Metformin represses bladder cancer progression by inhibiting stem cell repopulation via COX2/PGE2/STAT3 axis
Metformin represses bladder cancer progression by inhibiting stem cell repopulation via COX2/PGE2/STAT3 axis
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二甲双胍通过 COX2/PGE2/STAT3 轴抑制干细胞再增殖来抑制膀胱癌进展
DOI：
10.18632/oncotarget.8595
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发表时间：
2016-05-10
期刊：
影响因子：
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通讯作者：
Jiang, Jun
中科院分区：
文献类型：
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作者：
Liu, Qiuli;Yuan, Wenqiang;Jiang, Jun
肿瘤干细胞（Cancer stem cells, CSCs）是肿瘤细胞的一个亚群，在包括膀胱癌在内的多种癌症的发生、分化、复发、转移和耐药发展中发挥着重要作用。尽管多项证据表明二甲双胍能够抑制不同癌症中CSC的再生，但二甲双胍对膀胱癌CSC的影响在很大程度上仍然未知。利用n -甲基-n -亚硝基脲（MNU）诱导的大鼠原位各向异性膀胱癌模型，我们证明了二甲双胍能够抑制膀胱癌从轻度到中度/重度发育不良病变以及从原位癌（CIS）到侵袭性病变的进展。二甲双胍还能使膀胱癌细胞处于G1/S期，随后导致细胞凋亡。在动物和细胞模型中，二甲双胍还通过减少细胞角蛋白14 （CK14+）和八聚体结合转录因子3/4 （OCT3/4+）细胞来抑制膀胱癌CSC的再生。更重要的是，我们发现二甲双胍通过抑制COX2，随后抑制PGE2以及STAT3的激活来发挥这些抗癌作用。总之，我们是第一个系统地在动物和细胞模型中证明二甲双胍通过COX2/PGE2/STAT3轴抑制干细胞再生来抑制膀胱癌进展的研究。
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.