Chen Mengyue, Sun Xinwei, Wang Yanzhou, Ling Kaijian, Chen Cheng, Cai Xiongwei, Liang Xiaolong, Liang Zhiqing
Department of Obstetrics & Gynaecology, Southwest Hospital, Army Medical University Chongqing, China.
Int J Clin Exp Pathol. 2019 Oct 1;12(10):3807-3818. eCollection 2019.
FAT1 is a mutant gene found frequently in human cervical cancer (CC), but its expression and relevance in CC proliferation, invasion, and migration are still unknown. We aimed to explore the role and novel mechanism of FAT1 in CC progression. The expression of FAT1 in CC and adjacent normal tissues was analysed, and we investigated the proliferation, migration, and invasion of HeLa and C33A cells treated with wild-type FAT1 plasmid or FAT1 siRNA. Meanwhile, we evaluated the effect of FAT1 on the epithelial-mesenchymal transition (EMT) and the β-catenin-mediated transcription of target genes. Here, we showed that FAT1 expression was significantly lower in CC tissues than in adjacent tissues. FAT1 overexpression significantly dysregulated CC cell proliferation, invasion, and migration, whereas FAT1 knockdown had the opposite effect. FAT1 overexpression promoted the expression of phosphorylated β-catenin and E-cadherin protein and inhibited the expression of vimentin, TWIST, and several downstream targets of β-catenin, namely, c-MYC, TCF-4 and MMP14. In contrast, FAT1 silencing notably increased the expression c-MYC, TCF-4, and MMP14 and promoted the EMT in HeLa and C33A cells. Endogenous and exogenous FAT1 was confirmed to interact with β-catenin, and the overexpression of β-catenin could partially block the effect of FAT1 on the proliferation, migration, and invasion of HeLa and C33A cells. FAT1 acts as a tumor suppressor by inhibiting β-catenin-mediated transcription and might be used as a novel anti-metastatic agent in targeted CC therapy.
FAT1是一种在人类宫颈癌（CC）中频繁发现的突变基因，但其在CC增殖、侵袭和迁移中的表达及相关性仍不清楚。我们旨在探讨FAT1在CC进展中的作用和新机制。分析了FAT1在CC组织和相邻正常组织中的表达，并研究了用野生型FAT1质粒或FAT1 siRNA处理的HeLa和C33A细胞的增殖、迁移和侵袭情况。同时，我们评估了FAT1对上皮-间质转化（EMT）和β-连环蛋白介导的靶基因转录的影响。在此，我们表明FAT1在CC组织中的表达明显低于相邻组织。FAT1过表达显著失调CC细胞的增殖、侵袭和迁移，而FAT1敲低则产生相反的效果。FAT1过表达促进磷酸化β-连环蛋白和E-钙黏蛋白的表达，并抑制波形蛋白、TWIST以及β-连环蛋白的几个下游靶标，即c-MYC、TCF-4和MMP14的表达。相反，FAT1沉默显著增加c-MYC、TCF-4和MMP14的表达，并促进HeLa和C33A细胞中的EMT。证实内源性和外源性FAT1与β-连环蛋白相互作用，β-连环蛋白的过表达可部分阻断FAT1对HeLa和C33A细胞增殖、迁移和侵袭的影响。FAT1通过抑制β-连环蛋白介导的转录发挥肿瘤抑制作用，可能用作靶向CC治疗中的新型抗转移药物。
