结直肠癌侵袭转移的机制不明。我们在前一个国家自然科学基金项目的资助下，发现ZNF148可以双向调控结直肠癌的侵袭转移。ZNF148具有两个剪切异构体，即ZNF148全长（FL）和ZNF148剪切体（△N），后者比前者少一个p300结合域，可以拮抗前者的功能。下调ZNF148（FL）或上调ZNF148（△N），Wnt通路均被显著抑制。所以我们提出假设，ZNF148（FL）可能通过结合p300调控Wnt通路，促进结直肠癌的侵袭转移；ZNF148（△N）则可抑制这一通路。为了验证这一假说，本项目将通过人体组织、细胞、皮下移植瘤和肝转移瘤模型，采用组织芯片、免疫组化、RT-PCR、慢病毒转染、荧光素酶实验、Chip实验、GST-pull down实验，从分子、细胞、组织和动物整体水平深入研究调控的分子机制。本研究将从ZNF148的可变剪切这个新视点为揭示结直肠癌的侵袭转移机制奠定基础。

The mechanism of tumor invasion and metastasis in colorectal cancer is unknown. With the financial support from a previous National Natural Science Fund project, we find that ZNF148 is a key molecule regulating the invasion and metastasis of colorectal cancer, and exhibits bidirectional regulation effect. ZNF148 has two splice isoforms, ZNF148 full length (FL) and ZNF148 splicing isomer (△N). ZNF148(FL) has a p300 binding domain, but there is no one for ZNF148(△N). ZNF148(△N) can antagonize the function of ZNF148(FL). Down-regulation of ZNF148 (FL) and up-regulation of ZNF148 (△N) result in the inhibition of Wnt pathway. So, we hypothesize that ZNF148 (FL) may promote the invasion and metastasis of colorectal cancer through enhancing the Wnt pathway after combination with p300. Contrarily, ZNF148 (△N) can inhibit this pathway. We plan to validate this hypothesis in molecule, cell, human tissue and whole animal levels, using human colorectal cancer tissue, cell lines, subcutaneously transplanted tumor model and animal model of liver metastasis tumor. We aim to explore the molecular regulation mechanism, using tissue microarray, immunohistochemistry, RT-PCR, lentivirus transfection, luciferase test, Chip test and GST-pull down test. This study may lay a foundation for revealing the mechanism of invasion and metastasis of colorectal cancer from the new viewpoint of ZNF148 alternative spicing.