title: The activity of Gli transcription factors is essential for Kras-induced pancreatic tumorigenesis.
abstract: Pancreatic ductal adenocarcinoma (PDAC), one of the most aggressive human malignancies, is thought to be initiated by KRAS activation. Here we find that transcriptional activation mediated by the Gli family of transcription factors, although dispensable for pancreatic development, is required for Kras-induced proliferation and survival in primary pancreatic epithelial cells in culture and for Kras-driven pancreatic intraepithelial neoplasia and PDAC formation in vivo. Further, ectopic Gli1 activation in the mouse pancreas accelerates Kras-driven tumor formation, underscoring the importance of Gli transcription factors in pancreatic tumorigenesis. Interestingly, we demonstrate Gli-regulated I-kappa-B kinase epsilon (IKBKE) and NF-κB activity in pancreatic cancer cells and show that this activity is a critical downstream mediator for Gli-dependent PDAC cell transformation and survival. Together, these studies demonstrate the requirement for Gli in Kras-dependent pancreatic epithelial transformation, suggest a mechanism of Gli-NF-κB oncogenic activation, and provide genetic evidence supporting the therapeutic targeting of Gli activity in pancreatic cancer.
authors.affiliation: Department of Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Mihir
authors.initials: M
authors.lastname: Rajurkar
authors.forename: Wilfredo E
authors.initials: WE
authors.lastname: De Jesus-Monge
authors.forename: David R
authors.initials: DR
authors.lastname: Driscoll
authors.forename: Victoria A
authors.initials: VA
authors.lastname: Appleman
authors.forename: He
authors.initials: H
authors.lastname: Huang
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Cotton
authors.forename: David S
authors.initials: DS
authors.lastname: Klimstra
authors.forename: Lihua J
authors.initials: LJ
authors.lastname: Zhu
authors.forename: Karl
authors.initials: K
authors.lastname: Simin
authors.forename: Lan
authors.initials: L
authors.lastname: Xu
authors.forename: Andrew P
authors.initials: AP
authors.lastname: McMahon
authors.forename: Brian C
authors.initials: BC
authors.lastname: Lewis
authors.forename: Junhao
authors.initials: J
authors.lastname: Mao
mesh_terms: D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics* / Q000473:pathology; D049109:Cell Proliferation; D011905:Genes, ras; D020672:I-kappa B Proteins / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D020672:I-kappa B Proteins; D016328:NF-kappa B; C491366:Nfkbie protein, mouse; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors