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Hedgehog Signaling Regulates KIT Expression in Gastrointestinal Stromal Tumors /


Gastrointestinal Stromal Tumors (GISTs) arise within the gut due to overexpression of mutated KIT genes within the Interstitial Cells of Cajal (ICC). Earlier work demonstrated that gastrointestinal mesenchymal development depends upon Hedgehog (Hh) signaling, while Gli3, a Hh transcription factor, regulates KIT mRNA expression in murine ICC-like cells. Therefore, we hypothesized that Gli transcription factors (Gli1/2/3) within the Hh pathway may regulate KIT expression in human GISTs. We investigated the effects of regulating the activating (Gli1/Gli2) and the repressing (Gli3) members of the Gli family in two GIST lines (GIST-T1 and GIST882). In both lines, KIT mRNA expression is inverse to Gli3 expression (KIT/Gli3 ratio: T1=0.38; 882=1.98). Using genetic means, Gli3 siRNA induces a 62% increase in KIT mRNA, while Gli3 overexpression induces a 270% decrease in KIT mRNA and a 24% reduction in KIT protein levels in the KIThiGli3lo line (882). Inversely, Gli1 and Gli2 siRNA knockdowns result in 55% and 19% decreases in KIT mRNA, respectively. Pharmacologic treatment with GANT61, a Gli1/2 inhibitor, decreases KIT mRNA by 50%. Given that KIT is the target of anti-GIST therapies, viability and apoptosis assays show that increasing KIT (i.e. Gli3 siRNA) slightly increases cell viability (5%) while decreasing KIT decreases viability (Gli2 siRNA: 10%) and increases apoptosis (Gli3 overexpression: 20%). Herein, we provide the first evidence that Gli1/2/3 transcriptionally regulates expression of KIT in GIST. Gli1/2 activates KIT expression, while Gli3 represses KIT expression. Taken together, these transcription factors may serve as novel targets for treating KIT-driven GISTs

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