The RNA-binding protein LARP1 is a post-transcriptional regulator of survival and tumorigenesis in ovarian cancer.
The RNA-binding protein LARP1 is a post-transcriptional regulator of survival and tumorigenesis in ovarian cancer.
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DOI：
10.1093/nar/gkv1515
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发表时间：
2016-02-18
影响因子：
14.9
通讯作者：
Blagden SP
中科院分区：
文献类型：
--
作者：
Hopkins TG;Mura M;Al-Ashtal HA;Lahr RM;Abd-Latip N;Sweeney K;Lu H;Weir J;El-Bahrawy M;Steel JH;Ghaem-Maghami S;Aboagye EO;Berman AJ;Blagden SP
RNA结合蛋白(RBPs)越来越被认为是癌症进展的转录后驱动因素。RBP LARP1是一种mRNA稳定性调节因子，该蛋白在肝细胞癌和肺癌中的高表达与不良预后相关。LARP1与一个富含致癌转录物的mRNA相互作用组相关联。在这里，我们探索LARP1在上皮性卵巢癌中的作用，这种疾病的特征是通过诱导有利于生存的信号而迅速获得对化疗的耐药性。我们使用卵巢细胞系和异种移植证明，LARP1是癌细胞存活和化疗耐药所必需的。LARP1促进体内肿瘤的形成，并维持肿瘤干细胞样群。利用LARP1被敲除后的转录转录分析，并与LARP1相互作用组交叉参考，我们确定BCL2和BIK为LARP1的mRNA靶标。我们证明，通过与BCL2和BIK的3‘非翻译区(3’UTRs)相互作用，LARP1稳定了BCL2，但破坏了BIK的稳定，具有抗凋亡的净作用。总之，我们的数据表明，LARP1通过不同地调节一系列mRNAs的稳定性，促进卵巢癌的进展和化疗耐药。
RNA-binding proteins (RBPs) are increasingly identified as post-transcriptional drivers of cancer progression. The RBP LARP1 is an mRNA stability regulator, and elevated expression of the protein in hepatocellular and lung cancers is correlated with adverse prognosis. LARP1 associates with an mRNA interactome that is enriched for oncogenic transcripts. Here we explore the role of LARP1 in epithelial ovarian cancer, a disease characterized by the rapid acquisition of resistance to chemotherapy through the induction of pro-survival signalling. We show, using ovarian cell lines and xenografts, that LARP1 is required for cancer cell survival and chemotherapy resistance. LARP1 promotes tumour formation in vivo and maintains cancer stem cell-like populations. Using transcriptomic analysis following LARP1 knockdown, cross-referenced against the LARP1 interactome, we identify BCL2 and BIK as LARP1 mRNA targets. We demonstrate that, through an interaction with the 3′ untranslated regions (3′ UTRs) of BCL2 and BIK, LARP1 stabilizes BCL2 but destabilizes BIK with the net effect of resisting apoptosis. Together, our data indicate that by differentially regulating the stability of a selection of mRNAs, LARP1 promotes ovarian cancer progression and chemotherapy resistance.