title: Src plays a key role in ADAM28 expression in v-src-transformed epithelial cells and human carcinoma cells.
abstract: ADAM28, a disintegrin and metalloproteinase 28, is overexpressed by carcinoma cells with direct correlations with carcinoma cell proliferation and progression in human lung and breast carcinomas. However, the molecular mechanisms of ADAM28 gene expression in carcinoma cells remain elusive. Herein, we investigated the expression of ADAM28 in Madin-Darby canine kidney epithelial cells transformed by oncogenes, including v-src, LMP1, ErbB2, Ha-Ras, and c-Fos, and found that v-src transformants selectively induce ADAM28. Implantation of the v-src transformants showed a progressively growing tumor, which was significantly suppressed by local injections of anti-ADAM28 antibody. ADAM28 expression in v-src transformants was partially inhibited by treatment with inhibitors to Src kinase, mitogen-activated protein kinase kinase (MEK), phosphatidylinositol 3-kinase (PI3K), or mammalian target of rapamycin, and abrogated by v-Src kinase inhibitor, radicicol, or a mixture of MEK and PI3K inhibitors. Human carcinoma cell lines of the lung, breast, ovary, kidney, and colon showed ADAM28 expression, which was correlated with phosphorylation of c-Src and suppressed by the inhibitors in a similar way to v-src transformants. IHC of the human tumor tissues demonstrated co-expression of ADAM28 and phosphorylated Src in neoplastic cells of the breast, lung, and colon carcinomas and some adenomas of the colon, but not in nonneoplastic colon mucosa. Our data provide, to the best of our knowledge, the first evidence that Src is an inducer of ADAM28 gene expression through the MEK/extracellular signal-regulated kinase and PI3K/mammalian target of rapamycin pathways.
authors.affiliation: Department of Pathology, School of Medicine, Keio University, Tokyo, Japan; Department of Pathology and Oncology, School of Medicine, Juntendo University, Tokyo, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Abe
authors.affiliation: Department of Pathology, School of Medicine, Keio University, Tokyo, Japan.
authors.forename: Satsuki
authors.initials: S
authors.lastname: Mochizuki
authors.affiliation: Department of Pathology, School of Medicine, Keio University, Tokyo, Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Ohara
authors.affiliation: Department of Pathology, School of Medicine, Keio University, Tokyo, Japan.
authors.forename: Mari
authors.initials: M
authors.lastname: Ueno
authors.affiliation: Department of Surgery, School of Medicine, Keio University, Tokyo, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Ochiai
authors.affiliation: Department of Surgery, School of Medicine, Keio University, Tokyo, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Kitagawa
authors.affiliation: Department of Pathology and Oncology, School of Medicine, Juntendo University, Tokyo, Japan.
authors.forename: Okio
authors.initials: O
authors.lastname: Hino
authors.affiliation: Department of Molecular Virology and Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sato
authors.affiliation: Department of Pathology, School of Medicine, Keio University, Tokyo, Japan. Electronic address: okada@z6.keio.jp.
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Okada
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism*; D000818:Animals; D002277:Carcinoma / Q000201:enzymology* / Q000473:pathology* / Q000648:ultrastructure; D049109:Cell Proliferation; D048430:Cell Shape; D002471:Cell Transformation, Neoplastic; D004285:Dogs; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000201:enzymology* / Q000473:pathology* / Q000648:ultrastructure; D006801:Humans; D007150:Immunohistochemistry; D061985:Madin Darby Canine Kidney Cells; D051379:Mice; D016513:Mice, SCID; D008954:Models, Biological; D015688:Oncogene Protein pp60(v-src) / Q000378:metabolism*; D010766:Phosphorylation; D015398:Signal Transduction; D023041:Xenograft Model Antitumor Assays; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: D015688:Oncogene Protein pp60(v-src); D019061:src-Family Kinases; D051722:ADAM Proteins; C410224:ADAM28 protein, human