Metformin can block precancerous progression to invasive tumors of bladder through inhibiting STAT3-mediated signaling pathways

Journal of Experimental & Clinical Cancer Research

Juan-Jie Bo¹  Jian-Xin Gao³  Qiang Liu⁵  Ru-long Shen²  Yi-Ran Huang¹  Lian-Hua Zhang¹  Meng-Yao Liu⁴  Shan-Shan Liu⁴  Ning Liu⁴  Shi-Long Lin¹  Jiang-Hua Yang¹  Guo-Liang Yang¹  Qi Pan¹ 

[1] Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China;Department of Pathology, Ohio State University School of Medicine, Columbus, OH, USA;Laboratory of Tumorigenesis and Immunity, Clinical Stem Cell Research Center, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China;State Key Laboratory of Oncogene and Related Genes, Shanghai, China;Department of Pathology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China

关键词: Invasion;    Migration;    Apoptosis;    Cell cycle;    Rat;    Stat3;    Bladder cancer;    Preneoplasm;    Metformin;   

Others  :  1226286
DOI  :  10.1186/s13046-015-0183-0

 received in 2015-02-19, accepted in 2015-06-15,  发布年份 2015

【 摘 要 】

Background

Metformin is the first line of oral antidiabetic drug in the biguanide class for treatment of type 2 diabetes. Increasing evidence has suggested that it is a potential anti-tumor drug. However, the mechanisms underlying inhibiting tumor development remain elusive, especially in bladder tumors.

Methods

T24 and J82 cell lines were used as an in vitro model, and 24 female SD rats were used to build an N-methyl-N-nitrosourea (MNU)-induced orthotopic rat bladder cancer model. Transfection of lentivirus-based shRNA was used to construct the STAT3-KNOCKDOWN T24 cell line. After metformin treatment, the viability of bladde cancer cells was determined by CCK8. Cell cycle distribution and apoptosis were assessed by flow cytometry. The migration and invasion abilities of cells were evaluated by wound healing and transwell asssays. The inactivation of stat3 pahtway was examined by qRTPCR, western blot and Immunofluorescence.

Results

Metformin can effectively inhibit precancerous progression to invasive cancer in an MNU-induced rat orthotopic bladder tumor model, although it could not completely suppress normal cells transforming into tumor cells. While the MNU could induce 50 % rats (4/8) to develop invasive bladder cancers, the rats co-administrated with metformin failed to develop invasive tumors but retained at precancerous or non-invasive stages, exhibiting as dysplasia, papillary tumor and/or carcinoma in situ (CIS). Accordingly, phosphorylation of signal transducer and activator of transcription 3 (STAT3), which is a well known oncogene, was significantly inhibited in the tumors of rats treated with metformin. In vitro experiments revealed that the metformin could efficiently inhibit STAT3 activation, which was associated with the cell cycle arrest, reduction of cell proliferation, migration and invasiveness, and increase in apoptotic cell death of bladder cancer cell lines.

Conclusions

These findings provide for the first time the evidence that metformin can block precancerous lesions progressing to invasive tumors through inhibiting the activation of STAT3 pathway, and may be used for treatment of the non-invasive bladder cancers to prevent them from progression to invasive tumors.

【 授权许可】

   
2015 Pan et al.

【 图 表 】

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