碘[131I]美妥昔单抗对肝癌化疗栓塞后残留癌细胞上皮-间质转化的影响及其分子机制

Transcatheter arterial chemoembolization (TACE) is an important treatment choice of hepatocellular carcinoma (HCC). However, the extrahepatic metastasis rate of HCC was found to increase after treating with TACE as the result of epithelial-mesenchymal transition (EMT) of the residual HCC cells, which performed increased potential for invasion and distant metastasis after treating with chemotherapy or hypoxia. Radioimmunopharmaceutical agent 131I-metuximab was found to inhibit distant metastasis of HCC after treating with TACE. The target site HAb18G/CD147 recognized by metuximab was demonstrated to promote EMT during hepatocarcinogenesis. Moreover, metuximab was found to inhibit EMT of HCC cells induced by chemotherapy or anoxia. To investigate the role of CD147 in the invasion and metastasis of HCC after TACE and whether invasion and metastasis potential of residual HCC cells after TACE would be inversed by 131I-metuximab through down-regulating EMT, cell model and animal model and clinical samples would be used to explore the efficiency of 131I-metuximab in inhibiting the invasion and metastasis potential of HCC cells and to provide theoretical basis for 131I-metuximab in inhibiting HCC metastasis after TACE.

经导管动脉化疗栓塞术（TACE）是治疗肝癌的重要方法，但由于肝癌细胞经化疗或经缺氧处理后残癌细胞发生上皮-间质转化（EMT），其侵袭性和转移潜能升高，导致患者发生远处转移增多。研究发现，放射免疫药物"碘[131I]美妥昔单抗"可有效抑制肝癌TACE后的远处转移，HAb18G/ CD147介导了肝细胞恶变过程中EMT的发生，而美妥昔单抗能抑制化疗或缺氧诱导的肝癌细胞EMT。那么，"碘[131I]美妥昔单抗"是否可能通过下调EMT来逆转肝癌TACE后残癌细胞的侵袭性和远处转移呢？因此，本课题拟在前期研究基础上，应用细胞、动物模型和临床样本继续探索CD147在TACE对肝癌细胞侵袭性和转移潜能的影响中的作用及具体机制，并探讨使用"碘[131I]美妥昔单抗"靶向HAb18G/ CD147抑制肝癌细胞侵袭性和转移潜能的有效性，以期为"碘[131I]美妥昔单抗"对肝癌转移性抑制作用提供理论依据。

CD147在肝癌（HCC）细胞高表达并且与肝癌侵袭和转移有关。以CD147为靶点研制的抗肝癌新药I131-metuximab（I131-mab），在HCC局部放射免疫治疗中的疗效得到临床确认。但I131-mab偶联分子的不同成分所发挥的协同抗癌活性及其分子机制，还有很多未明之处。本项研究中，细胞学实验证实，I131-mab能够抑制HCC细胞的增殖活性和侵袭能力，其抑制作用主要来源于偶联分子中的抗体成分，其作用的机制是通过抑制VEGFR-2的磷酸化而逆转HCC细胞EMT过程。单独I131对HCC细胞增殖侵袭的抑制作用有限，但联合治疗时I131能显著增强癌细胞对CD147mab的敏感性，增强抗体杀伤癌细胞的效果，提示I131-mab中两个成分的抗肝癌功能具有协同增强作用。肝癌细胞SMMC-7721裸鼠移植瘤实验同样证明，I131-mab和CD147mab对SMMC-7721移植瘤都有明显的抑制作用，I131-mab的疗效明显强于CD147mab。研究结果阐明了I131-mab抗HCC增殖转移作用的机制，为指导临床I131-mab的应用奠定了理论基础。