Cancer Res:PHD3有望成为提高肺癌患者治疗效果的靶点!

2018-01-19 MedSci MedSci原创

本研究揭示了PHD3在肿瘤细胞转移和药物耐受方面的重要作用,并且可以通过沉默PHD3干扰前反馈信号通路激活,从而提高病人的治疗效果。

在全球范围内,肺癌是造成癌症相关性死亡的主要疾病,而肺癌的高度转移倾向和治疗抵抗的发展造成肺癌致死性高。肿瘤转移与表皮间质转换(epithelial-mesenchymal transition,EMT)样的程序激活有关,而这一过程包括细胞紧密程度降低,迁移和传播到远处部位的几率增加。

恶性肿瘤的多种特征,包括转移和药物耐受,都与缺氧相关。而缺氧应激反应的调节主要通过脯氨酰羟化酶结构域(prolyl hydroxylase domain,PHD)蛋白和低氧诱导因子(hypoxia-inducible factors,HIFs)完成。而PHD在肿瘤生长过程中的作用还没有被完全研究清楚。

因此,科学家研究了肺癌微环境中氧气感受器PHD与低氧信号通路和EMT之间的联系。PHD3能被诱导EMT的信号所抑制,并且PHD3是EMT,转移和治疗耐受的负性调控因子。EMT诱导因子TGFβ或者启动子甲基化导致的PHD3耗竭可以促进肿瘤细胞的EMT以及自发性转移。与此相反的是,使用TGFα刺激EGFR能够增强EMT和转移。

在肺癌的临床样本中,降低PHD3的表达与患者预后差和EGFR抑制剂例如厄洛替尼的治疗耐受相关。而在肺癌细胞中重新表达PHD3能够抑制肺癌细胞的EMT以及转移,并且能使肺癌细胞重新对厄洛替尼治疗敏感。

总之,本研究揭示了PHD3在肿瘤细胞转移和药物耐受方面的重要作用,并且可以通过沉默PHD3干扰前反馈信号通路激活,从而提高病人的治疗效果。

文章出处:Higinio Dopeso, Hui-ke Jiao, Angel M Cuesta, et al. PHD3 controls lung cancer metastasis and resistance to EGFR inhibitors through TGFα[J]. Cancer Research,January 16,2018.DOI: 10.1158/0008-5472.CAN-17-1346


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    2018-09-19 zhangxingru
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    2018-01-19 有备才能无患

    在全球范围内.肺癌是造成癌症相关性死亡的主要疾病.而肺癌的高度转移倾向和治疗抵抗的发展造成肺癌致死性高

    0

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    2018-01-19 1ddf0692m34(暂无匿称)

    学习了.涨知识

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    肺癌治疗又有新方法.

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