title: Overexpression of IFN-induced protein with tetratricopeptide repeats 3 (IFIT3) in pancreatic cancer: cellular "pseudoinflammation" contributing to an aggressive phenotype.
abstract: Inflammation contributes to important traits that cancer cells acquire during malignant progression. Gene array data recently identified upregulation of interferon-induced protein with tetratricopeptide repeats 3 (IFIT3) in aggressive pancreatic cancer cells. IFIT3 belongs to the group of interferon stimulated genes (ISG), can be induced by several cellular stress stimuli and by its tetratricopeptide repeats interacts with a multitude of cellular proteins. Upregulation of IFIT3 was confirmed in the aggressive pancreatic cancer cell line L3.6pl compared with its less aggressive cell line of origin, COLO357FG. Transgenic induction of IFIT3 expression in COLO357FG resulted in greater mass of orthotopic tumors and higher prevalence of metastases. Several important traits that mediate malignancy were altered by IFIT3: increased VEGF and IL-6 secretion, chemoresistance and decreased starvation-induced apoptosis. IFIT3 showed binding to JNK and STAT1, the latter being an important inducer of IFIT3 expression. Despite still being alterable by "classical" IFN or NFκB signaling, our findings indicate constitutive - possibly auto-regulated - upregulation of IFIT3 in L3.6pl without presence of an adequate inflammatory stimulus. The transcription factor SOX9, which is linked to regulation of hypoxia-related genes, was identified as a key mediator of upregulation of the oncogene IFIT3 and thereby sustaining a "pseudoinflammatory" cellular condition.
authors: Department of Surgery, Medical Center of the Ludwig-Maximilians-University, Campus Grosshadern, Munich, Germany.
authors: Hanno
authors: H
authors: Niess
authors: Department of Surgery, Medical Center of the Otto-von-Guericke-University, Magdeburg, Germany.
authors: Peter
authors: P
authors: Camaj
authors: Department of Surgery, Medical Center of the Ludwig-Maximilians-University, Campus Grosshadern, Munich, Germany.
authors: Ruth
authors: R
authors: Mair
authors: Department of Surgery, Medical Center of the Ludwig-Maximilians-University, Campus Grosshadern, Munich, Germany.
authors: Andrea
authors: A
authors: Renner
authors: Department of Surgery, Medical Center of the Ludwig-Maximilians-University, Campus Grosshadern, Munich, Germany.
authors: Yue
authors: Y
authors: Zhao
authors: Medizinische Klinik und Poliklinik IV, Campus Innenstadt, Klinikum der Universitaet Muenchen, Arbeitsgruppe Klinische Biochemie, Munich, Germany.
authors: Carsten
authors: C
authors: Jäckel
authors: Medizinische Klinik und Poliklinik IV, Campus Innenstadt, Klinikum der Universitaet Muenchen, Arbeitsgruppe Klinische Biochemie, Munich, Germany.
authors: Peter J
authors: PJ
authors: Nelson
authors: Department of Surgery, Medical Center of the Ludwig-Maximilians-University, Campus Grosshadern, Munich, Germany.
authors: Karl-Walter
authors: KW
authors: Jauch
authors: Department of Surgery, Medical Center of the Otto-von-Guericke-University, Magdeburg, Germany.
authors: Christiane J
authors: CJ
authors: Bruns
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism* / Q000556:secondary; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D055758:SOX9 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection; D015854:Up-Regulation
chemical_list: C116468:IFIT3 protein, human; D018836:Inflammation Mediators; D047908:Intracellular Signaling Peptides and Proteins; D055758:SOX9 Transcription Factor; C527932:SOX9 protein, human
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