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通过ERK/ELK1信号通路降低FEN1的调节,抑制雄激素受体增强前列腺癌的化学敏感性
Weijie Xie1, Shulin Li1,2, Huan Guo1
1Department of Urology and Carson International Cancer Center, Shenzhen University General Hospital and Shenzhen University Clinical Medical Academy Center, Shenzhen University, Shenzhen, People's Republic of China.
Cancer medicine
|June 16, 2023
概括
抗受体 (AR) 降低通过通过ERK/ELK1通路减少Flap内核酶1 (FEN1).通过ERK/ELK1通路,提高前列腺癌中多塞塔塞尔的敏感性. 这一发现为前列腺癌治疗提供了新的治疗策略.
科学领域:
- 在瘤学瘤学.
- 分子生物学分子生物学
- 癌症研究 癌症研究
背景情况:
- 片内核酶1 (FEN1) 在前列腺癌中被上调,促进瘤生长.
- 雄激素受体 (AR) 对前列腺癌的发展,进展和治疗反应至关重要.
- 前列腺癌中FEN1,AR和多塞塔克塞尔 (DTX) 敏感性之间的相互作用需要进一步研究.
研究的目的:
- 为了研究FEN1对前列腺癌中多塞 (DTX) 敏感性的作用.
- 阐明AR在FEN1表达上的调节机制.
- 探索针对AR-FEN1轴的潜在治疗策略,以改善前列腺癌治疗.
主要方法:
- 使用TCGA和GEO数据集进行生物信息学分析.
- 在体外研究使用前列腺癌细胞系 (22Rv1,LNCaP) 与FEN1和AR操纵 (siRNA,过度表达).
- 在体内异种移植试验以验证在临床前模型中的发现.
主要成果:
- 过度表达FEN1减少了DTX诱导的亡和细胞循环停止.
- 抑制AR增加了DTX的敏感性,这种效应被FEN1过度表达所逆转.
- 抑制AR导致FEN1,p-ERK1/2和p-ELK1的下调,ELK1被证实是FEN1.1的转录调节者.
- 在体内研究证实FEN1过度表达增加了瘤生长,降低了DTX的有效性,而AR敲击增强了DTX的敏感性.
结论:
- 在前列腺癌中,AR knockdown 增强了 DTX 敏感性.
- 这种敏感性发生在FEN1通过ERK/ELK1信号通路的下调.
- 针对AR-FEN1轴是一个有前途的前列腺癌治疗策略.
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