B7-H3在调控人乳腺癌细胞糖代谢中的作用及机制

项目名称： B7-H3在调控人乳腺癌细胞糖代谢中的作用及机制

项目编号： No.81201559

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 肿瘤学1

项目作者： 刘皓

作者单位： 四川大学

项目金额： 25万元

中文摘要： B7-H3为免疫调节蛋白B7家族的新成员，该分子在多种类型的肿瘤细胞包括乳腺癌细胞上高水平表达，并在肿瘤发展、转移及诱导肿瘤药物抗性中有重要作用，但迄今国内外尚无B7-H3与肿瘤代谢相关的报道。我们在前期研究中发现：B7-H3 沉默的人乳腺癌细胞糖酵解水平下调，在缺氧条件下这种下调更为明显；B7-H3沉默细胞中缺氧诱导因子HIF-1α及其下游靶基因LDHA及PDK1的蛋白水平也下调。基于上述结果，我们假设"B7-H3通过HIF-1α介导对人乳腺癌细胞糖代谢的调控并进而促进癌细胞增殖"。为验证上述假设，我们将从B7-H3沉默以及B7-H3过表达等多个角度探讨B7-H3对人乳腺癌细胞糖代谢及细胞增殖的影响；并围绕HIF-1α及其上下游调节通路进行信号通路研究。本研究的完成将在国内外首次揭示B7-H3在人乳腺癌细胞糖代谢中的调控作用和机制，并为人乳腺癌患者的靶向治疗提供新的思路。

中文关键词： B7-H3；缺氧诱导因子-1；LDHA；PDK1；糖酵解

英文摘要： Most cancer cells show increased glucose uptake and lactate production even in the presence of oxygen. This phenomenon, known as the Warburg effect (also termed as "aerobic glycolysis", is considered as one of the most fundamental metabolic alterations during malignant transformation. There is growing evidence to support the idea that the upregulation of glycolysis in cancer cells meet, partially if not all, the energetic requirement, as well as the metabolic requirement of tumor growth. In the reprogramming of metabolism in cancer cells, The transcription factor, hypoxia-inducible factor 1 (HIF-1), plays a crucial role by inducing the expression of nearly all the enzymes involved in glycolysis, as well as glucose transporters. HIF-1 consists of an O2-regulated HIF-1 alapha subunit and a constitutively expressed HIF-1 beta subunit. In the presence of oxygen, HIF-1 alapha undergoes a posttranslational modification and degraded quickly. Under hypoxic conditions, HIF-1 alapha is stabilized and activated. B7-H3, a newly indentified member of the B7 protein family, has been shown to play either immune stimulatory or inhibitory roles on T-cell proliferation, induction of CTL response, IFN-? production in T cells, and anti-tumor activity. Recently, B7-H3 protein has been found to be overexpressed in most human tumor ty

英文关键词： B7-H3；HIF-1；LDHA；PDK1；glycolysis