基质硬度通过PGK1介导的糖酵解及Arp2/3依赖的肌动蛋白聚合调控结直肠癌侵袭和转移的分子机制

基质硬度在肿瘤侵袭转移中的调控研究受到越来越多的重视。前期工作中，我们发现硬纤维蛋白凝胶能促进结直肠癌细胞侵袭能力，根据基因芯片及预实验结果，我们提出机械传导信号Integrinβ1/FAK、PGK1介导的糖酵解及Arp2/3依赖的肌动蛋白聚合参与基质硬度对结直肠癌演进的调控过程。本研究拟从细胞、动物水平及组织标本上探讨（1）基质硬度调控Integrinβ1/FAK/AKT/GSK-3β通路，促进癌细胞β-catenin入核及c-Myc表达上调；（2）c-Myc转录调控癌细胞中PGK1介导的糖酵解过程；（3）基质硬度调控FAK与Arp2/3相互作用，增强Arp2/3依赖的肌动蛋白聚合能力；（4）基质硬度增加通过PGK1介导的糖酵解及Arp2/3依赖的肌动蛋白聚合促进结直肠癌侵袭和转移。旨在为肿瘤转移机制研究提供新的观点，从微环境机械力学角度为抗肿瘤转移提供有效的靶点及治疗策略。

More and more attention has been paid to the study on the regulation of matrix stiffness on tumor invasion and metastasis. In the previous study, we found that higher matrix stiffnes promoted the invasion of colorectal carcinoma (CRC) cells. Based on the analysis of gene chip and pre-experimental results, we put forward that the mechanical sensing signaling integrinβ1/FAK, glycolysis induced by PGK1 and Arp2/3 dependent actin polymerization might be involved in the regulation of matrix stiffness on tumor progression. This study will explore at the levels of cell lines, nude mice and tissue samples, (1) matrix stiffness regulates integrinβ1/FAK/AKT/GSK-3βsignaling to promote the nuclear translocation of β-catenin and up-regulation of c-Myc; (2) c-Myc transcriptionally regulates the glycolysis induced by PGK1 in CRC cells; (3) matrix stiffness regulates the interactions between FAK and Arp2/3 to enhance Arp2/3 dependent actin polymerization; (4) high matrix stiffness promotes CRC invasion and metastasis through glycolysis induced by PGK1 and Arp2/3 dependent actin polymerization. This study aims to provide new clues for illustrating the molecular mechanism of tumor metastasis, and provided novel targets and therapy strategy against tumor metastasis in terms of mechanics.