Cao Jia, Wang Xi, Wang Danni, Ma Rong, Li Xiaohan, Feng Huimin, Wang Jia, Liu Shihai, Wang Libin
1School of Clinical Medicine, Ningxia Medical University, Yinchuan, 750004 China.
2Beijing National Biochip Research Center Sub-Center in Ningxia, The General Hospital of Ningxia Medical University, Yinchuan, 750004 China.
Cancer Cell Int. 2019 Apr 11;19:93. doi: 10.1186/s12935-019-0810-5. eCollection 2019.
Breast cancer is one of the most common malignancy among females from the worldwide cancer incidence statistics. Peroxisome gamma coactivator-1β (PGC-1β) has long been identified to be involved in this type of tumorigenesis. However, the mechanisms of PGC-1β in human breast cancer have not been fully understood and the function requires to be further elucidated.
mRNA and protein expression of PGC-1β and FOXA2 in breast cancer tissues and cell lines were determined by qRT-PCR and Western Blotting, respectively. To further visualize the expression and localization of PGC-1β and FOXA2, immunochemistry and immunofluorescence staining methods were employed. The effect of PGC-1β and FOXA2 on cell proliferation and migration were evaluated by CCK8, clone formation, transwell and wound-healing assays, which has been done either with stable PGC-1β knockdown or FOXA2 overexpression in vitro. Xenografts model of nude mice were used to evaluate tumor growth in vivo. In addition, proteins expression of the PI3K-AKT-mTOR signaling pathway involved in the regulation of breast cancer were detected by Western Blotting.
Our results showed that PGC-1β was upregulated and FOXA2 was downregulated in breast cancer tissues and cell lines. These two proteins can be interacted with each other to form the complex. Also, we found the combination of PGC-1β interference with FOXA2 overexpression significantly inhibited cell proliferation and migration in vitro as well as tumor growth in vivo. We further identified that PGC-1β and FOXA2 strongly correlated with the PI3K-AKT-mTOR signaling pathway, and they exerted their biological functions by activating this pathway.
We demonstrated that downregulation of PGC-1β combined with overexpression of FOXA2 obviously inhibited the function of breast cancer cells through regulating the PI3K-AKT-mTOR pathway.
从全球癌症发病率统计数据来看，乳腺癌是女性中最常见的恶性肿瘤之一。过氧化物酶体γ共激活因子-1β（PGC-1β）长期以来被认为参与了这类肿瘤的发生。然而，PGC-1β在人类乳腺癌中的作用机制尚未完全明确，其功能有待进一步阐明。
分别采用qRT-PCR和蛋白质免疫印迹法检测乳腺癌组织及细胞系中PGC-1β和FOXA2的mRNA及蛋白表达。为进一步观察PGC-1β和FOXA2的表达及定位，采用了免疫组织化学和免疫荧光染色方法。通过CCK8、克隆形成、Transwell和伤口愈合实验评估PGC-1β和FOXA2对细胞增殖和迁移的影响，这些实验在体外通过稳定敲低PGC-1β或过表达FOXA2来完成。利用裸鼠异种移植模型评估体内肿瘤生长情况。此外，通过蛋白质免疫印迹法检测参与乳腺癌调控的PI3K-AKT-mTOR信号通路的蛋白表达。
我们的结果显示，PGC-1β在乳腺癌组织和细胞系中上调，而FOXA2下调。这两种蛋白可相互作用形成复合物。此外，我们发现干扰PGC-1β并过表达FOXA2的组合显著抑制了体外细胞增殖和迁移以及体内肿瘤生长。我们进一步确定，PGC-1β和FOXA2与PI3K-AKT-mTOR信号通路密切相关，它们通过激活该通路发挥生物学功能。
我们证明，下调PGC-1β并过表达FOXA2可通过调节PI3K-AKT-mTOR通路明显抑制乳腺癌细胞的功能。
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