基于HIF-1α介导PI3K/AKT通路复方蜥蜴散从毒瘀交阻干预胃癌EMT作用机制及与胃癌浸润转移的相关性研究

EMT is the main cause of invasion and migration of gastric cancer, and inhibition of EMT is the key to blocking invasion and metastasis.The preliminary study found that gastric precancerous lesions(PLGC) and gastric cancer pathogenesis was principally toxin and blood stasis,the compound lizards powder and single taste eremias multiocellata can effectively inhibit the malignant tendency,intervention of human gastric cancer cells P53,Bax,eremias multiocellata also affect EMT related factor E-cad and MMP-9 of human gastric cancer BCG-823 cells.PI3K/AKT is the main pathway to regulate EMT, toxin and blood stasis can induce cell hypoxia and hypoxia,activate HIF-1α,and mediate PI3K/AKT.It may be the main mechanism regulating the invasion and metastasis of gastric cancer.We adopt the Jiedutongluo therapy with the compound lizards powder,improve the cell ischemia and hypoxia microenvironment,the intervention of HIF-1α,mediated PI3K/AKT,inhibition of EMT as the pointcut,the study of the gastric cancer cell lines EMT model migration infiltration and EMT related to factors of gastric cancer cells metastatic,in-depth study of the compound lizards powder effect and mechanism of anti tumor invasion and metastasis.This research not only on the traditional Chinese medicine plays an important role in tumor metastasis,and disease research in combination with the deepening of Chinese and Western medicine,to provide effective support and scientific basis for the clinical application of the compound lizards powder.

细胞上皮间质转化（EMT）是胃癌浸润迁移主要原因，抑制EMT是阻断浸润转移的关键。前期研究发现，胃癌前病变（PLGC）及胃癌病机以毒瘀交阻为主，复方蜥蜴散和单味密点麻蜥可有效抑制癌变趋势，干预人胃癌细胞P53、bax表达，密点麻蜥亦影响人胃癌BCG-823 细胞EMT相关因子E-cad、MMP-9，阻断癌变浸润转移。PI3K/AKT是调控EMT主要通路，毒瘀交阻致细胞缺血缺氧，激活HIF-1α，介导PI3K/AKT可能是调控胃癌浸润转移的主要机制。我们以复方蜥蜴散解毒通络,改善缺血缺氧微环境,干预HIF-1α,介导PI3K/AKT,抑制EMT为切入点，研究该方对人胃癌细胞株EMT模型迁移浸润及胃癌细胞转移瘤EMT的影响，深入探讨复方蜥蜴散抗肿瘤浸润转移的作用及机制。本课题不仅对中药抗肿瘤转移研究具有重要意义，且可深化胃癌中西医结合病机研究，为复方蜥蜴散临床转化应用提供有效支撑和科学依据。

细胞上皮间质转化（EMT）是胃癌浸润迁移的主要原因，抑制EMT即是阻断浸润转移的关键。前期研究发现，胃癌前病变（PLGC）及胃癌病机以毒瘀交阻为主，复方蜥蜴散可有效抑制癌变趋势，干预人胃癌细胞P53、bax表达，密点麻蜥亦影响人胃癌BCG-823 细胞EMT相关因子E-cad、MMP-9，阻断癌变浸润转移。PI3K/AKT是调控EMT主要通路，毒瘀交阻致细胞缺血缺氧，激活HIF-1α，介导PI3K/AKT可能是调控胃癌浸润转移的主要机制。我们以复方蜥蜴散解毒通络,改善缺血缺氧微环境，干预HIF-1α,介导PI3K/AKT，抑制EMT为切入点，从体内荷瘤实验证实复方蜥蜴散干预各组胃癌细胞凋亡率较高，且HIF-1α、PI3K、p-AKT、Integrin-β3相关蛋白表达水平降低，E-cadherin表达水平增高，均以复方蜥蜴散高剂量组最为明显。体外抗人胃癌细胞实验表明，复方蜥蜴散高、中、低剂量含药大鼠血清可诱导人胃癌细胞凋亡，阻滞细胞周期于G1期，有效抑制胃癌细胞生长，并可降低TGF-β1诱导不同分化人胃癌SGC-7901、BCG823细胞株EMT模型相关因子E-cad、Integrin、MMPs的水平，降低p-AKT及TGF-β蛋白表达水平进而阻断癌变，发挥抑制肿瘤增长的作用，以复方蜥蜴散高剂量组效果最明显。同时，宁夏密点麻蜥不同部位各组可明显抑制SGC-7901胃癌细胞增殖，诱导凋亡，以宁夏密点麻蜥尾部组细胞总凋亡率大于其他各组，Sirt1和P53蛋白表达降低明显。因此，实验结果表明，复方蜥蜴散能够通过解毒活血通络，改善细胞缺血缺氧微环境，诱导HIF-1α介导PI3K /AKT信号通路，进而影响EMT相关蛋白表达而抑制胃癌细胞浸润转移。通过项目实验研究表明，以疾病现代医学发病机制为基础，融合中医对疾病核心病机的认识进行立法组方，并结合地方特色药物的应用，对中医药防治现代医学诊断明确的疾病、提升疾病临床疗效提供了较好的思路和方法，具有较好的借鉴意义，也是中西医结合的一个有益探索。