LASP-1调控S100A4、14-3-3σ蛋白介导结直肠癌上皮-间质转化的机制研究

Our previous study have identified LIM and SH3 protein 1(LASP-1) as a novel colorectal carcinoma (CRC) metastasis-associated protein. We first reported that LASP-1 promote CRC invasion and metastasis, and related to poor prognosis of patients with CRC. The mechanism underlying CRC metastasis promoted by LASP-1, however, is still not clear. Our pre-trail study, using proteomic analysis based on 2-D DIGE, found that LASP-1 may regulate expression of tumor-assocated protein S100A4 and 14-3-3σ. The researches have reported that S100A4 and 14-3-3σ are closely related with epithelial-mesenchymal transition (EMT), which play important role in tumor invasion and metastasis. We proposed that LASP-1 mediate EMT by regulating S100A4 and 14-3-3σ, and promote CRC metastasis. Using proteomic technique, molecular pathological and biological strategy, the aim of the project is to obtain reliable evidence of CRC metastasis mediated by LASP-1. The study may illustrate biological mechanism of LASP-1, and provide the scientific basis for establishing LASP-1 as a novel target for clinical therapy of CRC metastasis.

LIM和SH3蛋白1(LASP-1)是我们前期研究新发现的结直肠癌转移相关蛋白，首次报道LASP-1促进结直肠癌的侵袭、转移，并与患者的不良预后密切相关。但是，究竟LASP-1如何促进结直肠癌转移目前尚不清楚。预实验我们通过2-D DIGE的蛋白质组学分析，发现肿瘤相关蛋白S100A4、14-3-3σ受LASP-1的调控。文献报道，S100A4和14-3-3σ与肿瘤细胞上皮-间质转化(EMT)过程相关，而EMT在肿瘤的侵袭转移中发挥重要作用。由此，我们提出LASP-1通过调控S100A4、14-3-3σ介导EMT发生，从而促进结直肠癌转移。本项目拟采用蛋白质组学研究技术、分子病理学技术及分子生物学方法，旨在获得LASP-1介导EMT从而促进结直肠癌转移的可靠证据，阐明LASP-1发挥生物学功能的分子机制，为确立LASP-1作为临床治疗的新靶点提供更为充分的科学依据。

申请者围绕结直肠癌转移的早期预警和发生机制进行系统研究：1、揭示了miR-1和miR-133a调控LASP1能抑制结直肠癌转移的发生，为结直肠癌转移药物筛选提供新的靶点；2、提出S100A4和S100A11在TGFβ/LASP1 /Smad2信号轴诱导上皮间质转化发生促进肿瘤转移的关键作用；3、揭示LASP1负向调控14-3-3σ表达，通过PI3K/AKT信号通路调节肿瘤转移的新机制；4、揭示microRNA-187和miR-490-3p多靶点抑制结直肠癌的转移的发生，为临床抗结直肠癌转移治疗的新策略。以通讯发表SCI论文12篇。获中国病理研究杰出青年奖和广东省自然科学杰出青年基金。以第二完成人获广东省科学技术一等奖、中华医学科技二等奖各1项。