Tobacco smoke stimulates the transcription of amphiregulin in human oral epithelial cells: Evidence of a cyclic AMP-responsive element binding protein-dependent mechanism
Tobacco smoke stimulates the transcription of amphiregulin in human oral epithelial cells: Evidence of a cyclic AMP-responsive element binding protein-dependent mechanism
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DOI：
10.1158/0008-5472.can-05-0628
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发表时间：
2005-07-01
期刊：
影响因子：
11.2
通讯作者：
Dannenberg, AJ
中科院分区：
文献类型：
--
作者：
Du, BH;Altorki, NK;Dannenberg, AJ
表皮生长因子受体（EGFR）介导的信号传导的激活与烟草烟雾诱导的癌症的发病机制有关。最近，在吸烟者的口腔粘膜中发现EGFR的配体双调蛋白水平升高。本研究的主要目的是阐明烟草烟雾诱导双调蛋白的机制。用烟草烟雾的盐水提取物处理非致瘤性人口腔上皮细胞系（MSK-Leuk 1）刺激双调蛋白（AR）转录，导致双调蛋白mRNA和蛋白量增加。烟草烟雾刺激环AMP（cAMF）->蛋白激酶A（PKA）途径，导致AR转录的cAMP响应元件结合蛋白依赖性激活增加。烟草烟雾的这些诱导作用依赖于芳烃受体（AhR）。事实上，α-萘酚酮，一种AhR拮抗剂，阻断烟草烟雾介导的cAMP反应元件结合蛋白与AR启动子结合的诱导，从而抑制双调蛋白的诱导。值得注意的是，用烟草烟雾或外源性双调蛋白处理MSK-Leuk 1细胞刺激DNA合成。EGFR酪氨酸激酶的抑制剂或双调蛋白的中和抗体消除了烟草烟雾介导的DNA合成增加。总之，这些发现表明，烟草烟雾刺激了由AhR -> cAMP -> PKA组成的信号通路，导致AR转录增强和DNA合成增加。烟草烟雾诱导双调蛋白从而增强DNA合成的能力可能有助于烟草烟雾的致癌作用。
Activation of epidermal growth factor receptor (EGFR)mediated signaling has been implicated in the pathogenesis of tobacco smoke-induced cancers. Recently, elevated levels of amphiregulin, a ligand of the EGFR, were found in the oral mucosa of smokers. The main objective of this study was to elucidate the mechanism by which tobacco smoke induces amphiregulin. Treatment of a nontumorigenic human oral epithelial cell line (MSK-Leuk1) with a saline extract of tobacco smoke stimulated amphiregulin (AR) transcription resulting in increased amounts of amphiregulin mRNA and protein. Tobacco smoke stimulated the cyclic AMP (cAMF) -> protein kinase A (PKA) pathway leading to increased cAMP-responsive element binding protein-dependent activation of AR transcription. These inductive effects of tobacco smoke were dependent on the aryl hydrocarbon receptor (AhR). In fact, alpha-naphthoflavone, an AhR antagonist, blocked tobacco smoke-mediated induction of binding of cAMP-responsive element binding protein to the AR promoter and thereby suppressed the induction of amphiregulin. Notably, treatment of MSK-Leuk1 cells with tobacco smoke or exogenous amphiregulin stimulated DNA synthesis. An inhibitor of EGFR tyrosine kinase or a neutralizing antibody to amphiregulin abrogated the increase in DNA synthesis mediated by tobacco smoke. Taken together, these findings suggest that tobacco smoke stimulated a signaling pathway comprised of AhR -> cAMP -> PKA resulting in enhanced AR transcription and increased DNA synthesis. The ability of tobacco smoke to induce amphiregulin and thereby enhance DNA synthesis is likely to contribute to the procarcinogenic effects of tobacco smoke.