Department of Obstetrics and Gynecology, the Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
Departments of Cell Systems & Anatomy, School of Medicine, University of Texas Health Science Center, San Antonio, TX, USA.
Lab Invest. 2018 Nov;98(11):1384-1396. doi: 10.1038/s41374-018-0089-5. Epub 2018 Jul 2.
Advanced, recurrent, or persistent cervical cancer is often incurable. Therefore, in-depth insights into the molecular mechanisms are needed for the development of novel therapeutic targets and the improvement of current therapeutic strategies. In this study, we investigated the role of GLI2 and GLI3 in the regulation of the malignant properties of cervical cancer. We showed that down-regulation of GLI2, but not GLI3, with an inducible GLI2 shRNA inhibited the growth and migration of cervical cancer cell lines, which could be rescued by ectopic expression of GLI2. GLI2 appeared to support cell growth by regulating the mitosis, but not the apoptosis, of the cervical cancer cells. Mechanistically, these functions of GLI2 were in part mediated by the activation of AKT pathway. Knockdown of GLI2, but not GLI3, also inhibited xenograft growth of cervical cancer cells in vivo. Finally, analysis of TCGA data showed that high levels of GLI2, but not GLI3, conferred a poor prognosis in cervical cancer patients. These observations for the first time suggest that GLI2, but not GLI3, exerts a tumor-promoting role in cervical cancer and may be targeted as a novel therapeutic strategy.
晚期、复发性或持续性宫颈癌通常无法治愈。因此，需要深入了解分子机制，以便开发新的治疗靶点并改进现有的治疗策略。在这项研究中，我们研究了 GLI2 和 GLI3 在调节宫颈癌恶性特性中的作用。我们发现，用诱导型 GLI2 shRNA 下调 GLI2，但不是 GLI3，可抑制宫颈癌细胞系的生长和迁移，而过表达 GLI2 可挽救这种抑制作用。GLI2 似乎通过调节宫颈癌细胞的有丝分裂，而不是凋亡，来支持细胞生长。从机制上讲，GLI2 的这些功能部分是通过激活 AKT 通路介导的。GLI2 的敲低而非 GLI3 的敲低也抑制了体内宫颈癌细胞的异种移植生长。最后，TCGA 数据分析表明，GLI2 水平高而不是 GLI3 水平高与宫颈癌患者预后不良相关。这些观察结果首次表明，GLI2 而不是 GLI3 在宫颈癌中发挥促肿瘤作用，可能成为一种新的治疗策略。
