Lin Chia-Liang, Ying Tsung-Ho, Yang Shun-Fa, Wang Shih-Wei, Cheng Shih-Ping, Lee Jie-Jen, Hsieh Yi-Hsien
Institute of Biochemistry, Microbiology, and Immunology, Chung Shan Medical University, Taichung, Taiwan; Department of Surgery, MacKay Memorial Hospital and Mackay Medical College, New Taipei City, Taiwan.
Department of Obstetrics and Gynecology, Chung Shan Medical University Hospital, Taichung, Taiwan; Department of Obstetrics and Gynecology, School of Medicine, College of Medicine, Chung Shan Medical University, Taichung, Taiwan.
Mol Ther Nucleic Acids. 2020 Jun 5;20:699-710. doi: 10.1016/j.omtn.2020.04.009. Epub 2020 Apr 28.
MTA2 is involved in tumor proliferation and metastasis. However, the role of MTA2 in cervical cancer thus far has not been identified. In this study, we report that elevated expression of MTA2 negatively correlates with Kallikrein-10 (KLK10) expression and poor prognosis of cervical cancer patients. Knockdown of MTA2 substantially inhibited tumor cell migration and invasion, and it enhanced KLK10 expression of the cervical cancer cells in vitro and in vivo. Functionally, shMTA2-mediated suppression of cell mobility was significantly restored by knockdown of KLK10. We also found that Sp1 (transcription factor specificity protein 1) is critical for shMTA2-induced transcriptional upregulation of KLK10 and subsequent biological functions. Furthermore, we found that the expression of miR-7 is elevated by MTA2 silencing and then by direct inhibition of Sp1 expression. Knockdown of Sp1 additively enhanced KLK10 expression in MTA2-knocked down cervical cancer cells, suggesting that the miR-7/Sp1 axis acts as an effector of MTA2 to impact KLK10 levels and mobility of cervical cancer cells. Taken together, our findings provide new insights into the physiological relationship between MTA2 and KLK10 via regulating the miR-7/Sp1 axis, and they provide a potential therapeutic target in cervical cancer.
MTA2参与肿瘤增殖和转移。然而，迄今为止MTA2在宫颈癌中的作用尚未明确。在本研究中，我们报告MTA2表达升高与激肽释放酶10（KLK10）表达及宫颈癌患者预后不良呈负相关。敲低MTA2可显著抑制肿瘤细胞迁移和侵袭，并在体外和体内增强宫颈癌细胞的KLK10表达。在功能上，敲低KLK10可显著恢复shMTA2介导的细胞迁移抑制。我们还发现，Sp1（转录因子特异性蛋白1）对于shMTA2诱导的KLK10转录上调及随后的生物学功能至关重要。此外，我们发现MTA2沉默可使miR-7表达升高，进而直接抑制Sp1表达。敲低Sp1可在MTA2敲低的宫颈癌细胞中累加增强KLK10表达，表明miR-7/Sp1轴作为MTA2的效应因子影响宫颈癌细胞的KLK10水平和迁移能力。综上所述，我们的研究结果通过调节miR-7/Sp1轴为MTA2与KLK10之间的生理关系提供了新见解，并为宫颈癌提供了潜在的治疗靶点。
