title: Partial inhibition of gp130-Jak-Stat3 signaling prevents Wnt-β-catenin-mediated intestinal tumor growth and regeneration.
abstract: Most colon cancers arise from somatic mutations in the tumor suppressor gene APC (adenomatous polyposis coli), and these mutations cause constitutive activation of the Wnt-to-β-catenin pathway in the intestinal epithelium. Because Wnt-β-catenin signaling is required for homeostasis and regeneration of the adult intestinal epithelium, therapeutic targeting of this pathway is challenging. We found that genetic activation of the cytokine-stimulated pathway mediated by the receptor gp130, the associated Jak (Janus kinase) kinases, and the transcription factor Stat3 (signal transducer and activator of transcription 3) was required for intestinal regeneration in response to irradiation-induced damage in wild-type mice and for tumorigenesis in Apc-mutant mice. Systemic pharmacological or partial genetic inhibition of gp130-Jak-Stat3 signaling suppressed intestinal regeneration, the growth of tumors in Apc-mutant mice, and the growth of colon cancer xenografts. The growth of Apc-mutant tumors depended on gp130-Jak-Stat3 signaling for induction of the polycomb repressor Bmi-1, and the associated repression of genes encoding the cell cycle inhibitors p16 and p21. However, suppression of gp130-Jak-Stat3 signaling did not affect Wnt-β-catenin signaling or homeostasis in the intestine. Thus, these data not only suggest a molecular mechanism for how the gp130-Jak-Stat3 pathway can promote cancer but also provide a rationale for therapeutic inhibition of Jak in colon cancer.
authors.affiliation: Ludwig Institute for Cancer Research, Melbourne, Victoria 3052, Australia. Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria 3052, Australia. Department of Medical Biology, University of Melbourne, Melbourne, Victoria 3052, Australia.
authors.forename: Toby J
authors.initials: TJ
authors.lastname: Phesse
authors.affiliation: Ludwig Institute for Cancer Research, Melbourne, Victoria 3052, Australia. Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria 3052, Australia. Department of Medical Biology, University of Melbourne, Melbourne, Victoria 3052, Australia.
authors.forename: Michael
authors.initials: M
authors.lastname: Buchert
authors.affiliation: Ludwig Institute for Cancer Research, Melbourne, Victoria 3052, Australia. Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria 3052, Australia. Department of Medical Biology, University of Melbourne, Melbourne, Victoria 3052, Australia.
authors.forename: Emma
authors.initials: E
authors.lastname: Stuart
authors.affiliation: Department of Anatomy and Cell Biology, University of Melbourne, Melbourne, Victoria 3052, Australia. Victorian Infectious Diseases Reference Laboratories, North Melbourne, Victoria 3051, Australia. School of Biomedical Sciences, Curtin University, Perth, Western Australia 6845, Australia.
authors.forename: Dustin J
authors.initials: DJ
authors.lastname: Flanagan
authors.affiliation: Ludwig Institute for Cancer Research, Melbourne, Victoria 3052, Australia. Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria 3052, Australia. Department of Medical Biology, University of Melbourne, Melbourne, Victoria 3052, Australia.
authors.forename: Maree
authors.initials: M
authors.lastname: Faux
authors.affiliation: Ludwig Institute for Cancer Research, Melbourne, Victoria 3052, Australia. Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria 3052, Australia. Department of Medical Biology, University of Melbourne, Melbourne, Victoria 3052, Australia.
authors.forename: Shoukat
authors.initials: S
authors.lastname: Afshar-Sterle
authors.affiliation: Ludwig Institute for Cancer Research, Melbourne, Victoria 3052, Australia. Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria 3052, Australia. Department of Medical Biology, University of Melbourne, Melbourne, Victoria 3052, Australia.
authors.forename: Francesca
authors.initials: F
authors.lastname: Walker
authors.affiliation: Ludwig Institute for Cancer Research, Melbourne, Victoria 3052, Australia. Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria 3052, Australia. Department of Medical Biology, University of Melbourne, Melbourne, Victoria 3052, Australia.
authors.forename: Hui-Hua
authors.initials: HH
authors.lastname: Zhang
authors.affiliation: Ludwig Institute for Cancer Research, Melbourne, Victoria 3052, Australia. Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria 3052, Australia. Department of Medical Biology, University of Melbourne, Melbourne, Victoria 3052, Australia.
authors.forename: Cameron J
authors.initials: CJ
authors.lastname: Nowell
authors.affiliation: Ludwig Institute for Cancer Research, Melbourne, Victoria 3052, Australia. Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria 3052, Australia. Department of Medical Biology, University of Melbourne, Melbourne, Victoria 3052, Australia.
authors.forename: Robert
authors.initials: R
authors.lastname: Jorissen
authors.affiliation: Ludwig Institute for Cancer Research, Melbourne, Victoria 3052, Australia. Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria 3052, Australia. Department of Medical Biology, University of Melbourne, Melbourne, Victoria 3052, Australia.
authors.forename: Chin Wee
authors.initials: CW
authors.lastname: Tan
authors.affiliation: Ludwig Institute for Cancer Research, Melbourne, Victoria 3052, Australia. Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria 3052, Australia. Department of Medical Biology, University of Melbourne, Melbourne, Victoria 3052, Australia.
