hnRNPA2/B1 activates cyclooxygenase‐2 and promotes tumor growth in human lung cancers

Molecular Oncology - Tập 10 - Trang 610-624 - 2016
Yang Xuan1,2, Jingshu Wang1, Liying Ban2, Jian-Jun Lu3, Canhui Yi2, Zhenglin Li2, Wendan Yu2, Mei Li2, Tingting Xu2, Wenjing Yang2, Zhipeng Tang2, Ranran Tang2, Xiangsheng Xiao1, Songshu Meng2, Yiming Chen2, Quentin Liu1,2, Wenlin Huang1,4, Wei Guo2, Xiaonan Cui2, Wuguo Deng1,4
1Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, PR China
2The First Affiliated Hospital & Institute of Cancer Stem Cell, Dalian Medical University, Dalian, PR China
3Department of Thoracic Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, PR China
4State Key Laboratory of Targeted Drug for Tumors of Guangdong Province, Guangzhou Double Bioproduct Inc., Guangzhou, PR China

Tóm tắt

Cyclooxygenase‐2 (COX‐2) is highly expressed in tumor cells and has been regarded as a hallmarker for cancers, but the excise regulatory mechanism of COX‐2 in tumorigenesis remains largely unknown. Here, we pulled down and identified a novel COX‐2 regulator, heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNPA2/B1), which could specifically bind to COX‐2 core promoter and regulate tumor growth in non‐small‐cell lung cancers (NSCLCs). Knockdown of hnRNPA2/B1 by shRNA or siRNA downregulated COX‐2 expression and prostaglandin E2 (PGE2) production, and suppressed tumor cell growth in NSCLC cells in vitro and in vivo. Conversely, overexpression of hnRNPA2/B1 up‐regulated the levels of COX‐2 and PGE2 and promoted tumor cell growth. We also showed that hnRNPA2/B1 expression was positively correlated with COX‐2 expression in NSCLC cell lines and tumor tissues, and the up‐regulated expression of hnRNPA2/B1 and COX‐2 predicted worse prognosis in NSCLC patients. Furthermore, we demonstrated that the activation of COX‐2 expression by hnRNPA2/B1 was mediated through the cooperation with p300, a transcriptional co‐activator, in NSCLC cells. The hnRNPA2/B1 could interact with p300 directly and be acetylated by p300. Exogenous overexpression of p300, but not its histone acetyltransferase (HAT) domain deletion mutation, augmented the acetylation of hnRNPA2/B1 and enhanced its binding on COX‐2 promoter, thereby promoted COX‐2 expression and lung cancer cell growth. Collectively, our results demonstrate that hnRNPA2/B1 promotes tumor cell growth by activating COX‐2 signaling in NSCLC cells and imply that the hnRNPA2/B1/COX‐2 pathway may be a potential therapeutic target for human lung cancers.

Tài liệu tham khảo

10.1007/s00432-014-1892-z 10.1016/j.ctrv.2011.05.009 10.1126/science.1116221 10.1016/S1470-2045(15)00059-5 10.1073/pnas.0914845107 10.1161/ATVBAHA.107.144352 10.1074/jbc.M209286200 10.4187/respcare.02559 10.1042/BJ20100396 10.1016/j.aogh.2014.10.002 10.1242/jcs.02448 10.1002/mc.20467 Katsimpoula S., 2009, Overexpression of hnRNPA2/B1 in bronchoscopic specimens: a potential early detection marker in lung cancer, Anticancer Res, 29, 1373 10.1016/j.aogh.2014.09.010 10.4143/crt.2014.46.3.297 10.1002/cbf.1562 10.1002/ijc.28831 Masferrer J.L., 2000, Antiangiogenic and antitumor activities of cyclooxygenase-2 inhibitors, Cancer Res, 60, 1306 10.1111/j.1349-7006.2000.tb00996.x 10.1111/j.1478-3231.2012.02778.x 10.1158/0008-5472.CAN-09-1852 10.1002/jcb.24944 10.1158/0008-5472.CAN-11-2449 Okada F., 2014, Inflammation-related carcinogenesis: current findings in epidemiological trends, causes and mechanisms, Yonago Acta Med, 57, 65 Patry C., 2003, Small interfering RNA-mediated reduction in heterogeneous nuclear ribonucleoparticule A1/A2 proteins induces apoptosis in human cancer cells but not in normal mortal cell lines, Cancer Res, 63, 7679 10.4161/rna.6.2.8195 10.1016/S0169-5002(03)00193-4 10.1530/ERC-13-0450 Razmi A., 2013, Evaluation of anti-nociceptive and anti-inflammatory activities of novel chalcone derivatives, Iran J. Pharm. Res, 12, 149 10.1016/j.cca.2010.12.026 10.1002/path.1292 10.1056/NEJMoa050405 10.1074/jbc.M007237200 Sueoka E., 2001, Heterogeneous nuclear ribonucleoprotein B1 as early cancer biomarker for occult cancer of human lungs and bronchial dysplasia, Cancer Res, 61, 1896 10.5306/wjco.v5.i4.660 10.1016/j.coph.2009.06.004 10.1158/0008-5472.CAN-10-0860 10.1038/onc.2010.2 10.1002/pmic.200300480 10.1016/S0304-3835(02)00168-4 10.1002/mc.22008 10.1158/1940-6207.CAPR-09-0243
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Molecular Oncology

Tập 10

610-624

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