title: Loss of the transcription factor GLI1 identifies a signaling network in the tumor microenvironment mediating KRAS oncogene-induced transformation.
abstract: Although the biological role of KRAS is clearly established in carcinogenesis, the molecular mechanisms underlying this phenomenon are not completely understood. In this study, we provide evidence of a novel signaling network regulated by the transcription factor GLI1 mediating KRAS-induced carcinogenesis. Using pancreatic cancer (a disease with high prevalence of KRAS mutations) as a model, we show that loss of GLI1 blocks the progression of KRAS-induced pancreatic preneoplastic lesions in mice with pancreas-specific Cre-activated oncogenic mutant kras. Mice lacking GLI1 develop only low-grade lesions at low frequency, and in most cases, the pancreata are histologically normal. Further characterization of the phenotype showed a decrease in the activation of STAT3 in pancreatic preneoplastic lesions; STAT3 is a transcription factor required for the development of premalignant lesions and their progression into pancreatic cancer. Analysis of the mechanisms revealed a key role for GLI1 in maintaining the levels of activated STAT3 through the modulation of IL-6 signaling. GLI1 binds to the IL-6 mouse promoter and regulates the activity and expression of this cytokine. This newly identified GLI1/IL-6 axis is active in fibroblasts, a known source of IL-6 in the tumor microenvironment. Sonic hedgehog induces GLI1 binding to the IL-6 promoter and increases IL-6 expression in fibroblasts in a paracrine manner. Finally, we demonstrate that mutant KRAS initiates this cascade by inducing the expression of Sonic hedgehog in cancer cells. Collectively, these results define a novel role for GLI1 in carcinogenesis acting as a downstream effector of oncogenic KRAS in the tumor microenvironment.
authors.affiliation: Schulze Center for Novel Therapeutics, Division of Oncology Research, Rochester, Minnesota 55905, USA.
authors.forename: Lisa D
authors.initials: LD
authors.lastname: Mills
authors.forename: Yaqing
authors.initials: Y
authors.lastname: Zhang
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Marler
authors.forename: Marta
authors.initials: M
authors.lastname: Herreros-Villanueva
authors.forename: Lizhi
authors.initials: L
authors.lastname: Zhang
authors.forename: Luciana L
authors.initials: LL
authors.lastname: Almada
authors.forename: Fergus
authors.initials: F
authors.lastname: Couch
authors.forename: Cynthia
authors.initials: C
authors.lastname: Wetmore
authors.forename: Marina
authors.initials: M
authors.lastname: Pasca di Magliano
authors.forename: Martin E
authors.initials: ME
authors.lastname: Fernandez-Zapico
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016283:Proto-Oncogene Proteins p21(ras) / Q000096:biosynthesis* / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D059016:Tumor Microenvironment; D000071676:Zinc Finger Protein GLI1
chemical_list: C498520:Gli1 protein, mouse; D053823:Hedgehog Proteins; D015850:Interleukin-6; D051741:Kruppel-Like Transcription Factors; D050796:STAT3 Transcription Factor; C465570:Shh protein, mouse; C494087:Stat3 protein, mouse; D000071676:Zinc Finger Protein GLI1; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)