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Hirokawa
authors.affiliation: Ludwig Institute for Cancer Research, Melbourne, Victoria 3052, Australia. Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria 3052, Australia. Department of Medical Biology, University of Melbourne, Melbourne, Victoria 3052, Australia.
authors.forename: Moritz F
authors.initials: MF
authors.lastname: Eissmann
authors.affiliation: Ludwig Institute for Cancer Research, Melbourne, Victoria 3052, Australia. Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria 3052, Australia. Department of Medical Biology, University of Melbourne, Melbourne, Victoria 3052, Australia.
authors.forename: Ashleigh R
authors.initials: AR
authors.lastname: Poh
authors.affiliation: Peter MacCallum Cancer Centre, Melbourne, Victoria 3002, Australia. Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Melbourne, Victoria 3052, Australia.
authors.forename: Jordane
authors.initials: J
authors.lastname: Malaterre
authors.affiliation: Peter MacCallum Cancer Centre, Melbourne, Victoria 3002, Australia. Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Melbourne, Victoria 3052, Australia.
authors.forename: Helen B
authors.initials: HB
authors.lastname: Pearson
authors.affiliation: Departments of Radiation Oncology, Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: David G
authors.initials: DG
authors.lastname: Kirsch
authors.affiliation: Department of Genetics, Biology and Biochemistry, University of Turin, 10126 Torino, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Provero
authors.affiliation: Department of Genetics, Biology and Biochemistry, University of Turin, 10126 Torino, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Poli
authors.affiliation: Peter MacCallum Cancer Centre, Melbourne, Victoria 3002, Australia. Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Melbourne, Victoria 3052, Australia.
authors.forename: Robert G
authors.initials: RG
authors.lastname: Ramsay
authors.affiliation: Ludwig Institute for Cancer Research, Melbourne, Victoria 3052, Australia. Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria 3052, Australia. Department of Medical Biology, University of Melbourne, Melbourne, Victoria 3052, Australia.
authors.forename: Oliver
authors.initials: O
authors.lastname: Sieber
authors.affiliation: Ludwig Institute for Cancer Research, Melbourne, Victoria 3052, Australia. Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria 3052, Australia. Department of Medical Biology, University of Melbourne, Melbourne, Victoria 3052, Australia.
authors.forename: Antony W
authors.initials: AW
authors.lastname: Burgess
authors.affiliation: Oncology iMED, AstraZeneca, Waltham, MA 02451, USA.
authors.forename: Dennis
authors.initials: D
authors.lastname: Huszar
authors.affiliation: Department of Anatomy and Cell Biology, University of Melbourne, Melbourne, Victoria 3052, Australia. Victorian Infectious Diseases Reference Laboratories, North Melbourne, Victoria 3051, Australia. School of Biomedical Sciences, Curtin University, Perth, Western Australia 6845, Australia.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Vincan
authors.affiliation: Ludwig Institute for Cancer Research, Melbourne, Victoria 3052, Australia. Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria 3052, Australia. Department of Medical Biology, University of Melbourne, Melbourne, Victoria 3052, Australia. matthias.ernst@wehi.edu.au.
authors.forename: Matthias
authors.initials: M
authors.lastname: Ernst
mesh_terms: D000818:Animals; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism*; D050822:Cytokine Receptor gp130 / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics / Q000502:physiology*; D017491:Genes, APC / Q000502:physiology*; D006652:Histological Techniques; D007150:Immunohistochemistry; D007413:Intestinal Mucosa / Q000502:physiology*; D053613:Janus Kinase 1 / Q000378:metabolism; D008156:Luciferases; D051379:Mice; D008807:Mice, Inbred BALB C; D008856:Microscopy, Fluorescence; D063150:Polycomb Repressive Complex 1 / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D012038:Regeneration / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000235:genetics / Q000502:physiology*; D051176:beta Catenin / Q000378:metabolism*
chemical_list: C489421:Bmi1 protein, mouse; D017931:DNA Primers; C494200:Il6st protein, mouse; D011518:Proto-Oncogene Proteins; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D051176:beta Catenin; D050822:Cytokine Receptor gp130; D008156:Luciferases; D063150:Polycomb Repressive Complex 1; C507905:Jak1 protein, mouse; D053613:Janus Kinase 1