Promotes Gemcitabine Resistance through Regulating the LncRNA-LET/NF90/miR-145 Signaling Axis in Bladder Cancer[J]. THERANOSTICS,2017,7(12):3053-3067.
APA Zhuang, Junlong.,Shen, Lan.,Yang, Lin.,Huang, Xiaojing.,Lu, Qun.,...&Yan, Jun.(2017).TGF beta 1 Promotes Gemcitabine Resistance through Regulating the LncRNA-LET/NF90/miR-145 Signaling Axis in Bladder Cancer.THERANOSTICS,7(12),3053-3067.
MLA Zhuang, Junlong,et al."TGF beta 1 Promotes Gemcitabine Resistance through Regulating the LncRNA-LET/NF90/miR-145 Signaling Axis in Bladder Cancer".THERANOSTICS 7.12(2017):3053-3067.

入库方式： OAI收割

来源：上海药物研究所

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