Ji Liang, Zhao Guannan, Zhang Peng, Huo Wenying, Dong Peixin, Watari Hidemichi, Jia Limin, Pfeffer Lawrence M, Yue Junming, Zheng Jinhua
Department of Anatomy, College of Basic Medical Science, Harbin Medical University, Harbin, China.
Department of Pathology and Laboratory Medicine, the University of Tennessee Health Science Center, Memphis, TN, 38163, USA.
J Cancer. 2018 Nov 11;9(24):4578-4585. doi: 10.7150/jca.28040. eCollection 2018.
Due to peritoneal metastasis and frequent recurrence, ovarian cancer has the highest mortality among gynecological cancers. Epithelial to mesenchymal transition (EMT) contributes to ovarian tumor metastasis. In this study, we report for the first time that metal regulatory transcription factor 1 (MTF1) was upregulated in ovarian cancer, and its high expression was associated with poor patient survival and disease relapse. Knockout of MTF1 using lentiviral CRISPR/Cas9 nickase vector-mediated gene editing inhibited EMT by upregulating epithelial cell markers E-cadherin and cytokeratin 7, and downregulating mesenchymal markers Snai2 and β-catenin in ovarian cancer SKOV3 and OVCAR3 cells. Loss of MTF1 reduced cell proliferation, migration, and invasion in both SKOV3 and OVCAR3 cells. Knockout of MTF1 upregulated the expression of the KLF4 transcription factor, and attenuated two cellular survival pathways, ERK1/2 and AKT. Our studies demonstrated that MTF1 plays an oncogenic role and contributes to ovarian tumor metastasis by promoting EMT. MTF1 may be a novel biomarker for early diagnosis as well as a drug target for clinical therapy.
由于腹膜转移和频繁复发，卵巢癌在妇科癌症中死亡率最高。上皮-间质转化（EMT）促进卵巢肿瘤转移。在本研究中，我们首次报道金属调节转录因子1（MTF1）在卵巢癌中上调，其高表达与患者生存率低和疾病复发相关。使用慢病毒CRISPR/Cas9切口酶载体介导的基因编辑敲除MTF1，通过上调上皮细胞标志物E-钙黏蛋白和细胞角蛋白7以及下调卵巢癌SKOV3和OVCAR3细胞中的间质标志物Snai2和β-连环蛋白来抑制EMT。MTF1缺失降低了SKOV3和OVCAR3细胞的增殖、迁移和侵袭能力。敲除MTF1上调了KLF4转录因子的表达，并减弱了两条细胞存活途径ERK1/2和AKT。我们的研究表明，MTF1发挥致癌作用，并通过促进EMT促进卵巢肿瘤转移。MTF1可能是早期诊断的新型生物标志物以及临床治疗的药物靶点。
