cAMP/CREB-regulated LINC00473 marks LKB1-inactivated lung cancer and mediates tumor growth

Chen Zirong; Li Jian-Liang; Lin ShuibinCao ChunxiaGimbrone Nicholas T.Yang RongqiangFu Dongtao A.Carper Miranda B.Haura Eric B.Schabath Matthew B.Lu JianrongAmelio Antonio L.Cress W. DouglasKaye Frederic J.Wu Lizi

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cAMP/CREB-regulated LINC00473 marks LKB1-inactivated lung cancer and mediates tumor growth

机译：cAMP/CREB 调节的LINC00473标记 LKB1 灭活肺癌并介导肿瘤生长

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The LKB1 tumor suppressor gene is frequently mutated and inactivated in non-small cell lung cancer (NSCLC). Loss of LKB1 promotes cancer progression and influences therapeutic responses in preclinical studies; however, specific targeted therapies for lung cancer with LKB1 inactivation are currently unavailable. Here, we have identified a long noncoding RNA (lncRNA) signature that is associated with the loss of LKB1 function. We discovered that LINC00473 is consistently the most highly induced gene in LKB1-inactivated human primary NSCLC samples and derived cell lines. Elevated LINC00473 expression correlated with poor prognosis, and sustained LINC00473 expression was required for the growth and survival of LKB1-inactivated NSCLC cells. Mechanistically, LINC00473 was induced by LKB1 inactivation and subsequent cyclic AMP-responsive element-binding protein (CREB)/CREB-regulated transcription coactivator (CRTC) activation. We determined that LINC00473 is a nuclear lncRNA and interacts with NONO, a component of the cAMP signaling pathway, thereby facilitating CRTC/CREB-mediated transcription. Collectively, our study demonstrates that LINC00473 expression potentially serves as a robust biomarker for tumor LKB1 functional status that can be integrated into clinical trials for patient selection and treatment evaluation, and implicates LINC00473 as a therapeutic target for LKB1-inactivated NSCLC.

机译：LKB1抑癌基因在非小细胞肺癌（NSCLC）中经常发生突变和失活。在临床前研究中，LKB1 的缺失会促进癌症进展并影响治疗反应;然而，目前尚无针对 LKB1 失活肺癌的特异性靶向治疗。在这里，我们鉴定出与LKB1功能丧失相关的长非编码RNA（lncRNA）特征。我们发现，LINC00473一直是LKB1灭活的人类原代NSCLC样本和衍生细胞系中诱导程度最高的基因。LINC00473表达升高与不良预后相关，LKB1灭活NSCLC细胞的生长和存活需要持续的LINC00473表达。从机制上讲，LKB1 失活和随后的环 AMP 反应元件结合蛋白（CREB）/CREB 调节的转录共激活因子（CRTC）激活诱导了 LINC00473。我们确定 LINC00473 是一种核 lncRNA，并与 cAMP 信号通路的一个组成部分 NONO 相互作用，从而促进 CRTC/CREB 介导的转录。总的来说，我们的研究表明，LINC00473表达可能作为肿瘤 LKB1 功能状态的可靠生物标志物，可以整合到临床试验中用于患者选择和治疗评估，并暗示LINC00473作为 LKB1 灭活 NSCLC 的治疗靶点。

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《The Journal of Clinical Investigation: The Official Journal of the American Society for Clinical Investigation》 |2016年第6期|2267-2279|共13页
作者
Chen Zirong; Li Jian-Liang; Lin ShuibinCao ChunxiaGimbrone Nicholas T.Yang RongqiangFu Dongtao A.Carper Miranda B.Haura Eric B.Schabath Matthew B.Lu JianrongAmelio Antonio L.Cress W. DouglasKaye Frederic J.Wu Lizi;
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Univ Florida, Dept Mol Genet & Microbiol, 2033 Mowry Rd, Gainesville, FL 32610 USA;

Sanford Burnham Prebys Med Discovery Inst Lake No, Orlando, FL USA;

Univ Florida, UF Hlth Canc Ctr, Coll Med, 2033 Mowry Rd, Gainesville, FL 32610 USAUniv S Florida, H Lee Moffitt Canc Ctr, Dept Mol Oncol, Tampa, FL 33682 USAUniv Florida, Coll Med, Dept Pathol Immunol & Lab Med, 2033 Mowry Rd, Gainesville, FL 32610 USAUniv N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USAUniv S Florida, H Lee Moffitt Canc Ctr, Dept Thorac Oncol, Tampa, FL 33682 USAUniv S Florida, H Lee Moffitt Canc Ctr, Dept Canc Epidemiol, Tampa, FL 33682 USA;

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cAMP/CREB-regulated LINC00473 marks LKB1-inactivated lung cancer and mediates tumor growth

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