title: Inactivation of the transcription factor GLI1 accelerates pancreatic cancer progression.
abstract: The role of GLI1 in pancreatic tumor initiation promoting the progression of preneoplastic lesions into tumors is well established. However, its function at later stages of pancreatic carcinogenesis remains poorly understood. To address this issue, we crossed the gli1 knock-out (GKO) animal with cre-dependent pancreatic activation of oncogenic kras concomitant with loss of the tumor suppressor tp53 (KPC). Interestingly, in this model, GLI1 played a tumor-protective function, where survival of GKO/KPC mice was reduced compared with KPC littermates. Both cohorts developed pancreatic cancer without significant histopathological differences in survival studies. However, analysis of mice using ultrasound-based imaging at earlier time points showed increased tumor burden in GKO/KPC mice. These animals have larger tumors, decreased body weight, increased lactate dehydrogenase production, and severe leukopenia. In vivo and in vitro expression studies identified FAS and FAS ligand (FASL) as potential mediators of this phenomenon. The FAS/FASL axis, an apoptotic inducer, plays a role in the progression of pancreatic cancer, where its expression is usually lost or significantly reduced in advanced stages of the disease. Chromatin immunoprecipitation and reporter assays identified FAS and FASL as direct targets of GLI1, whereas GKO/KPC mice showed lower levels of this ligand compared with KPC animals. Finally, decreased levels of apoptosis were detected in tumor tissue in the absence of GLI1 by TUNEL staining. Together, these findings define a novel pathway regulated by GLI1 controlling pancreatic tumor progression and provide a new theoretical framework to help with the design and analysis of trials targeting GLI1-related pathways.
authors.affiliation: From the Schulze Center for Novel Therapeutics.
authors.forename: Lisa D
authors.initials: LD
authors.lastname: Mills
authors.affiliation: Laboratory Medicine and Pathology.
authors.forename: Lizhi
authors.initials: L
authors.lastname: Zhang
authors.affiliation: the Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic Scottsdale, Arizona 85259.
authors.forename: Ronald
authors.initials: R
authors.lastname: Marler
authors.affiliation: Laboratory of Epigenetics and Chromatin Dynamics.
authors.forename: Phyllis
authors.initials: P
authors.lastname: Svingen
authors.affiliation: From the Schulze Center for Novel Therapeutics.
authors.forename: Maite G
authors.initials: MG
authors.lastname: Fernandez-Barrena
authors.affiliation: Laboratory of Epigenetics and Chromatin Dynamics.
authors.forename: Maneesh
authors.initials: M
authors.lastname: Dave
authors.affiliation: Division of Biomedical Statistics and Informatics.
authors.forename: William
authors.initials: W
authors.lastname: Bamlet
authors.affiliation: Department of Oncology, and.
authors.forename: Robert R
authors.initials: RR
authors.lastname: McWilliams
authors.affiliation: Division of Epidemiology, Mayo Clinic, Rochester, Minnesota 55905 and.
authors.forename: Gloria M
authors.initials: GM
authors.lastname: Petersen
authors.affiliation: Laboratory of Epigenetics and Chromatin Dynamics.
authors.forename: William
authors.initials: W
authors.lastname: Faubion
authors.affiliation: From the Schulze Center for Novel Therapeutics, fernandezzapico.martin@mayo.edu.
authors.forename: Martin E
authors.initials: ME
authors.lastname: Fernandez-Zapico
mesh_terms: D000818:Animals; D018450:Disease Progression; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000037:antagonists & inhibitors*; D051379:Mice; D018345:Mice, Knockout; D010190:Pancreatic Neoplasms / Q000473:pathology*; D000071676:Zinc Finger Protein GLI1
chemical_list: C498520:Gli1 protein, mouse; D051741:Kruppel-Like Transcription Factors; D000071676:Zinc Finger Protein GLI1
keywords: Cancer Biology; GLI1; Gene Expression; Pancreatic Cancer; Transcription Factors; Tumor Microenvironment; Tumor Progression
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