ICAM3通过Src/PI3K/AKT通路促进结直肠炎癌进展作用及机制的研究

Inflammation has proved to promote cancer transformation and maintain colon cancer cell stemness in colon. Therefore, identification of the mechanism and new targets for inflammatory cancer progression is an urgent need in colorectal cancer therapy. In our previous studies, we designed a novel high throughput siRNA interference platform to systemically screen genes that regulate cancer stemness, and discovered a novel candidate, ICAM3. ICAM3 was proved to regulate inflammation and cancer stemness, and promote cancer progression. However, the function of ICAM3 in inflammatory colorectal cancer progression was unknown. Here, we propose 1) to detect the expression of ICAM3 in colon tissues in different stages of inflammatory colorectal cancer, analyze the correlation with clinical pathology; 2) to investigate the function as well as the mechanism of ICAM3 in colorectal specific ICAM3 transgenic mice; 3) to explore the roles of inflammatory microenvironment in ICAM3-mediated cancer progression in various inflammatory mouse models. Our work will provide potential early target for colorectal cancer therapy.

结直肠中炎症的长期存在可以恶性转化为结直肠癌，并且可以维持结直肠癌干细胞干性，促进结直肠癌的进展。因此，发掘针对结直肠炎癌进展过程的早期靶点及揭示结直肠炎癌进展的机制是治疗结直肠炎相关的结直肠癌的关键。前期工作中，我们通过1027个炎性基因的siRNA文库筛选了调控肿瘤干细胞干性的炎性基因，并在乳腺癌和肺癌中证明候选基因ICAM3能够介导肿瘤细胞炎性与干性通路，促进肿瘤进展，但ICAM3能否促进结直肠炎癌进展尚不清楚。为此，本课题将首先探究ICAM3在结直肠炎癌进展不同阶段临床病例组织中的表达变化；然后利用结直肠特异性表达的ICAM3转基因小鼠，动态分析ICAM3对结直肠炎癌进展过程的作用，并阐明其分子机制；最后在不同的小鼠炎症模型中探讨慢性和急性炎性微环境对ICAM3介导的肿瘤发生和发展的影响。旨在为结直肠炎相关的结直肠癌的治疗提供新的早期治疗靶点。

结直肠中炎症的长期存在可以恶性转化为结直肠癌，并且可以维持结直肠癌干细胞干性，促进结直肠癌的进展。因此，发掘针对结直肠炎癌进展过程的早期靶点及揭示结直肠炎癌进展的机制是治疗结直肠炎相关的结直肠癌的关键。前期工作中我们证明ICAM3能够介导肿瘤细胞炎性与干性通路，促进肿瘤进展，但其能否促进结直肠炎癌进展尚不清楚。本项目研究发现，相对于正常结肠组织，ICAM3高表达于结肠癌组织中，并且ICAM3表达与结肠癌分期及分级呈现明显的正相关关系；然后通过结肠特异性表达ICAM3的转基因小鼠证明，ICAM3并不能介导结肠自发肿瘤的发生，但能够增强DSS诱导的肠道炎症反应，促进AOM+DSS诱导的结肠炎癌转化与进展；进一步，在体外细胞中发现ICAM3可能通过影响影响GSK3β的磷酸化，进而影响Wnt/β-catenin信号通路介导结肠炎癌转化与进展；最后在小鼠体内发现LPS诱导的急性炎性微环境能够促进ICAM3介导的结肠癌的发生。本研究对于深入理解ICAM3对结直肠炎癌进展的影响具有重要意义，为结直肠癌的预防、检测及治疗提供新的早期靶点及思路。