美国斯隆·凯特琳纪念癌症中心Steven D. Leach和Luisa F. Escobar-Hoyos研究团队合作取得最新进展。他们发现由p53突变改变的RNA剪接激活胰腺癌的致癌RAS信号。2020年6月18日出版的《癌细胞》杂志发表了这项成果。
他们揭示了由突变p53促进的RNA剪接中，增强KRAS活性的序列特异性变化。突变体p53可增加剪接调控子hnRNPK的表达，从而促进RAS家族成员的负调控子GTPase激活蛋白（GAPs）中富含胞嘧啶的外显子的含量。突变的p53增强的GAP亚型不能细胞膜结合，导致KRAS活性增强。
防止突变型KRAS / p53 胰腺导管腺癌（PDAC）中富含胞嘧啶的外显子含量会降低肿瘤的生长。而且，突变体p53 PDAC通过剪接体抑制子对剪接抑制敏感。这些数据提供了对KRAS和p53突变的共富集以及针对PDAC中这种机制的治疗方法的认知。
据悉, PDAC由KRAS和TP53中共存的突变驱动。 但是，尚不清楚这些突变如何协同作用，来促进这种癌症。
附：英文原文
Title: Altered RNA Splicing by Mutant p53 Activates Oncogenic RAS Signaling in Pancreatic Cancer
Author: Luisa F. Escobar-Hoyos, Alex Penson, Ram Kannan, Hana Cho, Chun-Hao Pan, Rohit K. Singh, Lisa H. Apken, G. Aaron Hobbs, Renhe Luo, Nicolas Lecomte, Sruthi Babu, Fong Cheng Pan, Direna Alonso-Curbelo, John P. Morris, Gokce Askan, Olivera Grbovic-Huezo, Paul Ogrodowski, Jonathan Bermeo, Joseph Saglimbeni, Cristian D. Cruz, Yu-Jui Ho, Sharon A. Lawrence, Jerry P. Melchor, Grant A. Goda, Karen Bai, Alessandro Pastore, Simon J. Hogg, Srivatsan Raghavan, Peter Bailey, David K. Chang, Andrew Biankin, Kenneth R. Shroyer, Brian M. Wolpin, Andrew J. Aguirre, Andrea Ventura, Barry Taylor, Channing J. Der, Daniel Dominguez, Daniel Kümmel, Andrea Oeckinghaus, Scott W. Lowe, Robert K. Bradley, Omar Abdel-Wahab, Steven D. Leach
Issue&Volume: 2020-06-18
Abstract: Pancreatic ductal adenocarcinoma (PDAC) is driven by co-existing mutations in KRAS and TP53. However, how these mutations collaborate to promote this cancer is unknown. Here,we uncover sequence-specific changes in RNA splicing enforced by mutant p53 whichenhance KRAS activity. Mutant p53 increases expression of splicing regulator hnRNPKto promote inclusion of cytosine-rich exons within GTPase-activating proteins (GAPs),negative regulators of RAS family members. Mutant p53-enforced GAP isoforms lose cellmembrane association, leading to heightened KRAS activity. Preventing cytosine-richexon inclusion in mutant KRAS/p53 PDACs decreases tumor growth. Moreover, mutant p53PDACs are sensitized to inhibition of splicing via spliceosome inhibitors. These dataprovide insight into co-enrichment of KRAS and p53 mutations and therapeutics targetingthis mechanism in PDAC.
DOI: 10.1016/j.ccell.2020.05.010
Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(20)30260-9
Cancer Cell：《癌细胞》，创刊于2002年。隶属于细胞出版社，最新IF：38.585
官方网址：https://www.cell.com/cancer-cell/home
投稿链接：https://www.editorialmanager.com/cancer-cell/default.aspx
本期文章：《癌细胞》：Online/在线发表
