IL-13Rα2与Notch1相互作用在抗失巢凋亡和肺癌转移中的分子机制研究

Invasion and metastasis are poor prognosis in lung cancer. The first step of metastasis is to obtain the ability of resistance to anoikis. IL-13 receptor α2 (IL-13Rα2) has a high affinity for IL-13. Our previous study revealed that the expression of IL-13 Rα2 significantly increased in lung cancer tissues. Co-Immunoprecipitation (Co-IP) assay preliminarily showed the interaction between IL-13 Rα2 and Notch1. Ectopic expression of IL-13 Rα2 increased lung cancer cell growth, anoikis resistance in vitro and lung metastasis in vivo, indicating the essential role of IL-13 Rα2 during anoikis resistance and metastasis in lung cancer. However, the detailed mechanism of IL-13 Rα2 in lung cancer remains unknown. The aim of our current study is to confirm the direct interaction between IL-13Rα2 and Notch1 by yeast two-hybrid technique, laser confocal microscopy, GST pull-down experiment, providing a novel insight into elucidating the function of interaction between IL-13 Rα2 and related protein during the process of anoikis and metastasis. Moreover, we will determine the function of IL-13 Rα2 in lung cancer metastasis in vivo and in vitro by gene gain-of-function and loss-of function strategy. The study will provide important theoretical basis of novel therapy targeting IL-13 Rα2 in lung cancer.

肺癌的侵袭与转移是患者预后不良的主要原因，而获得失巢凋亡抵抗能力是转移首要的关键步骤。IL-13受体α2（IL-13Rα2）与IL-13有高度亲和力。我们前期研究显示IL-13Rα2在肺癌组织中表达升高，免疫共沉淀初步验证IL-13Rα2与Notch1 的相互作用；IL-13Rα2 促进肺癌细胞生长、失巢凋亡抵抗和裸鼠皮下移植瘤肺转移，提示IL-13Rα2参与肺癌失巢凋亡抵抗及转移，但其具体作用机制尚未明确。本课题拟在前期研究基础上，通过酵母双杂交法、激光共聚焦共定位实验、GST pull-down技术分析等方法获取IL-13Rα2与Notch1直接相互作用的可靠证据，明确IL-13Rα2与其相互作用蛋白在肺癌失巢凋亡和转移中的作用和分子机制。通过基因功能获得和功能缺失策略，体内体外研究IL-13Rα2在肺癌转移中的作用。本研究将为以IL-13Rα2为靶点的肺癌治疗提供理论依据。

肺癌的侵袭与转移是患者预后不良的主要原因，而获得失巢凋亡抵抗能力是转移首要的关键步骤。IL-13受体α2（IL-13Rα2）与IL-13有高度亲和力。我们前期研究显示IL-13Rα2在肺癌组织中表达升高，免疫共沉淀初步验证IL-13Rα2与Notch1的相互作用；IL-13Rα2 促进肺癌细胞生长、失巢凋亡抵抗和裸鼠皮下移植瘤肺转移，提示IL-13Rα2参与肺癌失巢凋亡抵抗及转移，但其具体作用机制尚未明确。我们通过酵母双杂交法、免疫共沉淀、GST pull-down技术分析等方法证实IL-13Rα2与Notch1直接作用通过TAZ促进肺癌失巢凋亡抵抗和转移；IL-13Rα2和Notch1通过上调AKT抑制TAZ磷酸化，减少TAZ泛素化降解，促进TAZ进入细胞核内与TEAD结合。体外转染IL-13Rα2促进裸鼠肺癌生长和转移。本研究将为以IL-13Rα2为靶点的肺癌治疗提供理论依据。