The Mu opioid receptor promotes opioid and growth factor-induced proliferation, migration and Epithelial Mesenchymal Transition (EMT) in human lung cancer.
The Mu opioid receptor promotes opioid and growth factor-induced proliferation, migration and Epithelial Mesenchymal Transition (EMT) in human lung cancer.
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DOI：
10.1371/journal.pone.0091577
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Singleton PA
中科院分区：
文献类型：
--
作者：
Lennon FE;Mirzapoiazova T;Mambetsariev B;Poroyko VA;Salgia R;Moss J;Singleton PA
最近的流行病学研究表明，不同的麻醉方案会导致癌症复发，这可能是因为μ阿片受体（莫尔）可以影响癌症的进展。基于我们先前的观察，即在人非小细胞肺癌（NSCLC）细胞中过表达莫尔增加肿瘤生长和转移，本研究检测了莫尔是否调节人NSCLC细胞中生长因子受体信号传导和上皮间质转化（EMT）。我们在未经处理或用各种浓度的DAMGO、吗啡、芬太尼、EGF或IGF处理的人H358 NSCLC细胞中利用特异性siRNA、shRNA、化学抑制剂和过表达载体。然后进行细胞功能测定、免疫印迹和免疫沉淀测定。我们的研究结果表明，莫尔调节阿片和生长因子诱导的EGF受体信号传导（Src，Gab-1，PI3 K，Akt和STAT 3激活），这对随后的人NSCLC细胞增殖和迁移至关重要。此外，用阿片样物质、生长因子或莫尔过表达处理的人NSCLC细胞表现出蜗牛、蛞蝓和波形蛋白的增加以及ZO-1和claudin-1蛋白水平的降低，结果与EMT表型一致。此外，这些作用通过莫尔、Src、Gab-1、PI3K、Akt和STAT 3的沉默（shRNA）或化学抑制而逆转（p <0.05）。我们的数据表明，在肺癌进展过程中，莫尔对阿片样物质和生长因子信号传导以及随后的增殖、迁移和EMT转变可能有直接影响。这种效应为流行病学研究结果提供了合理的解释。
Recent epidemiologic studies implying differences in cancer recurrence based on anesthetic regimens raise the possibility that the mu opioid receptor (MOR) can influence cancer progression. Based on our previous observations that overexpression of MOR in human non-small cell lung cancer (NSCLC) cells increased tumor growth and metastasis, this study examined whether MOR regulates growth factor receptor signaling and epithelial mesenchymal transition (EMT) in human NSCLC cells. We utilized specific siRNA, shRNA, chemical inhibitors and overexpression vectors in human H358 NSCLC cells that were either untreated or treated with various concentrations of DAMGO, morphine, fentanyl, EGF or IGF. Cell function assays, immunoblot and immunoprecipitation assays were then performed. Our results indicate MOR regulates opioid and growth factor-induced EGF receptor signaling (Src, Gab-1, PI3K, Akt and STAT3 activation) which is crucial for consequent human NSCLC cell proliferation and migration. In addition, human NSCLC cells treated with opioids, growth factors or MOR overexpression exhibited an increase in snail, slug and vimentin and decrease ZO-1 and claudin-1 protein levels, results consistent with an EMT phenotype. Further, these effects were reversed with silencing (shRNA) or chemical inhibition of MOR, Src, Gab-1, PI3K, Akt and STAT3 (p<0.05). Our data suggest a possible direct effect of MOR on opioid and growth factor-signaling and consequent proliferation, migration and EMT transition during lung cancer progression. Such an effect provides a plausible explanation for the epidemiologic findings.
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