A novel protein RASON encoded by a lncRNA controls oncogenic RAS signaling in KRAS mutant cancers.
A novel protein RASON encoded by a lncRNA controls oncogenic RAS signaling in KRAS mutant cancers.
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由 lncRNA 编码的新型蛋白 RASON 控制 KRAS 突变癌症中的致癌 RAS 信号传导
DOI：
10.1038/s41422-022-00726-7
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发表时间：
2023-01
期刊：
影响因子：
44.1
通讯作者：
Zhang, Nu
中科院分区：
文献类型：
--
作者：
Cheng, Rongjie;Li, Fanying;Zhang, Maolei;Xia, Xin;Wu, Jianzhuang;Gao, Xinya;Zhou, Huangkai;Zhang, Zhi;Huang, Nunu;Yang, Xuesong;Zhang, Yaliang;Shen, Shunli;Kang, Tiebang;Liu, Zexian;Xiao, Feizhe;Yao, Hongwei;Xu, Jianbo;Yan, Chao;Zhang, Nu
RAS癌基因的突变在约30%的人类癌症中发现，但除了KRASG 12 C突变体之外，直接靶向RAS仍然被认为是临床上不切实际的。在这里，我们报告，RAS-ON（RASON），一个新的蛋白质编码的长基因间非蛋白质编码RNA 00673（LINC 00673），是一个积极的调节致癌RAS信号。RASON在胰腺导管腺癌（PDAC）患者中异常过表达，并且其在体外促进人PDAC细胞系的增殖和在体内促进肿瘤生长。CRISPR/Cas9介导的小鼠胚胎成纤维细胞中Rason敲除抑制KRAS介导的肿瘤转化Rason基因缺失消除了LSL-KrasG 12 D; Trp 53 R172 H/+小鼠中致癌KRAS驱动的胰腺癌和肺癌肿瘤发生。从机制上讲，RASON直接结合KRASG 12 D/V，并抑制内源性和GTP酶激活蛋白（GAP）介导的GTP水解，从而使KRASG 12 D/V维持在GTP结合的过度活跃状态。在治疗上，RASON的剥夺使KRAS突变胰腺癌细胞和患者来源的类器官对EGFR抑制剂敏感。我们的研究结果确定RASON是致癌KRAS信号传导的关键调节因子，也是KRAS突变型癌症有希望的治疗靶点。
Mutations of the RAS oncogene are found in around 30% of all human cancers yet direct targeting of RAS is still considered clinically impractical except for the KRASG12C mutant. Here we report that RAS-ON (RASON), a novel protein encoded by the long intergenic non-protein coding RNA 00673 (LINC00673), is a positive regulator of oncogenic RAS signaling. RASON is aberrantly overexpressed in pancreatic ductal adenocarcinoma (PDAC) patients, and it promotes proliferation of human PDAC cell lines in vitro and tumor growth in vivo. CRISPR/Cas9-mediated knockout of Rason in mouse embryonic fibroblasts inhibits KRAS-mediated tumor transformation. Genetic deletion of Rason abolishes oncogenic KRAS-driven pancreatic and lung cancer tumorigenesis in LSL-KrasG12D; Trp53R172H/+ mice. Mechanistically, RASON directly binds to KRASG12D/V and inhibits both intrinsic and GTPase activating protein (GAP)-mediated GTP hydrolysis, thus sustaining KRASG12D/V in the GTP-bound hyperactive state. Therapeutically, deprivation of RASON sensitizes KRAS mutant pancreatic cancer cells and patient-derived organoids to EGFR inhibitors. Our findings identify RASON as a critical regulator of oncogenic KRAS signaling and a promising therapeutic target for KRAS mutant cancers.
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影响因子：
2.9
作者：
Novelli, Elisa T.;First, Jeremy T.;Webb, Lauren J.
通讯作者：
Webb, Lauren J.
影响因子：
64.5
作者：
Margarit, SM;Sondermann, H;Kuriyan, J
通讯作者：
Kuriyan, J
DOI：
10.1073/pnas.1404639111
发表时间：
2014-06-17
影响因子：
11.1
作者：
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通讯作者：
Westover, Kenneth D.
影响因子：
7.3
作者：
Lanman, Brian A.;Allen, Jennifer R.;Cee, Victor J.
通讯作者：
Cee, Victor J.
影响因子：
3.7
作者：
Morlan JD;Qu K;Sinicropi DV
通讯作者：
Sinicropi DV