A KRAS-responsive long non-coding RNA controls microRNA processing.
A KRAS-responsive long non-coding RNA controls microRNA processing.
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DOI：
10.1038/s41467-021-22337-3
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发表时间：
2021-04-01
影响因子：
16.6
通讯作者：
Garofalo M
中科院分区：
文献类型：
--
作者：
Shi L;Magee P;Fassan M;Sahoo S;Leong HS;Lee D;Sellers R;Brullé-Soumaré L;Cairo S;Monteverde T;Volinia S;Smith DD;Di Leva G;Galuppini F;Paliouras AR;Zeng K;O'Keefe R;Garofalo M
野生型KRAS（KRASWT）扩增已被证明是癌症中KRAS激活的次要手段，并与生存率低相关。然而，KRASWT过表达在肺癌进展中的确切作用在很大程度上尚未探索。在这里，我们确定和表征KRAS响应lncRNA，KIMAT1（ENSG00000228709），并表明它与细胞系和肺癌标本中的KRAS水平相关。从机制上讲，KIMAT1是MYC靶点，通过DHX9和NPM1稳定促进致癌microRNA（miRNAs）的加工，同时通过MYC依赖性沉默p21（微处理器复合体的一种组分）停止具有肿瘤抑制功能的miRNAs的生物发生，从而驱动肺肿瘤发生。KIMAT1敲低不仅抑制KRAS表达，还抑制KRAS下游信号传导，从而在体外和体内阻止肺癌生长。总之，这项研究揭示了KIMAT1在维持肺癌进展过程中维持KRAS信号传导的正反馈回路中的作用，并提供了一个原则证据，即干扰KIMAT1可能是阻碍KRAS诱导的肿瘤发生的一种策略。已知野生型KRAS扩增诱导癌症中的KRAS活化，导致不良预后结果。在这里，作者鉴定了一种KRAS响应性lncRNA，即维持肺癌中KRAS信号传导的KIMAT1，这表明其靶向可能会阻止KRAS驱动的肿瘤发生。
Wild-type KRAS (KRASWT) amplification has been shown to be a secondary means of KRAS activation in cancer and associated with poor survival. Nevertheless, the precise role of KRASWT overexpression in lung cancer progression is largely unexplored. Here, we identify and characterize a KRAS-responsive lncRNA, KIMAT1 (ENSG00000228709) and show that it correlates with KRAS levels both in cell lines and in lung cancer specimens. Mechanistically, KIMAT1 is a MYC target and drives lung tumorigenesis by promoting the processing of oncogenic microRNAs (miRNAs) through DHX9 and NPM1 stabilization while halting the biogenesis of miRNAs with tumor suppressor function via MYC-dependent silencing of p21, a component of the Microprocessor Complex. KIMAT1 knockdown suppresses not only KRAS expression but also KRAS downstream signaling, thereby arresting lung cancer growth in vitro and in vivo. Taken together, this study uncovers a role for KIMAT1 in maintaining a positive feedback loop that sustains KRAS signaling during lung cancer progression and provides a proof of principle that interfering with KIMAT1 could be a strategy to hamper KRAS-induced tumorigenesis. Wild-type KRAS amplification is known to induce KRAS activation in cancer leading to poor prognostic outcomes. Here the authors identify a KRAS-responsive lncRNA, KIMAT1 that maintains KRAS signalling in lung cancer, suggesting that its targeting may prevent KRAS-driven tumourigenesis.
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DOI：
10.1083/jcb.201110008
发表时间：
2012-04-16
期刊：
The Journal of cell biology
影响因子：
--
作者：
Kawai S;Amano A
通讯作者：
Amano A
影响因子：
64.5
作者：
Huarte M;Guttman M;Feldser D;Garber M;Koziol MJ;Kenzelmann-Broz D;Khalil AM;Zuk O;Amit I;Rabani M;Attardi LD;Regev A;Lander ES;Jacks T;Rinn JL
通讯作者：
Rinn JL
影响因子：
3.7
作者：
Chen Y;McGee J;Chen X;Doman TN;Gong X;Zhang Y;Hamm N;Ma X;Higgs RE;Bhagwat SV;Buchanan S;Peng SB;Staschke KA;Yadav V;Yue Y;Kouros-Mehr H
通讯作者：
Kouros-Mehr H
影响因子：
24.5
作者：
Hur K;Toiyama Y;Takahashi M;Balaguer F;Nagasaka T;Koike J;Hemmi H;Koi M;Boland CR;Goel A
通讯作者：
Goel A
影响因子：
7.7
作者：
Davis MP;Carrieri C;Saini HK;van Dongen S;Leonardi T;Bussotti G;Monahan JM;Auchynnikava T;Bitetti A;Rappsilber J;Allshire RC;Shkumatava A;O'Carroll D;Enright AJ
通讯作者：
Enright AJ