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Hedgehog pathway dysregulation contributes to the pathogenesis of human gastrointestinal stromal tumors via GLI-mediated activation of KIT expression
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Abstract
Chih-Min Tang1,*, Tracy E. Lee1,*, Sabriya A. Syed2,3,*, Adam M. Burgoyne4, Stephanie Y. Leonard1, Fei Gao2, Jonathan C. Chan1, Eileen Shi5, Juliann Chmielecki6, Deborah Morosini6, Kai Wang6, Jeffrey S. Ross6, Michael L. Kendrick7, Michael R. Bardsley2, Martina De Siena1, Junhao Mao8, Olivier Harismendy9, Tamas Ordog2,10,* and Jason K. Sicklick1,5,*
1 Department of Surgery, Division of Surgical Oncology, Moores UCSD Cancer Center, University of California, San Diego, La Jolla, California, USA
2 Department of Physiology and Biomedical Engineering and Gastroenterology Research Unit, Enteric Neuroscience Program, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
3 Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota, USA
4 Department of Medicine, Division of Hematology/Oncology, Moores UCSD Cancer Center, University of California, San Diego, La Jolla, California, USA
5 School of Medicine, University of California, San Diego, La Jolla, California, USA
6 Foundation Medicine, Inc., Cambridge, Massachusetts, USA
7 Department of Surgery, Mayo Clinic, Rochester, Minnesota, USA
8 Department of Molecular, Cell and Cancer Biology, University of Massachusetts, Worchester, Massachusetts, USA
9 Division of Biomedical Informatics, Moores UCSD Cancer Center, University of California San Diego, La Jolla, California, USA
10 Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota, USA
* These authors have contributed equally to this work
Correspondence to:
Jason K. Sicklick, email:
Tamas Ordog, email:
Keywords: arsenic trioxide, GIST, GLI, ICC, imatinib-resistant
Received: February 16, 2016 Accepted: October 13, 2016 Published: October 25, 2016
Abstract
Gastrointestinal stromal tumors (GIST) arise within the interstitial cell of Cajal (ICC) lineage due to activating KIT/PDGFRA mutations. Both ICC and GIST possess primary cilia (PC), which coordinate PDGFRA and Hedgehog signaling, regulators of gastrointestinal mesenchymal development. Therefore, we hypothesized that Hedgehog signaling may be altered in human GIST and controls KIT expression. Quantitative RT-PCR, microarrays, and next generation sequencing were used to describe Hedgehog/PC-related genes in purified human ICC and GIST. Genetic and pharmacologic approaches were employed to investigate the effects of GLI manipulation on KIT expression and GIST cell viability. We report that Hedgehog pathway and PC components are expressed in ICC and GIST and subject to dysregulation during GIST oncogenesis, irrespective of KIT/PDGFRA mutation status. Using genomic profiling, 10.2% of 186 GIST studied had potentially deleterious genomic alterations in 5 Hedgehog-related genes analyzed, including in the PTCH1 tumor suppressor (1.6%). Expression of the predominantly repressive GLI isoform, GLI3, was inversely correlated with KIT mRNA levels in GIST cells and non-KIT/non-PDGFRA mutant GIST. Overexpression of the 83-kDa repressive form of GLI3 or small interfering RNA-mediated knockdown of the activating isoforms GLI1/2 reduced KIT mRNA. Treatment with GLI1/2 inhibitors, including arsenic trioxide, significantly increased GLI3 binding to the KIT promoter, decreased KIT expression, and reduced viability in imatinib-sensitive and imatinib-resistant GIST cells. These data offer new evidence that genes necessary for Hedgehog signaling and PC function in ICC are dysregulated in GIST. Hedgehog signaling activates KIT expression irrespective of mutation status, offering a novel approach to treat imatinib-resistant GIST.
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