ESRP1 Induces Cervical Cancer Cell G1-Phase Arrest Via Regulating Cyclin A2 mRNA Stability
ESRP1 Induces Cervical Cancer Cell G1-Phase Arrest Via Regulating Cyclin A2 mRNA Stability
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ESRP1通过调节细胞周期蛋白A2 mRNA稳定性诱导宫颈癌细胞G1期阻滞
DOI：
10.3390/ijms20153705
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发表时间：
2019-08-01
影响因子：
5.6
通讯作者：
Su, Xiu-Zhen
中科院分区：
文献类型：
--
作者：
Chen, Zhi-Hong;Jing, Ya-Jie;Su, Xiu-Zhen
越来越多的证据表明，上皮剪接调节蛋白1（epithelial splicing regulatory protein 1，ESRP 1）能够抑制上皮细胞向间质细胞转化（epithelial-to-mesenchymal transition，EMT），在肿瘤的转移过程中发挥重要作用。然而，目前尚不清楚ESRP 1是否直接影响细胞周期，或者可能的潜在分子机制是什么。在本研究中，我们发现ESRP 1蛋白水平与Ki-67增殖指数显著相关（r = -0.521; p < 0.01），ESRP 1过表达可显著抑制宫颈癌细胞增殖，并通过下调cyclin A2表达诱导G1期阻滞。重要的是，ESRP 1可以结合细胞周期蛋白A2 mRNA的3 ' UTR中的GGUGGU序列，并且ESRP 1过表达显著降低细胞周期蛋白A2 mRNA的稳定性。此外，我们的实验结果证实，ESRP 1过表达导致增强的CDC 20表达，这是已知的负责细胞周期蛋白A2降解。本研究首次证明ESRP 1过表达可通过降低cyclin A2 mRNA的稳定性，诱导细胞周期停滞于G1期，从而抑制宫颈癌细胞的增殖。研究结果表明，ESRP 1/细胞周期蛋白A2调节轴可能是必不可少的细胞增殖的调节器，因此可能是宫颈癌预防和治疗的一个有吸引力的目标。
Accumulating evidence indicates that epithelial splicing regulatory protein 1 (ESRP1) can inhibit the epithelial-to-mesenchymal transition (EMT), thus playing a central role in regulating the metastatic progression of tumors. However, it is still not clear whether ESRP1 directly influences the cell cycle, or what the possible underlying molecular mechanisms are. In this study, we showed that ESRP1 protein levels were significantly correlated with the Ki-67 proliferative index (r = -0.521; p < 0.01), and that ESRP1 overexpression can significantly inhibit cervical carcinoma cell proliferation and induced G1-phase arrest by downregulating cyclin A2 expression. Importantly, ESRP1 can bind to GGUGGU sequence in the 3 ' UTR of the cyclin A2 mRNA, and ESRP1 overexpression significantly decreases the stability of the cyclin A2 mRNA. In addition, our experimental results confirm that ESRP1 overexpression results in enhanced CDC20 expression, which is known to be responsible for cyclin A2 degradation. This study provides the first evidence that ESRP1 overexpression induces G1-phase cell cycle arrest via reducing the stability of the cyclin A2 mRNA, and inhibits cervical carcinoma cell proliferation. The findings suggest that the ESRP1/cyclin A2 regulatory axis may be essential as a regulator of cell proliferation, and may thus represent an attractive target for cervical cancer prevention and treatment.