Involvement of a cell adhesion molecule, TSLC1/IGSF4, in human oncogenesis.
The occurrence of aberrations in cell adhesion is a critical phase in the invasion and metastasis of human cancer. A tumor suppressor gene, TSLC1/IGSF4, from chromosomal region 11q23 was identified in non-small cell lung cancer (NSCLC) by its tumor suppressor activity in nude mice. TSLC1/IGSF4 is expressed in most tissues except for peripheral blood lymphocytes, but it is inactivated in 44% of NSCLC and 30-60% of various cancers, including liver, pancreatic, and prostate cancers, especially in those with invasion or metastasis. Inactivation occurs by two hits: through promoter methylation, and through loss of heterozygosity at the gene locus. TSLC1/IGSF4 encodes an immunoglobulin superfamily cell adhesion molecule and associates with an actin-binding protein, DAL-1/4.1B, and members of the membrane-associated guanylate kinase homologue (MAGuK) group, providing a novel tumor suppressor cascade that is inactivated in more than 80% of NSCLC. TSLC1/IGSF4 appears to be involved in the formation of an epithelial cell structure with DAL-1/4.1B and MAGuK. Furthermore, TSLC1/IGSF4 may act as a tumor antigen recognized by activated NK or CD8+ T cells. These two distinct mechanisms based on homophilic and heterophilic interactions would be responsible for tumor suppression by TSLC1/IGSF4. TSLC1/IGSF4 is ectopically expressed in adult T-cell leukemia (ATL) cells, providing not only a diagnostic marker for ATL, but also a possible therapeutic target against its invasion. The distinct roles of TSLC1/IGSF4 in the oncogenesis of carcinomas and ATL could be due to tissue-specific differences in the downstream cascades, and is a novel concept with respect to cell adhesion in human oncogenesis.
Murakami
Yoshinori
Y
Tumor Suppression and Functional Genomics Project, National Cancer Center Research Institute, 5-1-1, Tsukiji, Tokyo 104-0045, Japan. ymurakam@gan2.ncc.go.jp
D000818:Animals; D000951:Antigens, Neoplasm; D002448:Cell Adhesion; D000075982:Cell Adhesion Molecule-1; D015815:Cell Adhesion Molecules; D002471:Cell Transformation, Neoplastic; D019175:DNA Methylation; D005786:Gene Expression Regulation; D006801:Humans; D007136:Immunoglobulins / Q000235:genetics* / Q000502:physiology*; D019656:Loss of Heterozygosity; D008565:Membrane Proteins / Q000235:genetics* / Q000502:physiology*; D009369:Neoplasms / Q000235:genetics* / Q000503:physiopathology*; D011401:Promoter Regions, Genetic; D051381:Rats; D025521:Tumor Suppressor Proteins
D000951:Antigens, Neoplasm; C403514:CADM1 protein, human; D000075982:Cell Adhesion Molecule-1; D015815:Cell Adhesion Molecules; D007136:Immunoglobulins; D008565:Membrane Proteins; D025521:Tumor Suppressor Proteins