title: DOG1 regulates growth and IGFBP5 in gastrointestinal stromal tumors.
abstract: Gastrointestinal stromal tumors (GIST) are characterized by activating mutations of KIT or platelet-derived growth factor receptor α(PDGFRA), which can be therapeutically targeted by tyrosine kinase inhibitors (TKI) such as imatinib. Despite long-lasting responses, most patients eventually progress after TKI therapy. The calcium-dependent chloride channel DOG1 (ANO1/TMEM16A), which is strongly and specifically expressed in GIST, is used as a diagnostic marker to differentiate GIST from other sarcomas. Here, we report that loss of DOG1 expression occurs together with loss of KIT expression in a subset of GIST resistant to KIT inhibitors, and we illustrate the functional role of DOG1 in tumor growth, KIT expression, and imatinib response. Although DOG1 is a crucial regulator of chloride balance in GIST cells, we found that RNAi-mediated silencing or pharmacologic inhibition of DOG1 did not alter cell growth or KIT signaling in vitro. In contrast, DOG1 silencing delayed the growth of GIST xenografts in vivo. Expression profiling of explanted tumors after DOG1 blockade revealed a strong upregulation in the expression of insulin-like growth factor-binding protein 5 (IGFBP5), a potent antiangiogenic factor implicated in tumor suppression. Similar results were obtained after selection of imatinib-resistant DOG1- and KIT-negative cells derived from parental DOG1 and KIT-positive GIST cells, where a 5,000-fold increase in IGFBP5 mRNA transcripts were documented. In summary, our findings establish the oncogenic activity of DOG1 in GIST involving modulation of IGF/IGF receptor signaling in the tumor microenvironment through the antiangiogenic factor IGFBP5.
authors.affiliation: Sarcoma Center, Departments of Medical Oncology, Pathology and Neuropathology, Trauma and Orthopedic Surgery, Visceral and Transplant Surgery, West German Cancer Center, University Duisburg-Essen, University Hospital Essen, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Simon
authors.forename: Florian
authors.initials: F
authors.lastname: Grabellus
authors.forename: Loretta
authors.initials: L
authors.lastname: Ferrera
authors.forename: Luis
authors.initials: L
authors.lastname: Galietta
authors.forename: Benjamin
authors.initials: B
authors.lastname: Schwindenhammer
authors.forename: Thomas
authors.initials: T
authors.lastname: Mühlenberg
authors.forename: Georg
authors.initials: G
authors.lastname: Taeger
authors.forename: Grant
authors.initials: G
authors.lastname: Eilers
authors.forename: Juergen
authors.initials: J
authors.lastname: Treckmann
authors.forename: Frank
authors.initials: F
authors.lastname: Breitenbuecher
authors.forename: Martin
authors.initials: M
authors.lastname: Schuler
authors.forename: Takahiro
authors.initials: T
authors.lastname: Taguchi
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Fletcher
authors.forename: Sebastian
authors.initials: S
authors.lastname: Bauer
mesh_terms: D000818:Animals; D000075369:Anoctamin-1; D000970:Antineoplastic Agents / Q000494:pharmacology; D001549:Benzamides / Q000494:pharmacology; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018118:Chloride Channels / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D046152:Gastrointestinal Stromal Tumors / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000068877:Imatinib Mesylate; D018975:Insulin-Like Growth Factor Binding Protein 5 / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D008819:Mice, Nude; D009154:Mutation; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D009544:Niflumic Acid / Q000494:pharmacology; D009579:Nitrobenzoates / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics; D011743:Pyrimidines / Q000494:pharmacology; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: C476213:ANO1 protein, human; D000075369:Anoctamin-1; D000970:Antineoplastic Agents; D001549:Benzamides; D018118:Chloride Channels; D018975:Insulin-Like Growth Factor Binding Protein 5; D009363:Neoplasm Proteins; D009579:Nitrobenzoates; D010879:Piperazines; D011743:Pyrimidines; C058176:5-nitro-2-(3-phenylpropylamino)benzoic acid; D009544:Niflumic Acid; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit