Twist1 Enhances Hypoxia Induced Radioresistance in Cervical Cancer Cells by Promoting Nuclear EGFR Localization.
Twist1 Enhances Hypoxia Induced Radioresistance in Cervical Cancer Cells by Promoting Nuclear EGFR Localization.
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Twist1通过促进EGFR核定位增强宫颈癌细胞缺氧诱导的放射抗性
DOI：
10.7150/jca.16607
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发表时间：
2017
影响因子：
3.9
通讯作者：
Xiong H
中科院分区：
文献类型：
--
作者：
Xiong H;Nie X;Zou Y;Gong C;Li Y;Wu H;Qiu H;Yang L;Zhuang L;Zhang P;Zhang J;Wang Y;Xiong H
Twist 1是一个重要的转录因子，调节上皮间质转化并参与转移。最近的研究表明，Twist 1在低氧诱导的辐射抗性中起重要作用，但其机制尚不清楚。本研究探讨了Twist 1在人宫颈鳞癌细胞系SiHa中的表达变化。我们还通过调控Twist 1的表达水平，探讨了Twist 1在辐射抗性中的作用。我们观察到，缺氧处理提高SiHa细胞Twist 1的表达。siRNA敲低Twist 1基因可增加SiHa细胞在缺氧条件下的放射敏感性，同时降低细胞核表皮生长因子受体（EGFR）和DNA依赖性蛋白激酶（DNA-PK）的水平。相反，Twist 1的过表达导致SiHa细胞的放射抗性增加，这反过来又增加了核EGFR定位和核DNA-PK的表达水平。此外，宫颈癌患者原发灶中低氧诱导因子-1 α（HIF-1α）和Twist 1的高表达与放疗后的不良预后相关。总之，这些数据提供了新的见解缺氧诱导的宫颈癌细胞的放射抵抗的分子机制，并建议Twist 1是一个有前途的分子靶点，以提高癌症放射治疗的疗效。
Twist1 is a crucial transcription factor that regulates epithelial mesenchymal transition and involves in metastasis. Recent evidence suggests that Twist1 plays important role in hypoxia-induced radioresistance, but the underlying mechanism remains elusive. Here we investigated the change of Twist1 expression in human cervical squamous cancer cell line SiHa after hypoxia treatment. We also explored the role of Twist1 in radioresistance by manipulating the expression level of Twist1. We observed that hypoxia treatment elevated the expression of Twist1 in SiHa cells. Knockdown of Twist1 with siRNA increased the radiosensitivity of SiHa cells under hypoxia condition, accompanied by reduced levels of nuclear Epidermal Growth Factor Receptor (EGFR) and DNA-dependent protein kinase (DNA-PK). Conversely, overexpression of Twist1 led to increased radioresistance of SiHa cells, which in turn increased nuclear EGFR localization and expression levels of nuclear DNA-PK. Moreover, concomitant high expression of hypoxia-inducible factor-1α (HIF-1α) and Twist1 in primary tumors of cervical cancer patients correlated with the worse prognosis after irradiation treatment. Taken together, these data provide new insights into molecular mechanism underlying hypoxia-induced radioresistance in cervical cancer cells, and suggest that Twist1 is a promising molecular target to improve the efficacy of cancer radiotherapy.