Hedgehog pathway dysregulation contributes to the pathogenesis of human gastrointestinal stromal tumors via GLI-mediated activation of KIT expression

• Published in: Oncotarget Vol. 7; no. 48; pp. 78226 - 78241
• Main Authors: Tang, Chih-Min, Lee, Tracy E., Syed, Sabriya A., Burgoyne, Adam M., Leonard, Stephanie Y., Gao, Fei, Chan, Jonathan C., Shi, Eileen, Chmielecki, Juliann, Morosini, Deborah, Wang, Kai, Ross, Jeffrey S., Kendrick, Michael L., Bardsley, Michael R., De Siena, Martina, Mao, Junhao, Harismendy, Olivier, Ordog, Tamas, Sicklick, Jason K.
• Format: Journal Article
• Language: English
• Published: United States Impact Journals LLC 29.11.2016
• Subjects: Antineoplastic Agents - pharmacology; Arsenicals - pharmacology; Binding Sites; Cell Line, Tumor; Cell Survival; Cilia - metabolism; Cilia - pathology; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Gastrointestinal Neoplasms - drug therapy; Gastrointestinal Neoplasms - genetics; Gastrointestinal Neoplasms - metabolism; Gastrointestinal Neoplasms - pathology; Gastrointestinal Stromal Tumors - drug therapy; Gastrointestinal Stromal Tumors - genetics; Gastrointestinal Stromal Tumors - metabolism; Gastrointestinal Stromal Tumors - pathology; Gene Expression Regulation, Neoplastic; Humans; Imatinib Mesylate - pharmacology; Interstitial Cells of Cajal - drug effects; Interstitial Cells of Cajal - metabolism; Interstitial Cells of Cajal - pathology; Mutation; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Nuclear Proteins - antagonists & inhibitors; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Oxides - pharmacology; Priority Research Paper; Promoter Regions, Genetic; Proto-Oncogene Proteins c-kit - genetics; Proto-Oncogene Proteins c-kit - metabolism; Receptor, Platelet-Derived Growth Factor alpha - genetics; RNA Interference; RNA, Messenger - genetics; RNA, Messenger - metabolism; Signal Transduction - drug effects; Transfection; Zinc Finger Protein GLI1 - antagonists & inhibitors; Zinc Finger Protein GLI1 - genetics; Zinc Finger Protein GLI1 - metabolism; Zinc Finger Protein Gli2 - antagonists & inhibitors; Zinc Finger Protein Gli2 - genetics; Zinc Finger Protein Gli2 - metabolism; Zinc Finger Protein Gli3 - genetics; Zinc Finger Protein Gli3 - metabolism; imatinib-resistant; ICC; GIST; GLI; arsenic trioxide

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...