CXCR4/SDF-1通路调控E-cadherin/β-catenin复合物诱导结肠癌侵袭转移机制研究

CXCR4/SDF-1 pathway and E-cadherin/β-catenin complex are implicated in the metastatic process of colorectal cancer (CRC).In our previous study,we found that down-regulation of E-cadherin/β-catenin complex in HT29 colon cells was aroused by activation of CXCR4/SDF-1 pathway via the phosphorylation of PI3K/AKT.In addition,down-regulation of miRNA-21 and up-regulation of Spry2 are involved in the process.A new hypothesis was put forward based on previous studies.We hypothesized that activation of CXCR4/SDF-1 pathway induces the phosphorylation of PI3K/AKT and the decomposition of E-cadherin/β-catenin complex.β-catenin induces the expression of miRNA-21 via STAT3.miRNA-21 amplifies the phosphorylation of PI3K/AKT via down-regulating novel target Spry2,which creates a positive feedback loop by amplifying the phosphorylation of PI3K/AKT.We will explore the role of miRNA-21 in the process that CXCR4/SDF-1 pathway regulates E-cadherin/β-catenin complex in vitro and in vivo.This study will provide experimental proof to elucidate the mechanisms in colon cancer invasion and metastasis and may provide new potential clinical targets for anti-metastasis therapy.

CXCR4/SDF-1通路和E-cadherin/β-catenin复合物均与结直肠癌侵袭转移相关。我们研究发现CXCR4/SDF-1通路能激活PI3K/AKT下调结肠癌细胞E-cadherin/β-catenin表达，并观察到miRNA-21上调和Spry2下调，在此基础上提出了研究假说：CXCR4/SDF-1通路激活PI3K/AKT，细胞膜E-cadherin/β-catenin结构破坏，进入细胞浆的β-catenin与STAT3协同作用上调miRNA-21，miRNA-21下调靶基因Spry2，使PI3K/AKT激活效应放大，形成调控PI3K/AKT的正反馈环路。我们拟通过体外和体内实验揭示miRNA-21参与CXCR4/SDF-1通路调控E-cadherin/β-catenin表达诱导结肠癌侵袭转移机制，本研究将为阐明结肠癌侵袭转移理论提供实验证据，而且为抗结肠转移治疗提供新靶点。