基于HIF-1α介导的PI3K/Akt信号通路探讨从痰论治胃癌细胞上皮间质转化的机制研究

Epithelial-mesenchymal transition (EMT) is a prerequisite for tumor invasion and metastasis. Hypoxia inducible factor-1α (HIF-1α)，as a key effector molecule in tumor hypoxic microenvironment, is controlled by PI3K/Akt signaling pathways which considered to be closely related to EMT. Our previous research showed that the metastasis-associated molecules and signaling pathways could be attributed to "phlegm" which is called "Tanzhuo" in TCM . It confirmed that "Phlegm-Resolved Therapy" can inhibit gastric cancer invasion and reduce the expression of HIF-1α, but the exact molecular mechanism remains unclear.This study, focusing on the close correlation of EMT and "HIF-1α"－mediated PI3K/Akt signaling pathways, is undertaken to observe the role of HIF - 1α and the regulation mechanism of PI3K/Akt signaling pathways in gastric cancer EMT by HIF-1α silencing and PI3K/Akt blocking. Futhur observations would be developed so as to clarify the targets and molecular mechanisms of "Phlegm-Resolved Therapy" in gastric cancer，observing the impact of Jinlongshe granules on EMT of gastric cancer cell, gastric cancer invasion and PI3K/Akt signal pathway mediated by HIF-1α. The results are expected to provide scientific evidence for the prevention and cure of gastric cancer invasion by the theory of "Phlegm-Resolved Therapy" .

细胞上皮-间质转化(EMT)是肿瘤侵袭转移的前提。研究表明缺氧诱导因子-1α(HIF-1α）作为肿瘤缺氧微环境的关键效应分子，其介导的PI3K/Akt信号通路与EMT密切相关。我科前期研究认为与胃癌侵袭转移相关的分子及信号通路可归于"痰浊"范畴，并证实从"痰"论治胃癌能抑制胃癌侵袭转移，降低HIF-1α表达，但具体分子机制尚不明确。本项目以胃癌细胞EMT与HIF-1α介导的PI3K/Akt信号通路密切相关性为切入点，首先通过HIF-1α沉默及PI3K/Akt信号通路阻断，明确HIF-1α在胃癌EMT中的作用及PI3K/Akt信号通路对这一过程的调控；再观察基于"清化痰浊"思想研制的金龙蛇颗粒对胃癌细胞EMT（形态结构、分子标记物）、侵袭转移力及HIF-1α介导的PI3K/Akt信号通路的影响，从而阐明从"痰"论治胃癌侵袭转移的作用靶点及分子机制，为中医药防治胃癌侵袭转移提供依据。

细胞上皮-间质转化(EMT)是肿瘤侵袭转移的前提。研究表明缺氧诱导因子-1α(HIF-1α）作为肿瘤缺氧微环境中的关键效应分子，其介导的PI3K/Akt信号通路与EMT密切相关。我科前期研究认为与胃癌侵袭转移相关的分子及信号通路可归于“痰浊”范畴，并证实从“痰”论治胃癌能抑制胃癌侵袭转移，降低HIF-1α表达。本项目基于以上研究思路，首先证实了缺氧环境中HIF-1α沉默能抑制胃癌细胞EMT，其次进行PI3K/Akt信号通路阻断，明确阻断该通路能够干预HIF-1α从而影响胃癌细胞EMT。再从体外、体内论证了金龙蛇颗粒能够影响胃癌细胞EMT（形态结构、分子标记物）、侵袭转移力及HIF-1α介导的PI3K/Akt信号转导通路，以上实验结果将阐明从“痰”论治胃癌侵袭转移的作用靶点及分子机制，为中医药防治胃癌侵袭转移提供依据。