title: Up-regulated expression of ADAM17 in gastrointestinal stromal tumors: coexpression with EGFR and EGFR ligands.
abstract: Metalloproteinase activities of a disintegrin and metalloproteinases (ADAMs), matrix metalloproteinases (MMPs), and membrane type (MT-)MMPs are involved in many aspects of tumor biology. ADAMs are transmembrane proteins that cleave membrane-anchored proteins to release soluble factors, and thereby mediate important biological phenomena in tumors. The aim of this study was to analyze histopathology, expression and roles of metalloproteinases, especially ADAMs, in gastric gastrointestinal stromal tumor (GIST). Histopathology and immunohistochemical expression of ADAMs were examined in 89 gastric GISTs. In 11 GISTs, ADAM expression was examined at mRNA and protein levels by reverse transcription-polymerase chain reaction (RT-PCR) and immunoblotting, respectively. RT-PCR analysis showed frequent expression of ADAM9 (91%), ADAM10 (64%), ADAM17 (82%), MMP-2 (82%), and MT1-MMP (73%). However, ADAM17 and MMP-2 were the only metalloproteinases that were up-regulated in GISTs at the protein level compared with non-neoplastic gastric tissues. ADAM17 was immunohistochemically expressed in 93% of GIST versus 16% of normal gastric tissues. Furthermore, CD117-positive interstitial cells of Cajal in normal gastric tissues were all negative for ADAM17 with double immunostaining. Expressions of epidermal growth factor receptor (EGFR) and several EGFR ligands such as amphiregulin, heparin-binding epidermal growth factor (HB-EGF), betacellulin, and epiregulin were also demonstrated in GIST by RT-PCR. Protein expression of EGFR, phosphorylated EGFR, amphiregulin, and HB-EGF, both of which can be shed by ADAM17, was confirmed in tumors coexpressing ADAM17 by immunoblotting. Moreover, proteolytically cleaved soluble forms of amphiregulin were identified in tumor extracts. Considered together, the results suggest that ADAM17 may contribute to the progression and growth of GIST through shedding of EGFR ligands and consequent EGFR stimulation. ADAM17, as a major sheddase in GIST, could be potentially a suitable target in anticancer treatment of imatinib-resistant GISTs.
authors.affiliation: Department of Pathology, Fukuoka University Hospital and School of Medicine, Fukuoka 814-0180, Japan.
authors.forename: Motomichi
authors.initials: M
authors.lastname: Nakagawa
authors.forename: Kazuki
authors.initials: K
authors.lastname: Nabeshima
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Asano
authors.forename: Makoto
authors.initials: M
authors.lastname: Hamasaki
authors.forename: Noriko
authors.initials: N
authors.lastname: Uesugi
authors.forename: Hiroki
authors.initials: H
authors.lastname: Tani
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Yamashita
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Iwasaki
mesh_terms: D051722:ADAM Proteins / Q000032:analysis* / Q000235:genetics; D000072198:ADAM17 Protein; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019483:Disintegrins / Q000032:analysis / Q000235:genetics; D066246:ErbB Receptors / Q000032:analysis* / Q000235:genetics; D005260:Female; D046152:Gastrointestinal Stromal Tumors / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D008024:Ligands; D008297:Male; D008666:Metalloendopeptidases / Q000032:analysis* / Q000235:genetics; D008875:Middle Aged; D012333:RNA, Messenger / Q000032:analysis; D015854:Up-Regulation / Q000235:genetics
chemical_list: D019483:Disintegrins; D008024:Ligands; D012333:RNA, Messenger; D066246:ErbB Receptors; D051722:ADAM Proteins; D008666:Metalloendopeptidases; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human