Anxa2介导IL-6诱导的SHP2/Erk和JAK2/STAT3信号通路激活并促进乳腺癌细胞上皮间质转化的分子机制研究

白细胞介素6（IL-6）在诱导上皮间质转化（EMT）并促进乳腺癌进展和转移中起关键作用。IL-6主要通过激活SHP2/Erk和JAK2/STAT3信号通路来发挥作用，通常情况下SHP2的激活会抑制STAT3信号通路。然而我们前期研究发现IL-6诱导EMT的发生伴随着两条通路的同时激活，进一步研究发现Anxa2与SHP2和STAT3存在相互作用，下调Anxa2的表达可以明显抑制这两条信号通路的激活以及乳腺癌细胞EMT的发生，从而初步证实Anxa2参与了IL-6诱导的乳腺癌细胞EMT。本研究拟利用Anxa2不同表达水平和不同活性状态的细胞模型，采用免疫共沉淀、免疫荧光、染色质免疫沉淀和乳腺癌转移小鼠模型等多种实验方法，进一步阐明Anxa2与SHP2或者STAT3的相互作用模式，揭示Anxa2介导SHP2/Erk和JAK2/STAT3这两条信号通路同时激活以及乳腺癌细胞EMT发生的分子机制。

Epithelial-Mesenchymal Transition (EMT) induced by interleukin 6 (IL-6) plays a critical role in facilitating breast cancer progression and metastasis. IL-6 exerts its biological activities by activating SHP2/ERK and JAK/STAT3 signaling pathways. It has been established that activation of SHP2 results in inhibition of JAK2/STAT3 signaling cascade. However, our previous results found that constitutive activation of SHP2/ERK and JAK/STAT3 signaling during EMT induced by IL-6 in human breast cancer cells. Further studies showed that Anxa2 as a novel binding protein of both STAT3 and SHP2 in breast cancer cells. In addtion, down-regulation of Anxa2 by siRNA impaired activation of SHP2/ERK and JAK/STAT3 signaling and inhibited IL-6 induced EMT of breast cancer cells, suggesting that Anxa2 is required for IL6 induced EMT in human breast cancer cells. We hypothesize that Anxa2 up-regulation modulates the balance of the SHP2/ERK and JAK/STAT3 pathways and promotes EMT of breast cancer. In this study, we plan to use immunofluorescence, co-immunoprecipitation and chromatin immunoprecipitation methods and in vivo SCID mouse model to investigate the effect of expression level and phosphorylation status of Anxa2 on the activation of JAK2/STAT3 and SHP2/Erk pathway during EMT induced by IL-6. Our study will further reveal the mechanism of EMT induced by IL6 in breast cancer cells.