缝隙连接在肿瘤相关成纤维细胞反向Warburg效应调控非小细胞肺癌恶性进展中的作用及机制研究

项目名称： 缝隙连接在肿瘤相关成纤维细胞反向Warburg效应调控非小细胞肺癌恶性进展中的作用及机制研究

项目编号： No.81460447

项目类型： 地区科学基金项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 阳洁

作者单位： 广西医科大学

项目金额： 48万元

中文摘要： 肿瘤相关成纤维细胞（CAFs）存在反向Warburg效应（有氧糖酵解）并与肿瘤进展密切相关。肿瘤细胞与周围细胞间的缝隙连接（GJ）可促进肿瘤侵袭转移。我们前期研究发现，肿瘤细胞间GJ参与调控NSCLC进展。此外，共培养A549细胞与CAFs间存在单向性GJ功能，增强GJ功能可促进A549细胞增殖、侵袭及磷酸化Akt水平；共培养可增强CAFs反向Warburg效应，并促进A549细胞增殖和侵袭；抑制CAFs反向Warburg效应可减少A549细胞增殖及侵袭，此时增强GJ功能可明显逆转此效应。由此我们提出新的科学假设：CAFs反向Warburg效应可能通过GJ激活NSCLC的PI3K/Akt/mTOR信号通路，从而促进NSCLC恶性进展。本课题将通过细胞、动物及临床标本明确GJ在CAFs反向Warburg效应调控NSCLC恶性进展中的作用及机制，为靶向肿瘤微环境的NSCLC治疗策略提供新依据。

中文关键词： C05_气管；支气管；肺肿瘤；缝隙连接；肿瘤相关成纤维细胞；反向Warburg效应；非小细胞肺癌

英文摘要： Carcinoma-associated fibroblasts (CAFs) undergo reverse Warburg effect (aerobic glycolysis), which is closely associated with cancer progression. The gap junction (GJ) between cancer cells and the surrounding cells can promote tumor invasion and metastasis. Our previous study found that GJ between cancer cells was involved in the regulation of NSCLC progress.In addition, we found that the existence of one-way GJ function between co-cultured A549 cells and CAFs. Enhanced functionality of GJ by RA (a widely accepted GJ enhancer) can increase the proliferation, invasion and Akt phosphorylation levels of A549 cells. Moreover, the reverse Warburg effectof CAFs and proliferation and invasion of A549 cells were both increased in A549 cells/ CAFs co-cultures. Specifically, inhibition of reverse Warburg effect of CAFs by DCA (specific aerobic glycolysis inhibitor) significantly reduced proliferation and invasion of A549 cells, and this effect could be obviously reversed by combination treatment of DCA with GJ enhancer RA. Thus, we propose that reverse Warburg effect of CAFs might activate PI3K/Akt/mTOR signaling pathway in NSCLC via GJ, thereby promoting malignant progression of NSCLC. Based on these findings, the present study will clarify the role of GJ in the malignant progression of NSCLC regulated by reverse Warburg effect of CAFs and the underlying mechanisms in cells, animals and specimens of patients. Our study will provide the basis for the new therapeutic strategies targeting NSCLC tumor microenvironment.

英文关键词： C05_trachea;bronchus;lung cancer;gap junction;carcinoma-associated fibroblasts(CAFs);reverse Warburg effect;non-small cell lung cancer(NSCLC)