TRAP1 downregulation in human ovarian cancer enhances invasion and epithelial-mesenchymal transition.
TRAP1 downregulation in human ovarian cancer enhances invasion and epithelial-mesenchymal transition.
复制标题
人类卵巢癌中的TRAP1下调可增强入侵和上皮 - 间质转变。
DOI：
10.1038/cddis.2016.400
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发表时间：
2016-12-15
影响因子：
9
通讯作者：
Esposito F
中科院分区：
文献类型：
--
作者：
Amoroso MR;Matassa DS;Agliarulo I;Avolio R;Lu H;Sisinni L;Lettini G;Gabra H;Landriscina M;Esposito F
卵巢癌（OC）是全球妇科癌症死亡的第二大原因。尽管生物标志物清单仍在不断增加，但参与OC发生和进展的分子机制仍然难以捉摸。我们最近发现，OC患者中TRAP 1分子伴侣的低表达与较高的肿瘤分级和分期以及铂类耐药相关。在此，我们发现TRAP 1在高级别浆液性OC患者中经常缺失（N=579），并且TRAP 1表达与拷贝数相关，表明这可能是OC中TRAP 1表达缺失的驱动机制之一。在分子水平上，TRAP 1的下调与p70 S6 K的高表达相关，p70 S6 K是一种在OC中经常活跃的激酶，在细胞迁移和肿瘤转移中发挥新的作用。事实上，不同OC细胞中的TRAP 1沉默诱导p70 S6 K表达和活性的上调，细胞运动性和上皮-间充质转化（EMT）的增强。一致地，在一个大的OC患者队列中，TRAP 1表达在肿瘤转移中降低，并与上皮标志物E-钙粘蛋白直接相关，而它与转录因子Slug和基质金属肽酶2和9负相关。引人注目的是，p70 S6 K的药理学抑制逆转了TRAP 1敲低细胞的高运动性表型。然而，尽管p70 S6 K抑制或沉默降低了转录因子Snail和Slug的表达，从而诱导了E-Cadherin表达的上调，但它无法逆转TRAP 1沉默诱导的EMT;此外，p70 S6 K与患者中的EMT基因没有显示出任何显著相关性，也与总生存期或肿瘤分期无关，这表明TRAP 1在OC进展中具有独立和主要的作用。总而言之，这些结果可能为TRAP 1表达降低的OC提供新的方法，该方法可能对基于抑制p70 S6 K通路的治疗策略具有抗性，并可能在未来干预OC侵袭和转移。
Ovarian cancer (OC) is the second leading cause of gynecological cancer death worldwide. Although the list of biomarkers is still growing, molecular mechanisms involved in OC development and progression remain elusive. We recently demonstrated that lower expression of the molecular chaperone TRAP1 in OC patients correlates with higher tumor grade and stage, and platinum resistance. Herein we show that TRAP1 is often deleted in high-grade serous OC patients (N=579), and that TRAP1 expression is correlated with the copy number, suggesting this could be one of the driving mechanisms for the loss of TRAP1 expression in OC. At molecular level, downregulation of TRAP1 associates with higher expression of p70S6K, a kinase frequently active in OC with emerging roles in cell migration and tumor metastasis. Indeed, TRAP1 silencing in different OC cells induces upregulation of p70S6K expression and activity, enhancement of cell motility and epithelial–mesenchymal transition (EMT). Consistently, in a large cohort of OC patients, TRAP1 expression is reduced in tumor metastases and directly correlates with the epithelial marker E-Cadherin, whereas it inversely correlates with the transcription factor Slug and the matrix metallopeptidases 2 and 9. Strikingly, pharmacological inhibition of p70S6K reverts the high motility phenotype of TRAP1 knock-down cells. However, although p70S6K inhibition or silencing reduces the expression of the transcription factors Snail and Slug, thus inducing upregulation of E-Cadherin expression, it is unable to revert EMT induced by TRAP1 silencing; furthermore, p70S6K did not show any significant correlation with EMT genes in patients, nor with overall survival or tumor stage, suggesting an independent and predominant role for TRAP1 in OC progression. Altogether, these results may provide novel approaches in OC with reduced TRAP1 expression, which could be resistant to therapeutic strategies based on the inhibition of the p70S6K pathway, with potential future intervention in OC invasion and metastasis.