MIC1通过Akt调节食管鳞癌细胞化疗敏感性的研究

我国食管鳞癌危害严重、预后较差，化疗抵抗严重制约了化疗在食管鳞癌综合治疗中的作用，是影响预后的一个重要因素。巨噬细胞抑制因子1(MIC1)是一种细胞外泌的TGF-β超家族细胞因子，我们前期研究证实食管鳞癌细胞MIC1显著高表达，且患者MIC1血清水平升高并与预后呈显著负相关；后续研究发现MIC1抗体可显著提高食管鳞癌细胞KYSE150对化疗药物的敏感性，明显抑制Akt的活性。本课题拟从MIC1调节Akt活性为切入点，研究MIC1调控Akt活性的中间过程，以及Akt激酶下游与化疗抗拒相关的蛋白表达和活性改变，尤其是参与细胞凋亡调控和DNA损伤及修复相关蛋白，阐明MIC1影响食管鳞癌细胞化疗敏感性的分子机制；本课题不仅有助于进一步阐明食管鳞癌细胞对化疗药物抗拒的调控机制，而且可能为临床预测肿瘤化疗敏感性及个体化治疗提供一个有效的标志物，并为开发以MIC1为靶点的化疗增敏治疗提供理论指导。

Esophageal squamous cell carcinoma (ESCC) is a serious harmful malignant tumor with poor prognosis in China. Chemotherapy resistance severely restricted the role of chemotherapy in the comprehensive treatment of ESCC, which is an important factor of affecting clinical outcomes. Macrophage inhibitory cytokine 1 (MIC1) is a secreted cytokine of TGF-β superfamily. Our previous study confirmed that the expression of MIC1 significantly increased in ESCC tumor cells, and elevated serum MIC1 levels was significantly negative relevant with prognosis in patients. Further study found that MIC1 antibody could significantly improve the sensitivity of ESCC cell line KYSE150 to chemotherapy drugs, and inhibited Akt kinase activity obviously. This study intends to use the Akt kinase as a breaking point, studying the intermediate process of Akt activation by MIC1 and the change of downstream chemotherapy resistance associated protein expression and activity, especially involved in the regulation of apoptosis, DNA damage and repair, to clarify the molecular mechanisms of MIC1 in affecting chemosensitivity of ESCC. This study will not only help further elucidate the regulatory mechanism of chemotherapy resistance in ESCC, and also may provide an effective marker for predicting chemosensitivity in clinical settings and individualized treatment, furthermore, provide theoretical guidance for the development of MIC1-based sensitizing chemotherapy.