B[a]P/B[a]PDE可引起肺慢性炎症、进而导致肺癌，但机制不清。我们研究发现：B[a]PDE通过miRNA下调人支气管上皮Beas-2细胞内PHLPP2的表达诱发恶变；在B[a]P诱导的肺慢性炎症和肺癌组织中，PHLPP2与TNFα的表达两者间呈负相关；PHLPP2在转录水平负调控TNFα的表达，而TNFα表达持续上调对B[a]P诱导的肺慢性炎症和肺癌发生发展至关重要。因此，PHLPP2表达下调导致TNFα表达上调可能是B[a]P/BPDE致肺癌的关键分子事件。本项目旨在阐明B[a]P在诱导肺慢性炎症和肺癌发生发展中负调控PHLPP2的机制、PHLPP2负调控TNFα的机制，揭示并验证PHLPP2-TNFα通路是B[a]P诱导肺慢性炎症和肺癌发生发展的重要机制。本研究将有助于阐明B[a]P诱导肺慢性炎症和肺癌发生发展的机制，并为PHLPP2和/或TNFα作为肺癌防治的新靶标提供依据。

The sustained existence of chronic lung inflammation is a major driving force for the development of lung cancer. B[a]P and its metabolite B[a]PDE are the most important complete carcinogens that are responsible for both chronic lung inflammation and lung cancer. However, the molecular mechanisms to trigger and maintain chronic lung inflammation and thus lead to lung cancer following B[a]P exposure have not yet been explored. Our preliminary studies showed 1) that B[a]P/B[a]PDE exposure down-regulated PHLPP2 expression in human lung epithelial cell Beas-2B in vitro and also in mouse lung tissue in vivo, and the ectopic expression of PHLPP2 dramatically inhibited cell transformation upon B[a]PDE exposure; 2) that the down-regulation of PHLPP2 protein translation was mediated through targeting phlpp2-3’UTR by some microRNAs; 3) that PHLPP2 expression was inversely associated with TNFα expression, with low PHLPP2 and high TNFα expression in chronic lung inflammation and lung cancer tissues compared with the paired adjacent normal lung tissues; 4) that PHLPP2 exhibited its anti-inflammation/tumorigenic effect of B[a]P/B[a]PDE through the repression of inflammatory TNFα transcription; 5) and that the sustained induction of TNFα was crucial for the formation and maintenance of B[a]P-induced chronic lung inflammation and lung cancer development. Therefore, we anticipate that PHLPP2 down-regulation and therefrom TNFα up-regulation are key molecular events in the B[a]P-induced chronic lung inflammation and lung cancer development. Utilizing the Beas-2B cell model, B[a]P-induced lung carcinogenesis model of mice in combination with clinical specimens, we are going to elucidate the molecular mechanisms for B[a]P/BPDE down-regulation of PHLPP2 expression and thereafter PHLPP2 repression of TNFα transcription, and further validate the new signaling pathway PHLPP2-TNFα in the B[a]P-induced chronic lung inflammation and lung cancer development. Our findings will not only facilitate our understanding of the molecular mechanism for B[a]P-induced chronic lung inflammation and lung cancer development, but also provide the solid basis for utilizing PHLPP2 and/or TNFα as the targets for effective prevention and therapy of lung cancer.