Evidence map›Paper›PMID 27793025›Full record

ArticleOncotarget2016

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

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 and 9 more

Open access · diamondAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Oncotarget, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.

0numbers the graph read from it
0cells of the map it votes in
21citing papers in PubMed
3.5field-weighted citation impact, top 7% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

21 citing papers in PubMed, 33 citations in OpenAlex.

  1. Review
  2. Article
  3. Article
  4. Article
  5. Article
  6. Dysgerminoma with a Somatic Exon 17Diagnostics (Basel, Switzerland) · 2020
    Article
  7. Article
  8. Translational lung cancer research · 2020
    Article
  9. Review
  10. Article
  11. Hedgehog signalling pathway activation in gastrointestinal stromal tumours is mediated by primary cilia.Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association · 2020
    Article
  12. Article
  13. Article
  14. Review
  15. Article
  16. Review
  17. Review
  18. Bioinformatic Analysis of GLI1 and Related Signaling Pathways in Chemosensitivity of Gastric Cancer.Medical science monitor : international medical journal of experimental and clinical research · 2018
    Article
  19. Article
  20. The Call of "The Wild"-Type GIST: It's Time for Domestication.Journal of the National Comprehensive Cancer Network : JNCCN · 2017
    Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

19 authors at 5 institutions in 1 country.

Chih-Min TangDepartment of Surgery, Division of Surgical Oncology, Moores UCSD Cancer Center, University of California, San Diego, La Jolla, California, USA.
Tracy E LeeDepartment of Surgery, Division of Surgical Oncology, Moores UCSD Cancer Center, University of California, San Diego, La Jolla, California, USA.
Sabriya A SyedDepartment of Physiology and Biomedical Engineering and Gastroenterology Research Unit, Enteric Neuroscience Program, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA.
Adam M BurgoyneDepartment of Medicine, Division of Hematology/Oncology, Moores UCSD Cancer Center, University of California, San Diego, La Jolla, California, USA.
Stephanie Y LeonardDepartment of Surgery, Division of Surgical Oncology, Moores UCSD Cancer Center, University of California, San Diego, La Jolla, California, USA.
Fei GaoDepartment of Physiology and Biomedical Engineering and Gastroenterology Research Unit, Enteric Neuroscience Program, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA.
Jonathan C ChanDepartment of Surgery, Division of Surgical Oncology, Moores UCSD Cancer Center, University of California, San Diego, La Jolla, California, USA.
Eileen ShiSchool of Medicine, University of California, San Diego, La Jolla, California, USA.
Juliann ChmieleckiFoundation Medicine, Inc., Cambridge, Massachusetts, USA.
Deborah MorosiniFoundation Medicine, Inc., Cambridge, Massachusetts, USA.
Kai WangFoundation Medicine, Inc., Cambridge, Massachusetts, USA.
Jeffrey S RossFoundation Medicine, Inc., Cambridge, Massachusetts, USA.
Michael L KendrickDepartment of Surgery, Mayo Clinic, Rochester, Minnesota, USA.
Michael R BardsleyDepartment of Physiology and Biomedical Engineering and Gastroenterology Research Unit, Enteric Neuroscience Program, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA.
Martina De SienaDepartment of Surgery, Division of Surgical Oncology, Moores UCSD Cancer Center, University of California, San Diego, La Jolla, California, USA.
Junhao MaoDepartment of Molecular, Cell and Cancer Biology, University of Massachusetts, Worchester, Massachusetts, USA.
Olivier HarismendyDivision of Biomedical Informatics, Moores UCSD Cancer Center, University of California San Diego, La Jolla, California, USA.
Tamas OrdogDepartment of Physiology and Biomedical Engineering and Gastroenterology Research Unit, Enteric Neuroscience Program, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA.
Jason K SicklickDepartment of Surgery, Division of Surgical Oncology, Moores UCSD Cancer Center, University of California, San Diego, La Jolla, California, USA.
University of California, San Diego · USFoundation Medicine (United States)Mayo Clinic · USUniversity of Massachusetts Chan Medical School · USWinnMed · US

Funding

Women's Cancer ProgramP30CA015083 · NCI · MAYO CLINIC ROCHESTER · PI AKHILESH PANDEY · 1985 to 2026
$151.3M
PILOT AND FEASIBILTY PROGRAMP30DK084567 · NIDDK · MAYO CLINIC ROCHESTER · PI Nicholas F. LaRusso · 2009 to 2026
$22.2M
Interstitial Cells of Cajal in Diabetic GastropathyR01DK058185 · NIDDK · UNIVERSITY OF NEVADA RENO · PI ORDOG, TAMAS · 2002 to 2020
$5.2M
Novel Allosteric Kinase Inhibitors Target Imatinib-Resistant GISTK08CA168999 · NCI · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI SICKLICK, JASON KEITH · 2014 to 2018
$888k
Droplet Microfluidic Platform for Ultralow Input EpigeneticsR21CA191186 · NCI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI BAILEY, RYAN C · 2015 to 2017
$647k
Defining the Germline Genomic Landscape of a Novel GIST Multi-tumor SyndromeR21CA192072 · NCI · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI SICKLICK, JASON KEITH · 2016 to 2017
$399k
NCI NIH HHS K08 CA168999NCI NIH HHS P30 CA015083NCI NIH HHS R21 CA191186NCI NIH HHS R21 CA192072NIDDK NIH HHS P30 DK084567NIDDK NIH HHS R01 DK058185
6 · The paper itself

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.

Indexed as

Signal TransductionAntineoplastic AgentsArsenicalsArsenic TrioxideBinding SitesCell Line, TumorCell SurvivalCiliaDose-Response Relationship, DrugDrug Resistance, NeoplasmGastrointestinal NeoplasmsGastrointestinal Stromal TumorsGene Expression Regulation, NeoplasticHumansImatinib MesylateInterstitial Cells of CajalAntineoplastic AgentsArsenicalsArsenic TrioxideGLI1 protein, humanGLI2 protein, humanGLI3 protein, humanImatinib MesylateNerve Tissue ProteinsNuclear ProteinsOxidesProto-Oncogene Proteins c-kitReceptor, Platelet-Derived Growth Factor alphaRNA, MessengerZinc Finger Protein GLI1Zinc Finger Protein Gli2Zinc Finger Protein Gli3arsenic trioxideGISTGLIICCimatinib-resistant

Identifiers

PMID27793025
PMCPMC5346634
OpenAlexW2545270118

What OpenQuestion holds

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LicenceCC BY
Read underepoch 390

Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.