PTEN/FAK/CCL5通路调控的Tregs募集在结肠癌肝转移中的作用和机制研究

Liver metastasis correlates with poor prognosis of colon cancer. Previous studies demonstrated that CD4+CD25+FOXP3+ T-regulatory cells (Tregs) is a crucial factor in tumor microenvironment, facilitating the immune escape of cancer cell. Recent studies indicated that focal adhesion kinase (FAK) in nucleus of cancer cells increased the expression and secretion of chemokine (C-C motif) ligand 5(CCL5), and then recruited Tregs in tumor microenvironment, finally promoted cancer cell survive. Our data demonstrated that deletion of PTEN expression could induce the expression of FAK and then enhanced the ability of cancer cell metastasis. Herein, we hypothesize that PTEN deletion induced high expression of FAK in colon cancer cells may promote the CCL5 secretion after colon cancer cell traveling to the mesenchyme of liver; and then recruit Tregs in the tumor microenvironment to help colon cancer cells colonize in liver. The present research will utilize molecular biological techniques, animal models, and human samples to validate the above hypothesis. Our work may be helpful to clarify the potential mechanism of liver metastasis of colon cancer.

肝转移是结肠癌预后不良的重要原因。CD4+CD25+FOXP3+阳性的调节性T细胞（T-regulatory cells, Tregs）被认为是肿瘤微环境中帮助肿瘤细胞发生免疫逃逸的关键因素。最新研究显示，细胞核内的焦点粘附激酶FAK可以促进肿瘤细胞趋化因子chemokine (C-C motif) ligand 5(CCL5)的表达，并使其分泌至肿瘤微环境中以募集Tregs，从而促进肿瘤的存活。我们的前期研究发现，PTEN 表达的缺失可以促进FAK表达并促进肿瘤细胞转移。据此我们推测，结肠癌细胞进入肝脏间质中后，PTEN缺失介导的FAK高表达会造成CCL5大量分泌至转移灶的肿瘤微环境中以募集Tregs，从而帮助结肠癌细胞实现免疫逃逸，定植于肝脏。本研究将应用分子生物学技术和动物模型，结合临床样本的检测，验证上述假说，帮助阐明结肠癌肝转移的发病机制，为寻求该疾病的新治疗方案提供理论基础。

已知肝转移是结肠癌预后不良的重要原因。在本研究中我们建立了PTEN 过表达和敲低细胞株，构建了结肠癌肝转移动物模型，通过一系列分子生物学技术发现：在人CRC组织中，PTEN表达下降，FAK, Paxillin, CCL5表达上调。在结肠癌细胞中，PTEN可抑制FAK和Paxillin的表达；FAK和Paxillin可逆转PTEN介导的对结肠癌细胞侵袭、迁徙的抑制；PTEN的下调可通过FAK/Sp1,Paxillin/Sp1信号通路提高CCL5的表达。在裸鼠模型中，PTEN抑制了结肠肿瘤生长及转移。本研究通过以上实验，表明PTEN作为抑癌基因，在结肠癌中表达降低后，通过FAK/Sp1,Paxillin/Sp1信号通路提高CCL5的表达，促进了结肠癌肝转移。该研究为结肠癌肝转移的发病机制提供了理论依据，结果有望通过以该路径作为治疗靶点，早期干预，为结肠癌肝转移提供新的策略。