PHD2调控上皮间质转化介导结肠癌细胞侵袭转移的分子机制研究

缺氧微环境是导致肿瘤细胞EMT并促进其侵袭转移的重要因素之一，但缺氧启动肿瘤细胞发生表型转化的机制尚不清楚。我们前期研究发现PHD2在结肠癌表达普遍缺失，且可通过HIF-1α非依赖途径调控EMT发生，本项目拟在前期工作基础上，从探讨PHD2对IKK的影响机制入手，了解PHD2活性变化对结肠癌细胞IKK/NF-κB/snail信号通路的影响，通过研究PHD2与IKKβ相互作用，明确PHD2作用于IKKβ作用位点，继而研究NF-κB对Snail核转位及上皮标志E-cadherin和间叶细胞标志Vimentin的转录调控作用，以期证实PHD2通过IKK-NF-κB-Snail途径调控上皮间质转化，从一个全新的角度探讨缺氧信号通过HIF-1α非依赖途径直接作用于EMT调控因子介导EMT和侵袭转移的分子机制。这一研究不仅可进一步揭示缺氧启动EMT的分子机制，而且可为阻断EMT和侵袭转移提供新的靶点。

The hypoxic milieu of tumor mass is a well-recognized factor that causes progression and epithelial-mesenchymal transition (EMT) of cancer, but the mechanism how hypoxia initiates the phenotypic transition of tumor cells is remain unclear. In our previous study, we discovered that prolyl hydroxylase 2 (PHD2) is commonly low-expressed in colon cancer. PHD2 could additionally regulate the epithelial-mesenchymal transition of colon cancer through a hypoxia-inducible factor-1α independent pathway. In the present proposal, as an attempt to find out the potential PHD2-IKK/NF-κB-Snail signal axis, we plan to elucidate the interaction between PHD2 and IKKβ, then to reveal the regulation of E-cadherin and Vimentin via NF-κB-induced nuclear translocation of Snail. This study focuses on a novel mechanism that PHD2 acts on regulators of EMT via HIF-1α independent pathway, which may elucidate the molecular mechanism of EMT initiated by hypoxia and provide new target for tumor progression and epithelial-mesenchymal transition.