Xu Yichi, Pan Shuya, Chen Hong, Qian Hongfei, Wang Zhiwei, Zhu Xueqiong
Center for Uterine Cancer Diagnosis & Therapy Research of Zhejiang Province, Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Wenzhou Medical University Wenzhou, People's Republic of China.
Am J Cancer Res. 2021 Apr 15;11(4):1446-1462. eCollection 2021.
MEX3A, one member of the human MEX3 gene family, exerts different effects on a variety of human cancer cells. However, the biological functions and regulatory mechanism have not been explored in cervical cancer. In our study, we used multiple approaches to determine the functions and underlying molecular mechanism of MEX3A in cervical tumorigenesis, including CCK-8 assay, BrdU assay, FACS for cell cycle and apoptosis, wound healing assay, Transwell migration and invasion assays, immunohistochemistry (IHC) assay, Transfection, real-time RT-PCR and Western blotting analysis. IHC results showed that the expression levels of MEX3A were decreased in cervical cancer patients with advanced clinical stages and lymph node involvement. Moreover, upregulation of MEX3A attenuated cell proliferation, migration and invasion and induced cell cycle arrest at G0/G1 phase in human cervical cancer cells, whereas knockdown of MEX3A exhibited the opposite effects. Mechanistically, MEX3A exerted its tumor suppressive functions via inactivation of Akt signaling pathway and inhibiting epithelial to mesenchymal transition (EMT). Importantly, Akt activation by its activator SC79 reversed the biological functions of MEX3A overexpression. Furthermore, MEX3A inhibited tumor growth in xenograft models. Overall, our investigation suggested that MEX3A participated in antitumor activity in cervical cancer by inhibition of the Akt signaling pathway and EMT. Hence, targeting MEX3A might have a therapeutic potential to treat cervical cancer.
MEX3A是人类MEX3基因家族的成员之一，对多种人类癌细胞具有不同影响。然而，其在宫颈癌中的生物学功能和调控机制尚未得到探索。在我们的研究中，我们采用多种方法来确定MEX3A在宫颈肿瘤发生中的功能及潜在分子机制，包括CCK-8检测、BrdU检测、细胞周期和凋亡的流式细胞术检测、伤口愈合检测、Transwell迁移和侵袭检测、免疫组织化学（IHC）检测、转染、实时RT-PCR和蛋白质印迹分析。免疫组织化学结果显示，MEX3A的表达水平在临床晚期和有淋巴结转移的宫颈癌患者中降低。此外，MEX3A的上调减弱了人宫颈癌细胞的增殖、迁移和侵袭，并诱导细胞周期停滞在G0/G1期，而敲低MEX3A则表现出相反的效果。机制上，MEX3A通过使Akt信号通路失活并抑制上皮-间质转化（EMT）发挥其肿瘤抑制功能。重要的是，其激活剂SC79激活Akt可逆转MEX3A过表达的生物学功能。此外，MEX3A在异种移植模型中抑制肿瘤生长。总体而言，我们的研究表明MEX3A通过抑制Akt信号通路和EMT参与宫颈癌的抗肿瘤活性。因此，靶向MEX3A可能具有治疗宫颈癌的潜力。
