南方医科大学学报2024，Vol.44Issue(3)：428-436,9.DOI:10.12122/j.issn.1673-4254.2024.03.03
二甲双胍阻断乳腺癌细胞-间质细胞的交互作用:基于抑制肿瘤相关成纤维细胞缺氧诱导因子-1α的表达
Metformin suppresses hypoxia-inducible factor-1α expression in cancer-associated fibroblasts to block tumor-stromal cross-talk in breast cancer
摘要
Abstract
Objective To investigate the mechanism of metformin for regulating tumor-stromal cell cross-talk in breast cancer.Methods Tumor associated fibroblasts(CAFs)co-cultured with breast cancer cells were treated with metformin,and the changes in expressions of hypoxia-inducible factor-1α(HIF-1α),p-AMPK,stroma-derived factor-1(SDF-1)and interleukin-8(IL-8)in the CAFs were detected using ELISA,RT-qPCR or Western blotting;Transwell assay was used to evaluate the invasiveness of the tumor cells and its changes following treatment with exogenous SDF-1,IL-8 and TGF-β1.The effects of HIF-1α shRNA or overexpression plasmid,AMPK shRNA,and treatment with OG(a proline hydroxylase inhibitor)or 2-OXO(a proline hydroxylase activator)were examined on p-AMPK,HIF-1α,SDF-1 and IL-8 expressions and invasiveness of the CAFs.Results Metformin treatment significantly increased the expression levels of p-AMPK,SDF-1 and IL-8(P<0.05)and decreased HIF-1α expression(P<0.05)without affecting AMPK expression level(P>0.05)in the CAFs.The invasion ability of metformin-treated breast cancer cells was significantly decreased(P<0.05).Exogenous SDF-1 and IL-8,HIF-1α overexpression,and OG-induced upregulation of HIF-1α all significantly attenuated the inhibitory effects of metformin on breast cancer cell invasion(P<0.05)and HIF-1α,SDF-1 and IL-8 expressions in CAFs(P<0.05).Transfection with HIF-1α shRNA or treatment with 2-OXO significantly decreased the invasiveness of breast cancer cells(P<0.05).P-AMPK knockdown significantly suppressed the inhibitory effect of metformin on HIF-1α expression in CAFs and on invasion of breast cancer cells(P<0.05).Treatment with TGF-β1 partially decreased the inhibitory effect of metformin on HIF-1α expression in CAFs and invasiveness of the breast cancer cells(P<0.05).Conclusion Metformin suppresses HIF-1α expression in CAFs to block tumor-stromal cross talk in breast cancer.关键词
肿瘤相关成纤维细胞/缺氧诱导因子-1α/二甲双胍/磷酸化-AMPK/肿瘤微环境Key words
cancer-associated fibroblasts/hypoxia-inducible factor-1α/metformin/phospho-AMPK/tumor microenvironment引用本文复制引用
邵珊,白薇超,邹鹏程,罗敏娜,赵新汉,雷建军..二甲双胍阻断乳腺癌细胞-间质细胞的交互作用:基于抑制肿瘤相关成纤维细胞缺氧诱导因子-1α的表达[J].南方医科大学学报,2024,44(3):428-436,9.基金项目
国家自然科学基金(81502066,81702908) （81502066,81702908）
陕西省自然科学基础研究计划资助项目(面上)(2019JM-115,2018JQ8030) （面上）
西安交通大学基础科研业务费资助项目(xzy012019090)Supported by National Natural Science Foundation of China(81502066,81702908). （xzy012019090）
