家族性大腸腺腫症疾患モデルとしてのApc遺伝子ノックアウトマウス

抄録

Molecular genetic studies of familial adenomatous polyposis (FAP) kindreds led to the discovery of the APC (adenomatous polyposis coli) gene on human chromosome 5q21. Mutations in APC appear to be responsible for not only FAP but also many sporadic cancers of the colorectal axis, stomach, and esophagus. The APC protein contains regions that may form an α-helical coiled-coil structure, and a subdomain of the first 55 as form a stable, parallel helical dimer. Antibody studies showed that the wild-type, but not mutant, APC protein is associated with the microtubule cytoskeleton. The predicted structure of APC, its localization, and its interaction with β-catenin suggested its involvement in cell adhesion. In fact, recent studies demonstrated that APC is localized to plasma membrane sites involved in active cell migration. At the same time, β-catenin interacts with hTcf-4 and Lef transcription factors. hTcf-4 transactivates transcription only when associated with β-catenin. We recently constructed a gene knockout mouse strain in which the mouse homolog of the human APC was inactivated by homologous recombination. Using this mouse strain, we elucidated the mechanism how the polyp adenomas are formed in both morphological and genetic aspects. At the same time, we investigated the effects of carcinogens and anticancer agents on the polyposis. Accumulating evidence indicates that nonsteroidal antiinflammatory drugs (NSAIDs) reduce the incidence of colorectal cancers in human and experimental animals, and reduce the polyp number and size in FAP patients. Recently, evidence has been presented that COX-2 is induced in human colorectal cancers, and in the polyps of mouse FAP models. Accordingly, we inactivated the COX-2 gene in our FAP model mice, and demonstrated that both the number and size of polyps are reduced dramatically. In addition, a COX-2 selective inhibitor caused similar results to COX-2 gene knockout mutations. These genetic and pharmacological data open the possibility of effectively treating human FAP and various cancers with COX-2 selective inhibitors, a new class of NSAIDs.