CD147通过cathepsin B调控ECM重塑和肝癌细胞运动侵袭的分子机制研究

Tissue invasion and metastasis are significant characteristics of hepatocellular carcinoma progression. The invasive potential of hepatocellular carcinoma cells is closely related with extracellular matrix (ECM) remodeling. In the process of invasion and metastasis, CD147 plays an important role, which induces secretion of a variety of matrix metalloproteinases (MMPs) to degrade the ECM. In our previous work, we found that CD147 can still promote hepatocellular carcinoma cells invasion after treatment with MMPs inhibitor, however, the molecular mechanism remains unclear. A significant decrease of cathepsin B was observed in CD147 knockout cells by profiling of proteases. And the motility of hepatocellular carcinoma cells decreased after siRNA-mediated silencing of cathepsin B. In this study, the regulatory role of CD147 on cathepsin B will be determined and the molecular mechanism underlying cathepsin B-mediated ECM remodeling and cell motility regulated by CD147 will be explored using the three-dimension (3D) model for in vitro invasion. In addition, the correlation of CD147 and cathepsin B expression with clinical stage and postoperative metastasis will be analyzed. The present study will provide valuable clues for prognostic evaluation and the development of novel targeted therapies against CD147 for hepatocellular carcinoma.

侵袭和转移是肝癌进展的重要特征。肝癌细胞的侵袭潜能与细胞外基质（ECM）的重塑密切相关。CD147在肝癌侵袭转移过程中发挥重要作用，能够诱导分泌多种基质金属蛋白酶（MMPs）降解ECM。我们的前期工作发现，加入MMPs抑制剂后CD147仍能够促进肝癌侵袭，但其分子机制仍不清楚。通过分析CD147敲除的肝癌细胞及其亲本细胞的蛋白酶谱，我们发现敲除CD147后，cathepsin B显著下调。并且干扰cathepsin B表达后，肝癌细胞的运动能力降低。本项目拟在此基础上，通过3D体外侵袭模型，明确CD147对cathepsin B的调控作用，阐明CD147通过cathepsin B介导ECM重塑和细胞运动进而促进肝癌侵袭的分子机制。此外，还将分析CD147和cathepsin B的表达与肝癌临床分期和术后转移的相关性，以期为基于CD147的肝癌预后评估和靶向治疗提供新的线索。

肝癌发病率高，中位生存期短，发病机制未完全阐明。肝癌转移是肝癌复发、致死的重要原因，目前常规治疗尚不能有效控制肝癌转移，因此进一步探讨其发病机制，开发新靶点药物是肝癌治疗研究的焦点和发展趋势。组织的侵袭和转移是肝细胞癌（HCC）进展的重要特征。HCC细胞的侵袭潜力与细胞外基质（ECM）重塑密切相关。在侵袭和转移过程中，肿瘤相关抗原CD147起着重要的作用，它能够诱导多种基质金属蛋白酶（MMPs）的分泌以降解ECM。先前的研究发现，用MMPs抑制剂处理细胞后，CD147仍能促进HCC细胞侵袭，表明CD147可以促进其他蛋白酶对ECM的重塑。通过蛋白酶的基因表达微阵列分析发现，组织蛋白酶B（cathepsin B）在CD147基因敲除细胞中显着减少。在这项研究中，将确定CD147对cathepsin B的调节作用，并使用三维（3D）模型体外侵袭来探索cathepsin B介导的ECM重塑和CD147调节的细胞运动的分子机制。此外，将分析CD147和cathepsin B表达与临床分期和术后转移的相关性。本研究将为肝细胞癌的CD147抗CD147靶向治疗和新型靶向治疗提供有价值的线索。