Cao Chunxia, Gao Ruli, Zhang Min, Amelio Antonio L, Fallahi Mohammad, Chen Zirong, Gu Yumei, Hu Chengbin, Welsh Eric A, Engel Brienne E, Haura Eric B, Cress W Douglas, Wu Lizi, Zajac-Kaye Maria, Kaye Frederic J
Department of Medicine (CC, RG, MZ, FJK), Genetics Institute (RG, FJK), Genetics and Genomics Graduate Program (RG, FJK), and Molecular Genetics and Microbiology (ZC, YG, CH, LW), University of Florida, Gainesville, FL; Department of Cancer Biology and Informatics, the Scripps Research Institute, Jupiter, FL (ALA, MF); Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC (ALA); Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL (CH); Cancer Informatics Core (EAW), Department of Molecular Oncology (BEE, WDC), and Department of Thoracic Oncology (EBH), Moffitt Cancer Center, Tampa, FL; Department of Anatomy and Cell Biology, University of Florida, Gainesville, FL (MZK).
J Natl Cancer Inst. 2014 Dec 1;107(1):358. doi: 10.1093/jnci/dju358. Print 2015 Jan.
Cyclooxygenase-2 (COX-2) directs the synthesis of prostaglandins including PGE-2 linking inflammation with mitogenic signaling. COX-2 is also an anticancer target, however, treatment strategies have been limited by unreliable expression assays and by inconsistent tumor responses to COX-2 inhibition.
We analyzed the TCGA and Director's Challenge lung cancer datasets (n = 188) and also generated an LKB1-null lung cancer gene signature (n = 53) to search the Broad Institute/Connectivity-MAP (C-MAP) dataset. We performed ChIP analyses, real-time polymerase chain reaction, immunoblotting, and drug testing of tumor cell lines (n = 8) and primary lung adenocarcinoma surgical resections (n = 13).
We show that COX-2 is a target of the cAMP/CREB coactivator CRTC1 signaling pathway. In addition, we detected a correlation between LKB1 status, CRTC1 activation, and presence of glycosylated, but not inactive hypoglycosylated COX-2 in primary lung adenocarcinoma. A search of the C-MAP drug database discovered that all high-ranking drugs positively associated with the LKB1-null signature are known CRTC1 activators, including forskolin and six different PGE-2 analogues. Somatic LKB1 mutations are present in 20.0% of lung adenocarcinomas, and we observed growth inhibition with COX-2 inhibitors in LKB1-null lung cancer cells with activated CRTC1 as compared with LKB1-wildtype cells (NS-398, P = .002 and Niflumic acid, P = .006; two-tailed t test).
CRTC1 activation is a key event that drives the LKB1-null mRNA signature in lung cancer. We also identified a positive feedback LKB1/CRTC1 signaling loop for COX-2/PGE2 regulation. These data suggest a role for LKB1 status and glycosylated COX-2 as specific biomarkers that provide a framework for selecting patients for COX-2 inhibition studies.
环氧化酶-2（COX-2）指导前列腺素的合成，包括将炎症与促有丝分裂信号联系起来的PGE-2。然而，COX-2也是一个抗癌靶点，不过治疗策略一直受到不可靠的表达检测方法以及肿瘤对COX-2抑制反应不一致的限制。
我们分析了TCGA和主任挑战肺癌数据集（n = 188），并生成了一个LKB1缺失的肺癌基因特征（n = 53），以搜索布罗德研究所/连接性图谱（C-MAP）数据集。我们对肿瘤细胞系（n = 8）和原发性肺腺癌手术切除样本（n = 13）进行了染色质免疫沉淀分析、实时聚合酶链反应、免疫印迹和药物测试。
我们发现COX-2是cAMP/CREB共激活因子CRTC1信号通路的一个靶点。此外，我们在原发性肺腺癌中检测到LKB1状态、CRTC1激活与糖基化而非无活性的低糖基化COX-2的存在之间存在相关性。对C-MAP药物数据库的搜索发现，所有与LKB1缺失特征呈正相关的高排名药物都是已知的CRTC1激活剂，包括福斯高林和六种不同的PGE-2类似物。20.0%的肺腺癌存在体细胞LKB1突变，与LKB1野生型细胞相比，我们观察到在CRTC1激活的LKB1缺失肺癌细胞中，COX-2抑制剂具有生长抑制作用（NS-398，P = 0.002；氟尼辛，P = 0.006；双侧t检验）。
CRTC1激活是驱动肺癌中LKB1缺失mRNA特征的关键事件。我们还确定了一个用于COX-2/PGE2调节的正反馈LKB1/CRTC1信号回路。这些数据表明LKB1状态和糖基化COX-2作为特定生物标志物的作用，为选择患者进行COX-2抑制研究提供了一个框架。
