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dc.contributor.author
Rizvi, Sumera
dc.contributor.author
DeMars, Cathrine J.
dc.contributor.author
Comba, Andrea
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dc.contributor.author
Gainullin, Vladimir G.
dc.contributor.author
Rizvi, Zaheer
dc.contributor.author
Almada, Luciana L.
dc.contributor.author
Wang, Kenneth
dc.contributor.author
Lomberk, Gwen
dc.contributor.author
Fernández-Zapico, Martin E.
dc.contributor.author
Buttar, Navtej S.
dc.date.available
2023-02-22T09:44:33Z
dc.date.issued
2010-09-01
dc.identifier.citation
Rizvi, Sumera; DeMars, Cathrine J.; Comba, Andrea; Gainullin, Vladimir G.; Rizvi, Zaheer; et al.; Combinatorial chemoprevention reveals a novel smoothened-independent role of GLI1 in esophageal carcinogenesis; American Association for Cancer Research; Cancer Research; 70; 17; 1-9-2010; 6787-6796
dc.identifier.issn
0008-5472
dc.identifier.uri
http://hdl.handle.net/11336/188501
dc.description.abstract
Reflux-induced injury promotes esophageal adenocarcinoma, one of the most rapidly increasing, highly lethal cancers in Western countries. Here, we investigate the efficacy of a combinatorial chemoprevention strategy for esophageal adenocarcinoma and characterize the underlying molecular mechanisms. Specifically, our approach involves the use of ursodeoxycholic acid (Urso) due to its ability to decrease injury-inducing bile salts in combination with Aspirin to mitigate the consequences of injury. We find that Urso-Aspirin combination reduces the risk of adenocarcinoma in vivo in animals with reflux, decreases the proliferation of esophageal adenocarcinoma cells, and downregulates a key cell cycle regulator, CDK2. Mechanistically, using cell growth, luciferase reporter, expression, and chromatin immunoprecipitation assays, we identify GLI1, a Hedgehogregulated transcription factor, as a novel target of Urso-Aspirin combination. We show that GLI1 is upregulated during esophageal carcinogenesis, and GLI1 can bind to the CDK2 promoter and activate its expression. Although the Urso-Aspirin combination downregulates GLI1, the GLI1 overexpression not only abrogates the effect of this combination on proliferation but it also restores CDK-2 expression. These findings support that the chemopreventive effect of the Urso-Aspirin combination occurs, at least in part, through a novel GLI1-CDK2-dependent mechanism. To further understand the regulation of CDK2 by GLI1, both pharmacologic and RNAi-mediated approaches show that GLI1 is a transcriptional activator of CDK2, and this regulation occurs independent of Smoothened, the central transducer of the Hedgehog canonical pathway. Collectively, these results identify a novel GLI1-to-CDK2 pathway in esophageal carcinogenesis, which is a bona fide target for effective combinatorial chemoprevention with Urso and Aspirin.
dc.format
application/pdf
dc.language.iso
eng
dc.publisher
American Association for Cancer Research
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dc.rights
info:eu-repo/semantics/openAccess
dc.rights.uri
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.subject
GLI1
dc.subject
Hedgehog signaling
dc.subject
Chemoprevention
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Esophageal adenocarcinoma
dc.subject.classification
Bioquímica y Biología Molecular
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dc.subject.classification
Medicina Básica
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dc.subject.classification
CIENCIAS MÉDICAS Y DE LA SALUD
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dc.title
Combinatorial chemoprevention reveals a novel smoothened-independent role of GLI1 in esophageal carcinogenesis
dc.type
info:eu-repo/semantics/article
dc.type
info:ar-repo/semantics/artículo
dc.type
info:eu-repo/semantics/publishedVersion
dc.date.updated
2023-02-07T11:52:47Z
dc.identifier.eissn
1538-7445
dc.journal.volume
70
dc.journal.number
17
dc.journal.pagination
6787-6796
dc.journal.pais
Estados Unidos
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dc.journal.ciudad
Philadelphia
dc.description.fil
Fil: Rizvi, Sumera. Mayo Clinic Cancer Center; Estados Unidos. University of Pittsburgh; Estados Unidos
dc.description.fil
Fil: DeMars, Cathrine J.. Mayo Clinic Cancer Center; Estados Unidos. University of Pittsburgh; Estados Unidos
dc.description.fil
Fil: Comba, Andrea. Mayo Clinic Cancer Center; Estados Unidos. University of Pittsburgh; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba; Argentina
dc.description.fil
Fil: Gainullin, Vladimir G.. Mayo Clinic Cancer Center; Estados Unidos. University of Pittsburgh; Estados Unidos
dc.description.fil
Fil: Rizvi, Zaheer. Mayo Clinic Cancer Center; Estados Unidos. University of Pittsburgh; Estados Unidos
dc.description.fil
Fil: Almada, Luciana L.. Mayo Clinic Cancer Center; Estados Unidos. University of Pittsburgh; Estados Unidos
dc.description.fil
Fil: Wang, Kenneth. Mayo Clinic Cancer Center; Estados Unidos. University of Pittsburgh; Estados Unidos
dc.description.fil
Fil: Lomberk, Gwen. Mayo Clinic Cancer Center; Estados Unidos. University of Pittsburgh; Estados Unidos
dc.description.fil
Fil: Fernández-Zapico, Martin E.. Mayo Clinic Cancer Center; Estados Unidos. University of Pittsburgh; Estados Unidos
dc.description.fil
Fil: Buttar, Navtej S.. Mayo Clinic Cancer Center; Estados Unidos. University of Pittsburgh; Estados Unidos
dc.journal.title
Cancer Research
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dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/url/http://cancerres.aacrjournals.org/content/70/17/6787.long
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/doi/https://doi.org/10.1158/0008-5472.CAN-10-0197
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