DOG1 regulates growth and IGFBP5 in gastrointestinal stromal tumors

Susanne Simon, Florian Grabellus, Loretta Ferrera, Luis Galietta, Benjamin Schwindenhammer, Thomas Muḧlenberg, Georg Taeger, Grant Eilers, Juergen Treckmann, Frank Breitenbuecher, Martin Schuler, Takahiro Taguchi, Jonathan A. Fletcher, Sebastian Bauer

Research output: Contribution to journalArticle

Abstract

Gastrointestinal stromal tumors (GIST) are characterized by activating mutations of KIT or platelet-derived growth factor receptor a(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.

Original languageEnglish
Pages (from-to)3661-3670
Number of pages10
JournalCancer Research
Volume73
Issue number12
DOIs
Publication statusPublished - Jun 15 2013

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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  • Cite this

    Simon, S., Grabellus, F., Ferrera, L., Galietta, L., Schwindenhammer, B., Muḧlenberg, T., Taeger, G., Eilers, G., Treckmann, J., Breitenbuecher, F., Schuler, M., Taguchi, T., Fletcher, J. A., & Bauer, S. (2013). DOG1 regulates growth and IGFBP5 in gastrointestinal stromal tumors. Cancer Research, 73(12), 3661-3670. https://doi.org/10.1158/0008-5472.CAN-12-3839