Oncotarget

Research Papers:

Metformin represses bladder cancer progression by inhibiting stem cell repopulation via COX2/PGE2/STAT3 axis

Qiuli Liu, Wenqiang Yuan, Dali Tong, Gaolei Liu, Weihua Lan, Dianzheng Zhang, Hualiang Xiao, Yao Zhang, Zaoming Huang, Junjie Yang, Jun Zhang and Jun Jiang _

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Oncotarget. 2016; 7:28235-28246. https://doi.org/10.18632/oncotarget.8595

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Abstract

Qiuli Liu1,*, Wenqiang Yuan1,*, Dali Tong1, Gaolei Liu1, Weihua Lan1, Dianzheng Zhang2, Hualiang Xiao3, Yao Zhang1, Zaoming Huang1, Junjie Yang1, Jun Zhang1, Jun Jiang1

1Department of Urology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, 400042, PR China

2Department of Bio-Medical Sciences, Philadelphia College of Osteopathic Medicine, Philadelphia, PA, 19131, USA

3Department of Pathology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, 400042, PR China

*These authors have contributed equally to this work

Correspondence to:

Jun Jiang, email: [email protected]

Keywords: metformin, CSC, COX2, PGE2, STAT3 signaling

Received: January 30, 2016    Accepted: March 28, 2016    Published: April 5, 2016

ABSTRACT

Cancer stem cells (CSCs) are a sub-population of tumor cells playing essential roles in initiation, differentiation, recurrence, metastasis and development of drug resistance of various cancers, including bladder cancer. Although multiple lines of evidence suggest that metformin is capable of repressing CSC repopulation in different cancers, the effect of metformin on bladder cancer CSCs remains largely unknown. Using the N-methyl-N-nitrosourea (MNU)-induced rat orthotropic bladder cancer model, we demonstrated that metformin is capable of repressing bladder cancer progression from both mild to moderate/severe dysplasia lesions and from carcinoma in situ (CIS) to invasive lesions. Metformin also can arrest bladder cancer cells in G1/S phases, which subsequently leads to apoptosis. And also metformin represses bladder cancer CSC repopulation evidenced by reducing cytokeratin 14 (CK14+) and octamer-binding transcription factor 3/4 (OCT3/4+) cells in both animal and cellular models. More importantly, we found that metformin exerts these anticancer effects by inhibiting COX2, subsequently PGE2 as well as the activation of STAT3. In conclusion, we are the first to systemically demonstrate in both animal and cell models that metformin inhibits bladder cancer progression by inhibiting stem cell repopulation through the COX2/PGE2/STAT3 axis.


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