Cyclooxygenase-2 (COX-2) is a key enzyme in the production of prostaglandins and thromboxanes from free arachidonic acid. Increasing evidence suggests that COX-2 plays a role in tumorigenesis. A variety of stimuli induce COX-2 and it is overexpressed in many tumors, including non-small cell lung cancer (NSCLC). We studied the regulation of COX-2 expression in immortalized human bronchial epithelial cells (HBECs) by transforming growth factor-beta1 (TGF-beta1) and epidermal growth factor (EGF) because these two growth factors are present in both the pulmonary milieu of those at risk for lung cancer as well as in the tumor microenvironment. EGF significantly enhanced TGF-beta1-mediated induction of COX-2 and corresponding prostaglandin E2 (PGE2) production. TGF-beta1 and EGF induced COX-2 at the transcriptional and post-transcriptional levels. EGF receptor (EGFR) inhibition, neutralizing antibody against amphiregulin, or mitogen-activated protein kinase kinase (MEK) inhibition blocked TGF-beta1-mediated COX-2 induction. COX-2 induction by TGF-beta1 depended upon Smad3 signaling and required the activity of EGFR or its downstream mediators. Autocrine amphiregulin signaling maintains EGFR in a constitutively active state in HBECs, allowing for COX-2 induction by TGF-beta1. Thus, EGFR ligands, which are abundant in the pulmonary microenvironment of those at risk for lung cancer, potentiate and are required for COX-2 induction by TGF-beta1 in HBEC. These findings emphasize the central role of EGFR signaling in COX-2 induction by TGF-beta1 and suggest that inhibition of EGFR signaling should be investigated further for lung cancer prevention.

译文

:环氧合酶2(COX-2)是由游离花生四烯酸生产前列腺素和血栓烷的关键酶。越来越多的证据表明,COX-2在肿瘤发生中起作用。多种刺激可诱导COX-2的表达,并在许多肿瘤中过度表达,包括非小细胞肺癌(NSCLC)。我们通过转化生长因子-beta1(TGF-beta1)和表皮生长因子(EGF)研究了永生化人支气管上皮细胞(HBECs)中COX-2表达的调节,因为这两个生长因子均存在于它们的肺环境中处于肺癌以及肿瘤微环境中的风险。 EGF显着增强了TGF-beta1介导的COX-2诱导和相应的前列腺素E2(PGE2)的产生。 TGF-beta1和EGF在转录和转录后水平诱导COX-2。 EGF受体(EGFR)抑制,抗双调蛋白的中和抗体或丝裂原激活的蛋白激酶激酶(MEK)抑制可阻止TGF-beta1介导的COX-2诱导。 TGF-beta1诱导COX-2依赖于Smad3信号传导,并需要EGFR或其下游介质的活性。自分泌两性调节蛋白信号转导使HBEC中的EGFR保持组成型活性状态,从而允许TGF-beta1诱导COX-2。因此,在有肺癌风险的人的肺微环境中丰富的EGFR配体增强了,并且是HBEC中TGF-beta1诱导COX-2所必需的。这些发现强调了EGFR信号传导在TGF-beta1诱导COX-2诱导中的核心作用,并建议应进一步研究EGFR信号传导的抑制作用以预防肺癌。

+1
+2
100研值 100研值 ¥99课程
检索文献一次
下载文献一次

去下载>

成功解锁2个技能,为你点赞

《SCI写作十大必备语法》
解决你的SCI语法难题!

技能熟练度+1

视频课《玩转文献检索》
让你成为检索达人!

恭喜完成新手挑战

手机微信扫一扫,添加好友领取

免费领《Endnote文献管理工具+教程》

微信扫码, 免费领取

手机登录

获取验证码
登录