title: Metformin represses bladder cancer progression by inhibiting stem cell repopulation via COX2/PGE2/STAT3 axis.
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.
authors.affiliation: Department of Urology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, 400042, PR China.
authors.forename: Qiuli
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Department of Urology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, 400042, PR China.
authors.forename: Wenqiang
authors.initials: W
authors.lastname: Yuan
authors.affiliation: Department of Urology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, 400042, PR China.
authors.forename: Dali
authors.initials: D
authors.lastname: Tong
authors.affiliation: Department of Urology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, 400042, PR China.
authors.forename: Gaolei
authors.initials: G
authors.lastname: Liu
authors.affiliation: Department of Urology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, 400042, PR China.
authors.forename: Weihua
authors.initials: W
authors.lastname: Lan
authors.affiliation: Department of Bio-Medical Sciences, Philadelphia College of Osteopathic Medicine, Philadelphia, PA, 19131, USA.
authors.forename: Dianzheng
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Department of Pathology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, 400042, PR China.
authors.forename: Hualiang
authors.initials: H
authors.lastname: Xiao
authors.affiliation: Department of Urology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, 400042, PR China.
authors.forename: Yao
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Urology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, 400042, PR China.
authors.forename: Zaoming
authors.initials: Z
authors.lastname: Huang
authors.affiliation: Department of Urology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, 400042, PR China.
authors.forename: Junjie
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Urology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, 400042, PR China.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Urology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, 400042, PR China.
authors.forename: Jun
authors.initials: J
authors.lastname: Jiang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2 / Q000187:drug effects / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D018450:Disease Progression; D006801:Humans; D008687:Metformin / Q000494:pharmacology*; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000473:pathology; D051381:Rats; D050796:STAT3 Transcription Factor / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D001749:Urinary Bladder Neoplasms / Q000473:pathology*
chemical_list: D000970:Antineoplastic Agents; D050796:STAT3 Transcription Factor; D008687:Metformin; D051546:Cyclooxygenase 2; D015232:Dinoprostone
keywords: COX2; CSC; PGE2; STAT3 signaling; metformin