Pseudohypoxia induced by miR-126 deactivation promotes migration and therapeutic resistance in renal cell carcinoma.
Pseudohypoxia induced by miR-126 deactivation promotes migration and therapeutic resistance in renal cell carcinoma.
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DOI：
10.1016/j.canlet.2017.02.025
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发表时间：
2017-05-28
期刊：
影响因子：
9.7
通讯作者：
Wang X
中科院分区：
文献类型：
--
作者：
Liu W;Chen H;Wong N;Haynes W;Baker CM;Wang X
假性缺氧在透明细胞肾细胞癌（ccRCC）的进展和治疗抗性中起着核心作用;然而，对其潜在机制知之甚少。与原发性肿瘤相比，microRNA miR-126在转移性或复发性ccRCC中的表达降低，但miR-126与RCC相关的机制仍不清楚。通过RNA-seq分析来评估miR-126的过表达或CRISPR敲除的影响，我们已经将SERPINE 1鉴定为调节细胞运动性的miR-126- 5 p靶标，并且将SLC 7A 5鉴定为调节mTOR/HIF途径的miR-126- 3 p靶标。具体而言，miR-126抑制HIFα蛋白表达，与von Hippel-Lindau肿瘤抑制因子（VHL）无关。另一方面，miR-126的失活由于HIFα表达增加而诱导假缺氧状态，这进一步增强分别由SLC 7A 5和SERPINE 1介导的治疗抗性和细胞运动性。最后，miR-126调节的基因调控在ccRCC中的临床相关性已经通过来自癌症基因组图谱的分析数据得到证实。
Pseudohypoxia plays a central role in the progression and therapeutic resistance of clear cell renal cell carcinoma (ccRCC); however, the underlying mechanisms are poorly understood. MicroRNA miR-126 has decreased expression in metastatic or relapsed ccRCC as compared to primary tumors, but the mechanisms by which miR-126 is implicated in RCC remain unknown. Through RNA-seq profiling to evaluate the impact of overexpression or CRISPR knockout of miR-126, we have identified SERPINE1 as a miR-126-5p target regulating cell motility, and SLC7A5 as a miR-126-3p target regulating the mTOR/HIF pathway. Specifically, miR-126 inhibits HIFα protein expression independent of von Hippel-Lindau tumor suppressor (VHL). On the other hand, deactivation of miR-126 induces a pseudohypoxia state due to increased HIFα expression, which further enhances therapeutic resistance and cell motility mediated by SLC7A5 and SERPINE1, respectively. Finally, the clinical relevance of miR-126 modulated gene regulation in ccRCC has been confirmed with profiling data from The Cancer Genome Atlas.