MACC1调控PI3K/Akt及MAPK信号通路促进结直肠癌发生发展的分子机制

Metastasis-associated in colon cancer 1 (MACC1) is a newly identified key gene, which is closely associated with metastasis of colorectal carcinoma (CRC). In our previous study, we found that MACC1 was up-regulated in CRC compared with matched normal colorectal cell and tissues. Gene microarray data showed that PI3K/Akt signaling pathway and MAPK signaling pathway may be the important regulating target genes of MACC1. Furthermore, we observed MACC1 knockdown downregulated the protein expression of Phospho-PI3K, Phospho-Akt and Phospho-JNK compared with control group by Western blot analysis. The interaction between MACC1 and PI3K/Akt signaling pathway or MAPK signaling pathway in CRC has not been reported in the literature. Therefore, we make a hypothesis that MACC1 regulating PI3K/Akt signaling pathway or MAPK signaling pathway might be crucial in carcinogenesis and progression of CRC. In this project, we first verify whether MACC1 regulating PI3K/Akt and MAPK signaling pathway in carcinogenesis and progression of colorectal carcinoma by the study on CRC cell lines, tissues and in vivo. Second, we explore the molecular mechanisms of MACC1 regulating PI3K/Akt or MAPK signaling pathway in promoting carcinogenesis and progression of CRC by Dual Luciferase reporter, Co-IP and ChIP methods. Our object is to provide new and valuable experiment evidence for exploring the mechanism of carcinogenesis and progression of CRC and to find a novel target gene for CRC treatment.

MACC1是新近发现与结直肠癌转移密切相关的重要基因。申请者前期研究发现结直肠癌中MACC1高表达；且对结肠癌细胞基因表达谱芯片分析，提示MACC1所调控的下游基因网络中，PI3K/Akt和MAPK信号通路可能是其重要的调控靶基因；进而申请者下调结直肠癌细胞MACC1表达，发现磷酸化的PI3K、Akt和JNK蛋白表达水平明显下调。目前，结直肠癌中MACC1是否通过调控PI3K/Akt和MAPK信号通路促进结直肠癌的发生发展尚未见报道。本课题拟通过结直肠癌细胞、组织和体内实验研究MACC1是否通过调控PI3K/Akt及MAPK信号通路促进结直肠癌的发生发展，并应用双荧光素酶报告基因系统、Co-IP和ChIP等技术研究MACC1调控PI3K/Akt和MAPK信号通路的分子机制，为MACC1调控结直肠癌中PI3K/Akt和MAPK信号通路及对结直肠癌发生发展分子机制的阐明提供理论和实验依据。

申请者前期研究发现结直肠癌中MACC1高表达，对结肠癌细胞基因表达谱芯片分析，提示MACC1所调控的下游基因网络中，PI3K/Akt和MAPK信号通路可能是其重要的调控靶基因；进而申请者发现沉默结直肠癌细胞MACC1表达后，磷酸化的PI3K、Akt和JNK蛋白表达水平明显下调。目前，结直肠癌中MACC1是否通过调控PI3K/Akt或MAPK信号通路促进结直肠癌的发生发展少见报道。本课题通过结直肠癌细胞、组织和体内实验研究并验证MACC1通过调控Akt信号通路促进结直肠癌的发生发展，进一步探索相关的分子机制，为MACC1调控结直肠癌中Akt信号通路及对结直肠癌发生发展分子机制的阐明提供理论和实验依据。