JWA调节HSP27磷酸化抑制肝癌细胞迁移的研究

Abnormal p38MAPK-MK2-HSP27 pathway plays an important role in HCC cell migration. Our previous study found that high expression of JWA in human HCC cells significantly decreased expression and phosphorylation levels of HSP27, which caused HSP27 inactivation. However, the molecular mechanisms that JWA regulated HSP27 phosphorylated have not been elucidated. We found that JWA inhibited p38MAPK phosphorylation. Besides, we was also found that downregulated JWA promoted HCC cell migration. Accordingly, we supposed that: downregulated of JWA in HCC increased p38MAPK phosphorylation levels and activated p38MAPK-MK2-HSP27 pathway, causing HCC cell migration. This project intends to study the interactions and molecular mechanisms of JWA regulation of HSP27 from cell, animal and clinical levels to clarify that JWA inhibited migration capabilities through regulating p38MAPK-MK2 signaling pathway by inhibiting HSP27 phosphorylation of HCC. This study will reveal a new mechanism that JWA inhibits HCC migration through regulating p38MAPK-MK2-HSP27 signaling pathway to inhibit HCC metastasis, providing new targets for drug research and clinical treatment of HCC.

p38MAPK-MK2-HSP27通路异常在肝癌迁移中起着重要作用，前期工作发现人工高表达JWA肝癌细胞中HSP27表达和磷酸化水平显著下降，使HSP27处于失活状态，而目前JWA调节HSP27磷酸化的分子机制尚未阐明。申请人还发现JWA可抑制p38MAPK磷酸化，同时发现下调肝癌细胞中JWA促进细胞迁移。据此我们认为：在肝癌中异常下调JWA使p38MAPK磷酸化水平增高，引起p38MAPK-MK2-HSP27通路异常活化，引起细胞的迁移。本课题拟进一步研究JWA调控HSP27在肝癌转移中的作用及分子机制；并从细胞、动物和临床水平阐明JWA调控p38MAPK-MK2信号通路抑制肝癌中HSP27磷酸化，进而抑制肝癌细胞的迁移能力。本研究拟明确JWA调控p38MAPK-MK2-HSP27信号通路抑制肝癌迁移的作用和分子机制，揭示JWA抑制肝癌转移的新机制，为肝癌的药物研发和临床治疗提供新靶点。

p38MAPK-MK2-HSP27通路异常在肝癌迁移中起着重要作用，高表达JWA肝癌细胞中HSP27表达和磷酸化水平显著下降，使HSP27处于失活状态， JWA可抑制p38MAPK磷酸化，同时发现下调肝癌细胞中JWA促进细胞迁移。研究表明在肝癌中异常下调JWA使p38MAPK磷酸化水平增高，引起p38MAPK-MK2-HSP27通路异常活化，引起细胞的迁移。本课题研究JWA调控HSP27在肝癌转移中的作用及分子机制；并从细胞、动物和临床水平阐明JWA调控p38MAPK-MK2信号通路抑制肝癌中HSP27磷酸化，进而抑制肝癌细胞的迁移能力。本研究明确JWA调控p38MAPK-MK2-HSP27信号通路抑制肝癌迁移的作用和分子机制，揭示JWA抑制肝癌转移的新机制，为肝癌的药物研发和临床治疗提供新靶点。