PKHD1基因突变所致非可控性炎症与结直肠癌发病机制的研究

It is one of focuses on the tumorigenesis relationship with noncontrollable inflammatory.We newly established the PKHD1 gene knock-out mouse model and found that non-controllable inflammatory phenotrpe appeared in the gastrointestinal pipeline.Interestingly, recent genome scan reports showed that PKHD1 is highly associated with colorectal cancer which implying that the uncontrolled inflammation caused by PKHD1 deletion may be related to the development of colorectal cancer.The PKHD1 gene knock-out mouse model combining with the colorectal tumor mouse model was established for this project.The relationship between uncontrolled inflammation caused by mutations in PKHD1 and colorectal cancer will be revealed, also the roles and molecular mechanisms of PKHD1 gene in carcinogenesis of colorectal tumor, that will provide new targets for the early diagnosis and treatment of colorectal cancer.

肿瘤的发生与非可控性炎症的关系是当今研究的热点之一。我们新近建立了PKHD1基因敲除小鼠模型，发现在建模小鼠的胃肠组织呈现非可控性炎症病理改变。基因组扫描发现，PKHD1异常与结直肠癌的发生发展密切相关，提示PKHD1基因异常所致的非可控性炎症可能参与结直肠癌的发生发展。本项目拟采用已建立的PKHD1基因敲除小鼠模型，探明PKHD1基因突变与非可控性炎症及结直肠癌之间的关系，揭示PKHD1基因在结直肠癌发生发展中的作用与分子机制，将为结直肠癌的早期诊断及治疗寻找新靶点。

目前关于人类常染色体隐性遗传性多囊肾病致病基因PKHD1突变与非可控性炎症及结直肠癌之间的关系仍不清楚。本项目施用制备的PKHD1单克隆和多克隆抗体，检测PKHD1蛋白在结直肠癌组织中的表达与定位；应用shRNA干扰技术，建立PKHD1稳定干涉的结直肠癌细胞株，从体内水平上，观察其对肿瘤细胞增殖的作用；利用实验动物模型分析PKHD1缺失在ApcMin/+小鼠肠道肿瘤发生发展中的作用，从而揭示PKHD1在人类结直肠癌发生发展中的作用。结果显示，PKHD1蛋白定位于结直肠粘膜上皮细胞的胞浆，在结直肠癌组织中表达弱；PKHD1基因低表达后，可明显促进CT26细胞裸鼠移植瘤生长；PKHD1基因缺失可导致ApcMin/+小鼠肠道肿瘤总数及大小均显著增加，并具有促进其肿瘤恶性转化的趋势; PKHD1基因参与结肠癌发生的可能机制与促进ApcMin/+小鼠肠道肿瘤细胞增殖，抑制肿瘤细胞凋亡，激活肿瘤细胞Wnt信号通路有关。本项目深化了对PKHD1基因功能的认识，确定了PKHD1与肿瘤的关系，深入揭示了PKHD1所致非可控性炎症在结直肠癌的发生过程中所发挥的作用，为阐明结直肠癌发病机制提供新的理论依据。