title: Aberrations of a cell adhesion molecule CADM4 in renal clear cell carcinoma.
abstract: Renal clear cell carcinoma (RCCC) is the most frequent subpopulation of renal cell carcinoma and is derived from the proximal uriniferous tubules. We have previously reported that an actin-binding protein, 4.1B/DAL-1, is expressed in renal proximal tubules, whereas it is inactivated in 45% of RCCC by promoter methylation. In the lung and several epithelial tissues, 4.1B is shown to associate with a tumor suppressor protein, CADM1, belonging to the immunoglobulin-superfamily cell adhesion molecules. Here, we demonstrate by immunohistochemistry that another member of the CADM-family protein, CADM4, as well as 4.1B is expressed specifically in human proximal tubules, while CADM1 and 4.1N, another member of the 4.1 proteins, are expressed in the distal tubules. Immunoprecipitation analysis coupled with Western blotting revealed that CADM4 associated with 4.1B, while CADM1 associated with 4.1N in the lysate from normal human kidney, implicating that a cascade of CADM4 and 4.1B plays an important role in normal cell adhesion of the proximal tubules. On the other hand, CADM4 expression was lost or markedly reduced in 7 of 10 (70%) RCC cell lines and 28 of 40 (70%) surgically resected RCCC, including 10 of 16 (63%) tumors with T1a. CADM4 expression was more preferentially lost in RCCC with vascular infiltration (p = 0.04), suggesting that loss of CADM4 is involved in tumor invasion. Finally, introduction of CADM4 into an RCC cell line, 786-O, dramatically suppressed tumor formation in nude mice. These findings suggest that CADM4 is a novel tumor suppressor candidate in RCCC acting with its binding partner 4.1B.
authors.affiliation: Division of Molecular Pathology, Institute of Medical Science, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Nagata
authors.forename: Mika
authors.initials: M
authors.lastname: Sakurai-Yageta
authors.forename: Daisuke
authors.initials: D
authors.lastname: Yamada
authors.forename: Akiteru
authors.initials: A
authors.lastname: Goto
authors.forename: Akihiko
authors.initials: A
authors.lastname: Ito
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Fukuhara
authors.forename: Haruki
authors.initials: H
authors.lastname: Kume
authors.forename: Teppei
authors.initials: T
authors.lastname: Morikawa
authors.forename: Masashi
authors.initials: M
authors.lastname: Fukayama
authors.forename: Yukio
authors.initials: Y
authors.lastname: Homma
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Murakami
mesh_terms: D000818:Animals; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002448:Cell Adhesion / Q000235:genetics; D000075982:Cell Adhesion Molecule-1; D015815:Cell Adhesion Molecules / Q000096:biosynthesis / Q000235:genetics*; D045744:Cell Line, Tumor; D003598:Cytoskeletal Proteins / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D016147:Genes, Tumor Suppressor; D006801:Humans; D007136:Immunoglobulins / Q000096:biosynthesis / Q000235:genetics*; D007150:Immunohistochemistry / Q000379:methods; D007680:Kidney Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D007686:Kidney Tubules, Distal / Q000378:metabolism / Q000473:pathology; D007687:Kidney Tubules, Proximal / Q000378:metabolism / Q000473:pathology; D008562:Membrane Glycoproteins; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009479:Neuropeptides / Q000096:biosynthesis / Q000235:genetics; D011485:Protein Binding / Q000235:genetics; D054730:Protein Interaction Domains and Motifs; D000098853:Podoplanin
chemical_list: D000075982:Cell Adhesion Molecule-1; D015815:Cell Adhesion Molecules; D003598:Cytoskeletal Proteins; D007136:Immunoglobulins; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D009479:Neuropeptides; C403514:CADM1 protein, human; C498601:CADM4 protein, human; C117468:PDPN protein, human; D000098853:Podoplanin; C028841:erythrocyte membrane band 4.1 protein; C120557:erythrocyte membrane protein band 4.1-like 1