Induction of osteopontin expression by nicotine and cigarette smoke in the pancreas and pancreatic ductal adenocarcinoma cells
Induction of osteopontin expression by nicotine and cigarette smoke in the pancreas and pancreatic ductal adenocarcinoma cells
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DOI：
10.1002/ijc.24388
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发表时间：
2009-07-15
影响因子：
6.4
通讯作者：
Arafat, Hwyda A.
中科院分区：
文献类型：
--
作者：
Chipitsyna, Galina;Gong, Qiaoke;Arafat, Hwyda A.
胰腺导管腺癌（PDA）是一种致死性疾病，其病因与吸烟有关。尼古丁是香烟的重要成分，在吸烟者的血液中浓度很高。骨桥蛋白（OPN）是一种分泌型磷蛋白，其赋予癌细胞迁移表型并激活诱导细胞存活、增殖、侵袭和转移的信号传导途径。在这里，我们通过研究尼古丁对骨桥蛋白的影响，研究了尼古丁在PDA中作用的潜在分子基础。尼古丁通过激活PDA细胞OPN基因启动子，显著（p < 0.02）增加OPN mRNA和蛋白的分泌。尼古丁乙酰胆碱受体拮抗剂甲磺乙胺可抑制OPN mRNA的诱导。此外，酪氨酸激酶抑制剂genistein抑制尼古丁介导的OPN诱导，表明丝裂原活化蛋白激酶信号转导机制参与。尼古丁激活ERK 1/2的磷酸化，但不激活p38或c-Jun NH 2-末端MAP激酶。抑制ERK 1/2的活化可减少尼古丁诱导的OPN合成。暴露于香烟烟雾的大鼠胰腺OPN呈剂量依赖性增加，抑制胰腺和血浆尼古丁水平的升高。对来自侵袭性PDA患者（其中大多数是吸烟者）的癌组织的分析显示，在恶性导管和周围的胰腺腺泡中存在大量的OPN。我们的数据表明，尼古丁可能通过上调OPN促进PDA发病。他们提供了第一个洞察尼古丁启动的信号转导途径，调节OPN作为一个可能的致瘤机制在PDA。(C)2009年UICC
Pancreatic ductal adenocarcinoma (PDA) is a lethal disease with etiological association with cigarette smoking. Nicotine, an important component of cigarettes, exists at high concentrations in the bloodstream of smokers. Osteopontin (OPN) is a secreted phosphoprotein that confers on cancer cells a migratory phenotype and activates signaling pathways that induce cell survival, proliferation, invasion, and metastasis. Here, we investigated the potential molecular basis of nicotine's role in PDA through studying its effect on OPN. Nicotine significantly (p < 0.02) increased OPN mRNA and protein secretion in PDA cells through activation of the OPN gene promoter. The OPN mRNA induction was inhibited by the nicotinic acetylcholine receptor antagonist, mechamylamine. Further, the tyrosine kinase inhibitor genistein inhibited the nicotine-mediated induction of OPN, suggesting that mitogen activated protein kinase signaling mechanism is involved. Nicotine activated the phosphorylation of ERK1/2, but not p38 or c-Jun NH2-terminal MAP kinases. Inhibition of ERK1/2 activation reduced the nicotine-induced OPN synthesis. Rats exposed to cigarette smoke showed a dose-dependent increase in pancreatic OPN that paralleled the rise of pancreatic and plasma nicotine levels. Analysis of cancer tissue from invasive PDA patients, the majority of whom were smokers, showed the presence of significant amounts of OPN in the malignant ducts and the surrounding pancreatic acini. Our data suggest that nicotine may contribute to PDA pathogenesis through upregulation of OPN. They provide the first insight into a nicotine-initiated signal transduction pathway that regulates OPN as a possible tumorigenic mechanism in PDA. (C) 2009 UICC