PHLPP2 Downregulation Contributes to Lung Carcinogenesis Following B[a]P/B[a]PDE Exposure.
PHLPP2 Downregulation Contributes to Lung Carcinogenesis Following B[a]P/B[a]PDE Exposure.
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B[a]P/B[a]PDE 暴露后 PHLPP2 下调导致肺癌发生
DOI：
10.1158/1078-0432.ccr-14-2829
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发表时间：
2015-08-15
期刊：
影响因子：
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通讯作者：
Huang C
中科院分区：
文献类型：
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作者：
Huang H;Pan X;Jin H;Li Y;Zhang L;Yang C;Liu P;Liu Y;Chen L;Li J;Zhu J;Zeng X;Fu K;Chen G;Gao J;Huang C
目的：流行病学研究支持B[a]P/B[a]PDE的致癌能力。然而，负责B[a]P/B[a] PDE引起的肺癌的分子机制尚未得到很好的研究。我们在此评估了新靶点PHLPP 2在B[a]P/B[a]PDE暴露后肺部炎症和癌变中的作用。实验设计：我们使用Western印迹、RT-PCR、[35 S]蛋氨酸脉冲和免疫组织化学染色来确定B[a]P/B[a]PDE暴露后PHLPP 2的下调。采用B[a] PDE诱导的Beas-2 B细胞转化模型和B[a] P诱导的小鼠肺癌模型，探讨PHLPP 2下调和肺癌发生的机制。这些重要的发现也被扩展到人体内的研究。结果如下：我们发现，B[a]P/B[a]PDE暴露下调PHLPP 2在体外人肺上皮细胞和在体内小鼠肺组织中的表达。PHLPP 2的异位表达显著抑制了B[a]PDE暴露后的细胞转化。机制研究表明，miR-205通过靶向PHLPP 2 -3′-UTR，对PHLPP 2蛋白翻译产生抑制作用。有趣的是，PHLPP 2表达与肿瘤坏死因子α（TNFα）表达呈负相关，与配对的相邻正常肺组织相比，肺癌组织中PHLPP 2表达较低，TNFα表达较高。进一步的研究表明PHLPP 2通过抑制炎性TNFα的转录而发挥B[a]P/B[a]PDE的抗肿瘤作用。结论：本研究不仅首次证实了肺致癌物B[a]P/B[a]PDE对PHLPP 2表达的下调作用，而且阐明了B[a]P/B[a]PDE致肺炎症和致癌的分子机制。临床癌症研究; 21（16）; 3783-93。©2015 AACR.
Purpose: The carcinogenic capacity of B[a]P/B[a]PDE is supported by epidemiologic studies. However, the molecular mechanisms responsible for B[a]P/B[a]PDE-caused lung cancer have not been well investigated. We evaluated here the role of novel target PHLPP2 in lung inflammation and carcinogenesis upon B[a]P/B[a]PDE exposure. Experimental Design: We used the Western blotting, RT-PCR, [35S]methionine pulse and immunohistochemistry staining to determine PHLPP2 downregulation following B[a]P/B[a]PDE exposure. Both B[a]PDE-induced Beas-2B cell transformation model and B[a]P-caused mouse lung cancer model were used to elucidate the mechanisms leading to PHLPP2 downregulation and lung carcinogenesis. The important findings were also extended to in vivo human studies. Results: We found that B[a]P/B[a]PDE exposure downregulated PHLPP2 expression in human lung epithelial cells in vitro and in mouse lung tissues in vivo. The ectopic expression of PHLPP2 dramatically inhibited cell transformation upon B[a]PDE exposure. Mechanistic studies showed that miR-205 induction was crucial for inhibition of PHLPP2 protein translation by targeting PHLPP2-3′-UTR. Interestingly, PHLPP2 expression was inversely associated with tumor necrosis factor alpha (TNFα) expression, with low PHLPP2 and high TNFα expression in lung cancer tissues compared with the paired adjacent normal lung tissues. Additional studies revealed that PHLPP2 exhibited its antitumorigenic effect of B[a]P/B[a]PDE through the repression of inflammatory TNFα transcription. Conclusions: Our studies not only first time identify PHLPP2 downregulation by lung carcinogen B[a]P/B[a]PDE, but also elucidate a novel molecular mechanisms underlying lung inflammation and carcinogenesis upon B[a]P/B[a]PDE exposure. Clin Cancer Res; 21(16); 3783–93. ©2015 AACR.