Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.
Department of Obstetrics and Gynecology, School of Medicine, College of Medicine, Chung Shan Medical University, Taichung, Taiwan.
Cell Death Dis. 2021 May 6;12(5):451. doi: 10.1038/s41419-021-03729-1.
Metastasis-associated protein 2 (MTA2) is a transcription factor that is highly associated with matrix metalloproteinase 12 (MMP12). Thus, we hypothesized that MTA2 may regulate MMP12 expression and is involved in cervical cancer metastasis. Results showed that MTA2 and MMP12 were highly expressed in cervical cancer cells, and MTA2 knockdown reduced MMP12 expression and inhibited the metastasis of cervical cancer cells in xenograft mice. MMP12 knockdown did not influence the viability of cervical cancer cells but clearly inhibited cell migration and invasion both in vitro and in vivo. MMP12 was highly expressed in cervical tumor tissues and correlated with the poor survival rate of patients with cervical cancer. Further investigations revealed that p38 mitogen-activated protein kinase (p38), mitogen-activated protein kinase kinase 3 (MEK3), and apoptosis signal-regulating kinase 1 (ASK1) were involved in MMP12 downregulation in response to MTA2 knockdown. Results also demonstrated that p38-mediated Y-box binding protein1 (YB1) phosphorylation disrupted the binding of AP1 (c-Fos/c-Jun) to the MMP12 promoter, thereby inhibiting MMP12 expression and the metastatic potential of cervical cancer cells. Collectively, targeting both MTA2 and MMP12 may be a promising strategy for the treatment of cervical cancer.
转移相关蛋白 2（MTA2）是一种转录因子，与基质金属蛋白酶 12（MMP12）高度相关。因此，我们假设 MTA2 可能调节 MMP12 的表达，并参与宫颈癌的转移。结果表明，MTA2 和 MMP12 在宫颈癌细胞中高表达，MTA2 敲低降低了 MMP12 的表达，并抑制了异种移植小鼠中宫颈癌细胞的转移。MMP12 敲低不影响宫颈癌细胞的活力，但明显抑制了细胞的迁移和侵袭，无论是在体外还是体内。MMP12 在宫颈癌组织中高表达，与宫颈癌患者生存率差相关。进一步的研究表明，p38 丝裂原活化蛋白激酶（p38）、丝裂原活化蛋白激酶激酶 3（MEK3）和凋亡信号调节激酶 1（ASK1）参与了 MTA2 敲低后 MMP12 的下调。结果还表明，p38 介导的 Y 盒结合蛋白 1（YB1）磷酸化破坏了 AP1（c-Fos/c-Jun）与 MMP12 启动子的结合，从而抑制了 MMP12 的表达和宫颈癌细胞的转移潜力。总之，靶向 MTA2 和 MMP12 可能是治疗宫颈癌的一种有前途的策略。
