Disruption of the mouse protein tyrosine kinase 6 gene prevents STAT3 activation and confers resistance to azoxymethane

Gastroenterology. 2011 Oct;141(4):1371-80, 1380.e1-2. doi: 10.1053/j.gastro.2011.06.071. Epub 2011 Jul 8.

Abstract

Background & aims: Protein tyrosine kinase 6 (PTK6) is expressed throughout the gastrointestinal tract and is a negative regulator of proliferation that promotes differentiation and DNA-damage-induced apoptosis in the small intestine. PTK6 is not expressed in normal mammary gland, but is induced in most human breast tumors. Signal transducer and activator of transcription 3 (STAT3) mediates pathogenesis of colon cancer and is a substrate of PTK6. We investigated the role of PTK6 in colon tumorigenesis.

Methods: Ptk6+/+ and Ptk6-/- mice were injected with azoxymethane alone or in combination with dextran sodium sulfate; formation of aberrant crypt foci and colon tumors was examined. Effects of disruption of Ptk6 on proliferation, apoptosis, and STAT3 activation were examined by immunoblot and immunohistochemical analyses. Regulation of STAT3 activation was examined in the HCT116 colon cancer cell line and young adult mouse colon cells.

Results: Ptk6-/- mice developed fewer azoxymethane-induced aberrant crypt foci and tumors. Induction of PTK6 increased apoptosis, proliferation, and STAT3 activation in Ptk6+/+ mice injected with azoxymethane. Disruption of Ptk6 impaired STAT3 activation following azoxymethane injection, and reduced active STAT3 levels in Ptk6-/- tumors. Stable knockdown of PTK6 reduced basal levels of active STAT3, as well as activation of STAT3 by epidermal growth factor in HCT116 cells. Disruption of Ptk6 reduced activity of STAT3 in young adult mouse colon cells.

Conclusions: PTK6 promotes STAT3 activation in the colon following injection of the carcinogen azoxymethane and regulates STAT3 activity in mouse colon tumors and in the HCT116 and young adult mouse colon cell lines. Disruption of Ptk6 decreases azoxymethane-induced colon tumorigenesis in mice.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aberrant Crypt Foci / enzymology
  • Aberrant Crypt Foci / genetics
  • Aberrant Crypt Foci / pathology
  • Aberrant Crypt Foci / prevention & control*
  • Animals
  • Apoptosis
  • Azoxymethane*
  • Carcinogens*
  • Cell Proliferation
  • Colon / enzymology*
  • Colon / pathology
  • Colonic Neoplasms / chemically induced
  • Colonic Neoplasms / enzymology
  • Colonic Neoplasms / genetics
  • Colonic Neoplasms / pathology
  • Colonic Neoplasms / prevention & control*
  • Dextran Sulfate
  • Disease Models, Animal
  • HCT116 Cells
  • Humans
  • Immunoblotting
  • Immunohistochemistry
  • Mice
  • Mice, Knockout
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism
  • Phosphorylation
  • Protein-Tyrosine Kinases / genetics
  • Protein-Tyrosine Kinases / metabolism
  • RNA Interference
  • STAT3 Transcription Factor / genetics
  • STAT3 Transcription Factor / metabolism*
  • Signal Transduction
  • Time Factors
  • src-Family Kinases / deficiency*
  • src-Family Kinases / genetics

Substances

  • Carcinogens
  • Neoplasm Proteins
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Stat3 protein, mouse
  • Dextran Sulfate
  • Protein-Tyrosine Kinases
  • PTK6 protein, human
  • Ptk6 protein, mouse
  • src-Family Kinases
  • Azoxymethane