MED12/Arp2调控血管生成拟态的作用和机制及其在NSCLC放疗抵抗中的意义

放疗抵抗是局部晚期非小细胞肺癌（non-small cell lung cancer，NSCLC）治疗面临的巨大难题。血管生成拟态(Vasculogenic mimicry，VM)可介导NSCLC放疗抵抗，但其形成的调控机制不明。我们预实验发现，MED12低表达的NSCLC患者放疗抵抗；抑制MED12表达可增强NSCLC细胞VM形成能力，促进细胞放射抵抗。进一步研究显示，抑制MED12表达可上调Arp2转录，细胞中F-actin聚合及膜定位增多，细胞骨架发生重塑。本课题拟通过解决“MED12如何调控NSCLC的VM形成”这一关键科学问题，来验证我们的科学假说，即“抑制MED12表达可激活NSCLC中Arp2转录，使F-actin聚合及膜定位增多，细胞骨架发生重塑，进而增强NSCLC的VM形成，促进放疗抵抗”，阐明NSCLC中VM形成的新机制，为克服NSCLC放疗抵抗提供新靶标。

Radiation resistance is a significant challenge to the therapy of advanced non-small cell lung cancer（NSCLC）. Vasculogenic mimicry (VM) can mediate the radioresistance of NSCLC, but the regulation mechanism of its formation is unknown. In previous study, we found that MED12 was low expression in NSCLC patients with radioresistance. In addition, inhibits MED12 expression could enhance VM formation of NSCLC cells, which in turn promoted cell radiation resistance. More importantly, down-regulation of MED12 expression could enhance Arp2 transcription, increase F-actin polymerization and membrane localization, and then the cell cytoskeleton was remodeling. We thus raise the question that how MED12 regulates VM formation of NSCLC. We propose that inhibits MED12 expression can enhance Arp2 transcription, which subsequently increase F-actin polymerization and membrane localization, and then the cell cytoskeleton was remodeling, thereby enhancing VM formation and promoting radioresistance of NSCLC. This study intends to clarify the new mechanism of VM formation of NSCLC and to seek new treatment options to overcome NSCLC radioresistance and improve prognosis.