在EndMPTC细胞间质转化中CaMKII的作用及其对结肠癌细胞侵袭、转移的影响

Endothelial-to-mesenchymal transition (EndMT)is recognized as a crucial source of cancer-associated fibroblast (CAF) which modulate cancer progression and are involved in other pathological processes, especially in fibrosis. Our previous work on endothelial-mesenchymal potential transitional cell (EndMPTC) from the mesentery revealed that EndMPTC belonged to a peculiar phenotype between endothelial cell and mesenchymal cell. In vitro, transforming growth factor β1(TGFβ1) induced EndMPTC undergoing mesenchymal transition. Currently, utilizing molecular and cellular biological techniques, we attempt to investigate the role and mechanism of Ca2+/calmodulin dependent protein kinase II (CaMKII) in TGFβ 1-induced EndMPTC mesenchymal transition. The effect of colon cancer cells on EndMPTC mesenchymal transition and CaMKII-dependent mechanism of EndMPTC on colon cancer cell invasion and metastasis are also planned to investigate. Our research will provide a novel and convincing evidence for EndMT which might also contribute to normal physiological and development processes. The mesenchymal transition of EndMPTC induced by colon cancer cells will strongly support the presumption that EndMPTC is a novel source of CAF and plays an important role in colon cancer cell invasion and metastasis. We believe that our present research project will disclose a new target for colon cancer therapeutic strategy and must be a crucial and attractive work in cancer research.

内皮细胞间质转化(EndMT)是癌相关成纤维细胞(CAF)的重要来源，在肿瘤及纤维化等病理过程中发挥着极其重要的作用。本项目组前期研究表明，肠系膜内皮-间质潜在分化细胞(EndMPTC)是一种间于内皮和间质、具有潜在分化能力的特殊细胞；在体外，转化生长因子β1(TGFβ1)可诱导EndMPTC间质转化。本项目拟在前期工作的基础上，应用分子生物学和细胞生物学技术，研究Ca2+/钙调蛋白依赖性蛋白激酶II（CaMKII）在TGFβ1诱导EndMPTC间质转化中的作用与机制，并探讨结肠癌细胞在EndMPTC间质转化中的作用及EndMPTC对结肠癌细胞侵袭、转移的影响，旨在为EndMT机制提供新的理论依据，为其参与正常生理发育过程提供有力证据；通过验证EndMPTC作为潜能细胞参与CAF形成的设想，揭示EndMPTC在结肠癌细胞侵袭、转移中的重要作用，从而为结肠癌转移防治提供新的靶点和理论支撑。

内皮细胞间质转化(EndMT)是癌相关成纤维细胞(CAF)的重要来源细胞，在肿瘤及纤维化等病理过程中发挥着极其重要的作用。本项目组前期研究表明，肠系膜内皮-间质潜在分化细胞(EndMPTC)是一种间于内皮和间质，具有潜在分化能力的特殊细胞，在体外，TGFβ1可诱导其发生间质转化。. 本项目旨在研究CaMKII在TGFβ1诱导EndMPTC间质转化中的作用与机制，探讨结肠癌细胞对EndMPTC间质转化的作用及EndMPTC对结肠癌细胞生物学行为的影响，并揭示EndMPTC在结肠癌细胞浸润、转移中的重要作用。. 本项目组取得的重要结果如下：.[1] 在EndMPTC细胞，CaMKII 作为TGF-β1的重要靶分子，在其间质转化中发挥了极其重要的作用。.[2] ERK1/2、p38、Smad3和AKT是CaMKII调控EndMPTC细胞的重要下游因子。明确了CaMKII在TGF-β1诱导EndMPTC间质转化中的关键性作用及分子调控机制，为EndMT机制提供新的理论依据。.[3] 与CT26细胞共培养后，EndMPTC细胞的迁移能力、αSMA、desmin的表达明显增强，CD31的表达明显减弱。明确了结肠癌细胞可促进EndMPTC细胞向间质的转化，因此EndMPTC作为潜能细胞参与了CAF形成。.[4] EndMPTC细胞可促使的CT26细胞细胞增殖、其迁移、侵袭能力明显增强，MMP-2、MMP-9的表达明显增加，TIMP-1表达明显降低，而CaMKII是其重要的调控因子。从而揭示了EndMPTC在促进结肠癌细胞浸润、转移的作用，为结肠癌转移防治提供新的靶点和理论依据。