食管癌微环境中外泌的Stat3促进癌侵袭转移的机制研究

新疆哈萨克族食管癌发病率高于全国平均水平，五年生存率低。侵袭转移是食管癌患者死亡的主要原因。本课题组前期研究发现：转移型食管癌伴随Stat3持续激活，并且不同途径激活的Stat3在癌细胞中去向不同；经M2型丙酮酸激酶（PKM2）、赖氨酸乙酰转移酶CBP、酪氨酸磷酸激酶c-Src激活的Stat3，可借助蛋白质转运小体Sec分泌到细胞外，推测：可能参与重构食管癌的微环境。科学假说：食管癌细胞外泌的Stat3在微环境中进入到不具有激活Stat3的食管癌细胞，从而促进其浸润转移。围绕此假说，拟运用外泌体检测、RNA干扰、流式细胞分选、质谱分析等技术，聚焦食管癌临床表型、细胞体系功能、动物模型机制层面：1）揭示食管癌细胞Stat3转运分泌机制；2）分析在食管癌微环境癌细胞对Stat3的转运内吞；3）探索抑制Stat3微环境转运对食管癌浸润性转移的控制。此项目将为食管癌的浸润转移治疗提供新的思路。

The incidence and metastases of esophageal squamous cell carcinoma (ESCC) in Kazakhs in Xinjiang have been far higher than the national average, with the five-year survival rate being low.The main causes of death in patients with esophageal cancer are invasion and metastasis.Our team has been devoting to the study of the molecular mechanism of ESCC in Kazakhs for decades. It has been found that metastatic ESCC cells are mostly accompanied by sustained activation of Stat3 and that Stat3 activated by different pathways has different destinations within ESCC cancer cells. Part of Stat3 secretion enters ESCC microenvironment taking the form of extracellular vesicles, which comprise c-Src, PKM2 and acetyltransferase CBP. We reasoned that in the microenvironment of ESCC, growth factor contacted some cancer cells and activated Stat3. Once activated, Stat3 can be secreted into the microenvironment by means of protein transporters and thereby enters other cancer cells that are not exposed to cytokines to promote their development and metastasis. Based on the hypothesis, we aim to focus on the clinical phenotype, cell function and animal model of ESCC by using exogenous detection and mass spectrometry techniques: (1)Revealing the transport and secretion mechanism of Stat3 in ESCC cell; (2)Analyzing the endocytosis of Stat3 in ESCC microenvironment; (3)Exploring the control of Stat3 microenvironment transport on aggressive metastasis of ESCC. This project will provide a new idea and method for the control of invasion and metastasis of ESCC.