炎症因子TNFα调控TAZ诱导乳腺癌干细胞的机制研究

乳腺癌是世界范围内女性发病率最高的癌症类型。近年来，乳腺癌的早期诊断和治疗水平显著提高，然而患者治疗后的复发和转移是导致乳腺癌死亡的主要原因。目前研究认为乳腺癌干细胞（BCSCs）驱动了乳腺癌的转移侵袭和耐药等恶性过程。乳腺癌患者中存在高水平的炎症因子如TNFα，在乳腺癌的发生发展和复发过程中有重要作用。Hippo信号通路中的转录共活化因子TAZ具有促进乳腺癌干细胞自我更新的能力。我们前期研究发现TNFα通过上调TAZ来诱导乳腺癌干细胞，但具体机制尚不清楚。本项目中，我们将首先确定TAZ是否介导了炎症因子TNFα刺激的干细胞增加；阐明TNFα是否通过非经典NF-κB信号通路上调TAZ；并评价TAZ和TNFα在乳腺癌组织样本中是否存在表达相关性；然后建立TAZ启动子双荧光素酶报告基因系统来筛选靶向抑制TAZ转录的化合物。本项研究有望发展靶向乳腺癌干细胞治疗的新策略。

Breast cancer is the most prevalent type of cancer among women worldwide. Despite advancements in the early detection and treatment of breast caner, treated patients often suffer from disease relapse and metastasis due to the presence of breast cancer stem cells (BCSCs). There are high levels of inflammation mediators in breast cancer. Inflammation mediators, such as tumor necrosis factor alpha (TNFα), play major roles in breast cancer pathogenesis, progression and relapse. TAZ, a transcriptional co-activator in Hippo pathway, is required to maintain self-renewal capacity in BCSCs. Previous studies suggest that TNFα treatment of human breast cancer cells up-regulates TAZ, engendering breast cancer cells with stem-like properties. However the mechanism is unclear. First, we will analyze whether TAZ mediates TNFα inducing cancer stem cells. Second, we will elucidate whether TNFα induces TAZ through NF-κB non-canonical pathway. Third, we will investigate the expression of TAZ and TNFα in breast cancer tissue. Finally, we will establish the dual-luciferase report gene system of TAZ promoter in order to screen compounds that can inhibit cancer stem cells by down-regulating the expression of TAZ. TAZ targeting could be a new therapeutic strategy for breast cancer.