Zhang Manying, Liang Lin, He Junyu, He Zhengxi, Yue Chunxue, Jin Xi, Gao Mengxiang, Xiao Songshu, Zhou Yanhong
Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China.
NHC Key Laboratory of Carcinogenesis, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China.
Front Cell Dev Biol. 2020 Sep 30;8:579629. doi: 10.3389/fcell.2020.579629. eCollection 2020.
The oncogenesis of cervical cancer is a multi-factor and multi-step process, and major risk factors include oncogene activation with tumor suppressor gene inactivation, viral factors, and immune factors. For example, the human papillomavirus (HPV) has been linked to the occurrence of cervical cancer. At present, the pathogenesis of cervical cancer remains unclear. Fra-1 (Fos-related antigen 1, also known as FOSL1) is a member of the Fos family and an important nuclear transcription factor that regulates normal cell growth, differentiation, and apoptosis. In the present study, we found that Fra-1 inhibited the proliferation of cervical cancer cells while also promoting apoptosis and affecting cell cycle distribution. Moreover, Fra-1 up-regulated STAT1 expression and modulated p53 signal pathway activity in cervical cancer cells. Overexpression of Fra-1 inhibited cell senescence by altering sirtuin 1 (SIRT1) expression in HeLa cells, and Fra-1 overexpression restored mitochondrial disorder and suppressed metabolic reprogramming in HeLa cells. Silencing of STAT1 impaired the inhibitory effect of Fra-1 on cervical cancer cell growth, while knock-down of STAT1 reversed the effect on cell senescence and mitochondrial dysfunction caused by Fra-1 in HeLa cells. Silencing of STAT1 also recovered metabolic reprogramming in cervical cancer cells. In summary, our results show that Fra-1 inhibited cervical cancer cell growth and the Warburg effect via STAT1-mediated regulation of the p53 signaling pathway.
宫颈癌的发生是一个多因素、多步骤的过程，主要危险因素包括癌基因激活与肿瘤抑制基因失活、病毒因素和免疫因素。例如，人乳头瘤病毒（HPV）与宫颈癌的发生有关。目前，宫颈癌的发病机制仍不清楚。Fra-1（Fos相关抗原1，也称为FOSL1）是Fos家族的成员，是一种重要的核转录因子，可调节正常细胞的生长、分化和凋亡。在本研究中，我们发现Fra-1抑制宫颈癌细胞的增殖，同时促进细胞凋亡并影响细胞周期分布。此外，Fra-1上调STAT1的表达并调节宫颈癌细胞中p53信号通路的活性。Fra-1的过表达通过改变HeLa细胞中沉默调节蛋白1（SIRT1）的表达来抑制细胞衰老，并且Fra-1的过表达恢复了HeLa细胞中的线粒体紊乱并抑制了代谢重编程。STAT1的沉默削弱了Fra-1对宫颈癌细胞生长的抑制作用，而STAT1的敲低逆转了Fra-1对HeLa细胞中细胞衰老和线粒体功能障碍的影响。STAT1的沉默还恢复了宫颈癌细胞中的代谢重编程。总之，我们的结果表明，Fra-1通过STAT1介导的p53信号通路调节抑制宫颈癌细胞生长和瓦伯格效应。
