钙结合蛋白S100A11亚细胞定位多层次介导TGFβ诱导结直肠癌上皮间质转化的机制

LIM and SH3 protein 1 (LASP1) has been identified as a colorectal cancer (CRC) metastasis-associated protein. The proteomic analysis showed that S100 calcium binding protein A11 (S100A11) was a downstream mediator of LASP1, however, its role in CRC metastasis is still unclear. Our preliminary experiment showed that S100A11 was regulated by LASP1 and involved in epithelial-mesenchymal transition (EMT) process induced by transforming growth factor β (TGFβ). Therefore, we proposed that S100A11, as a receptor of extracellular TGFβ stimulation, may occur in cytoplasm and nuclear and induced EMT at the multi-levels and promoted CRC metastasis. Using molecular pathological and biological strategy combined with in vivo and in vitro study, the aim of the project is to systematically illustrate the role of S100A11 in CRC metastasis, provide reliable evidences of LASP1 mediated by S100A11 and supply the scientific basis for establishing S100A11 as a novel target for clinical therapy of patients with advanced CRC.

LIM和SH3蛋白1（LASP1）是我们研究已鉴定的结直肠癌转移相关蛋白，通过蛋白质组学技术研究发现钙调蛋白S100A11是LASP1下游调节蛋白，目前关于S100A11在结直肠癌转移中的作用目前尚不清楚。预实验我们证实S100A11受LASP1的调控，并参与转化生长因子β（TGFβ）介导的上皮间质转化（EMT）过程。由此，我们提出S100A11作为细胞接收胞外TGFβ刺激的关键信号分子，通过细胞胞浆和胞核不同的亚细胞定位，多层次介导EMT的发生，从而诱导结直肠癌的转移。本项目拟采用分子病理及分子生物学方法，结合体内外研究，全方位阐明S100A11促进结直肠癌转移发生的作用，提供LASP1通过S100A11发挥生物学功能的直接证据，为确立S100A11作为晚期结直肠癌患者临床治疗靶点提供充分的科学依据。

LIM和SH3蛋白1（LASP1）是我们研究已鉴定的结直肠癌转移相关蛋白，通过蛋白质组学技术研究发现钙调蛋白S100A11是LASP1下游调节蛋白，其在结直肠癌转移中的作用目前尚不清楚。本项目拟采用分子病理及分子生物学方法，结合体内外研究，全方位阐明S100A11促进结直肠癌转移发生的作用，提供LASP1通过S100A11发挥生物学功能的直接证据，为确立S100A11作为晚期结直肠癌患者临床治疗靶点提供充分的科学依据。通过该项目研究，围绕结直肠癌领域这一重大科学问题，从结直肠癌转移的早期预警、发生机制及综合防治三方面进行了系统研究：1、鉴定一批结直肠癌转移相关分子标志物， 用于临床分子分型及预后判断(Oncogene 2019)；2、系统阐明LIM和SH3蛋白1（LASP1）为代表的结直肠癌转移相关分子在肿瘤演进中的新机制(Sci Rep 2016; Int J Cancer 2018)；3、基于肿瘤微环境关键环节设计特异性的靶向抑制剂，提出抗结直肠癌转移治疗新策略(Theranostics 2019；Cell Death Differ 2019)。迄今，上述相关成果以通讯作者在Cell Death Differ、Oncogene、Theranostics、Sci Rep等SCI收录期刊发表学术论文14篇。入选广东省“珠江学者”特聘教授。