| Title |
Hedgehog pathway dysregulation contributes to the pathogenesis of human gastrointestinal stromal tumors via GLI-mediated activation of KIT expression
|
|---|---|
| Published in |
Oncotarget, October 2016
|
| DOI | 10.18632/oncotarget.12909 |
| Pubmed ID | |
| Authors |
Chih-Min Tang, Tracy E. Lee, Sabriya A. Syed, Adam M. Burgoyne, Stephanie Y. Leonard, Fei Gao, Jonathan C. Chan, Eileen Shi, Juliann Chmielecki, Deborah Morosini, Kai Wang, Jeffrey S. Ross, Michael L. Kendrick, Michael R. Bardsley, Martina De Siena, Junhao Mao, Olivier Harismendy, Tamas Ordog, Jason K. Sicklick |
| 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. |
Mendeley readers
The data shown below were compiled from readership statistics for 34 Mendeley readers of this research output. Click here to see the associated Mendeley record.
Geographical breakdown
| Country | Count | As % |
|---|---|---|
| Unknown | 34 | 100% |
Demographic breakdown
| Readers by professional status | Count | As % |
|---|---|---|
| Student > Ph. D. Student | 9 | 26% |
| Researcher | 6 | 18% |
| Student > Master | 3 | 9% |
| Professor | 2 | 6% |
| Student > Bachelor | 2 | 6% |
| Other | 8 | 24% |
| Unknown | 4 | 12% |
| Readers by discipline | Count | As % |
|---|---|---|
| Medicine and Dentistry | 10 | 29% |
| Biochemistry, Genetics and Molecular Biology | 10 | 29% |
| Agricultural and Biological Sciences | 4 | 12% |
| Unspecified | 2 | 6% |
| Computer Science | 2 | 6% |
| Other | 0 | 0% |
| Unknown | 6 | 18% |
Attention Score in Context
This research output has an Altmetric Attention Score of 78. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 04 November 2016.
All research outputs
#466,138
of 22,899,952 outputs
Outputs from Oncotarget
#135
of 14,331 outputs
Outputs of similar age
#10,126
of 313,872 outputs
Outputs of similar age from Oncotarget
#16
of 808 outputs
Altmetric has tracked 22,899,952 research outputs across all sources so far. Compared to these this one has done particularly well and is in the 97th percentile: it's in the top 5% of all research outputs ever tracked by Altmetric.
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We're also able to compare this research output to 808 others from the same source and published within six weeks on either side of this one. This one has done particularly well, scoring higher than 98% of its contemporaries.