Cleavage and polyadenylation specific factor 4 targets NF-κB/cyclooxygenase-2 signaling to promote lung cancer growth and progression
Cleavage and polyadenylation specific factor 4 targets NF-κB/cyclooxygenase-2 signaling to promote lung cancer growth and progression
复制标题
裂解和聚腺苷酸化特异性因子 4 靶向 NF-kappaB/cyclooxygenase-2 信号传导，促进肺癌生长和进展。
DOI：
10.1016/j.canlet.2016.07.016
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发表时间：
2016-10-10
期刊：
影响因子：
9.7
通讯作者：
Deng，Wuguo
中科院分区：
文献类型：
--
作者：
Yi，Canhui;Wang，Yan;Deng，Wuguo
环氧化酶2（考克斯-2）的过度表达常见于早期和晚期肺癌。然而，肺癌中考克斯-2的确切调控机制尚不清楚。本研究将切割和多聚腺苷酸化特异性因子4（CPSF 4）作为考克斯-2的一个新的调节因子，并证实了CPSF 4/考克斯-2信号通路在肺癌生长和进展中的调节作用。CPSF 4的过表达或敲低可在mRNA和蛋白水平上调或抑制考克斯-2的表达，促进或抑制肺癌细胞的增殖、迁移和侵袭。抑制或诱导考克斯-2可逆转CPSF 4介导的肺癌细胞生长调节。CPSF 4过表达或敲低表达的癌细胞p-IKKα/β和p-IκBα表达增加或减少，p50/p65从胞浆易位到胞核，p65结合在考克斯-2启动子区。此外，发现CPSF 4直接结合到考克斯-2启动子序列并激活考克斯-2的转录。抑制NF-κB的表达或阻断NF-κB的活性可抑制CPSF 4与考克斯-2启动子的结合，从而减弱CPSF 4介导的考克斯-2的上调。此外，在异种移植肺癌小鼠模型中，发现CPSF 4通过上调考克斯-2表达促进肺肿瘤生长和进展。CPSF 4过表达或敲低促进或抑制小鼠中的肿瘤生长，而这种由CPSF 4介导的肿瘤生长调节可以通过抑制或激活考克斯-2信号来挽救。相应地，CPSF 4过表达或敲低也会升高或减弱小鼠肿瘤组织中的考克斯-2表达，而用考克斯-2诱导剂LPS或NF-κB抑制剂治疗可逆转这种升高或减弱。此外，我们发现CPSF 4与肺癌患者肿瘤组织中的考克斯-2水平呈正相关。CPSF 4和考克斯-2蛋白同时高表达预示肺癌患者预后不良。因此，我们的研究结果为肺癌中CPSF 4对考克斯-2的转录调控提供了一种新的机制，同时也为CPSF 4/考克斯-2信号异常激活的肺癌提供了一个潜在的治疗靶点。
Overexpression of cyclooxygenase 2 (COX-2) is frequently found in early and advanced lung cancers. However, the precise regulatory mechanism of COX-2 in lung cancers remains unclear. Here we identified cleavage and polyadenylation specific factor 4 (CPSF4) as a new regulatory factor for COX-2 and demonstrated the role of the CPSF4/COX-2 signaling pathway in the regulation of lung cancer growth and progression. Overexpression or knockdown of CPSF4 up-regulated or suppressed the expression of COX-2 at mRNA and protein levels, and promoted or inhibited cell proliferation, migration and invasion in lung cancer cells. Inhibition or induction of COX-2 reversed the CPSF4-mediated regulation of lung cancer cell growth. Cancer cells with CPSF4 overexpression or knockdown exhibited increased or decreased expression of p-IKKα/β and p-IκBα, the translocation of p50/p65 from the cytoplasm to the nucleus, and the binding of p65 on COX-2 promoter region. In addition, CPSF4 was found to bind to COX-2 promoter sequences directly and activate the transcription of COX-2. Silencing of NF-κB expression or blockade of NF-κB activity abrogated the binding of CPSF4 on COX-2 promoter, and thereby attenuated the CPSF4-mediated up-regulation of COX-2. Moreover, CPSF4 was found to promote lung tumor growth and progression by up-regulating COX-2 expression in a xenograft lung cancer mouse model. CPSF4 overexpression or knockdown promoted or inhibited tumor growth in mice, while such regulation of tumor growth mediated by CPSF4 could be rescued through the inhibition or activation of COX-2 signaling. Correspondingly, CPSF4 overexpression or knockdown also elevated or attenuated COX-2 expression in tumor tissues of mice, while treatment with a COX-2 inducer LPS or a NF-κB inhibitor reversed this elevation or attenuation. Furthermore, we showed that CPSF4 was positively correlated with COX-2 levels in tumor tissues of lung cancer patients. Simultaneous high expression of CPSF4 and COX-2 proteins predicted poor prognosis of patients with lung cancers. Our results therefore demonstrated a novel mechanism for the transcriptional regulation of COX-2 by CPSF4 in lung cancer, and also offer a potential therapeutic target for lung cancers bearing aberrant activation of CPSF4/COX-2 signaling.