Tumor necrosis factor α stimulates invasion of Src-activated intestinal cells

Naoki Kawai, Shingo Tsuji, Masahiko Tsujii, Toshifumi Ito, Masakazu Yasumaru, Yoshimi Kakiuchi, Arata Kimura, Masato Komori, Yutaka Sasaki, Norio Hayashi, Sunao Kawano, Raymond Dubois, Masatsugu Hori

Research output: Contribution to journalArticlepeer-review

32 Scopus citations


Background & Aims: Src activation is correlated with progression of colorectal cancer (CRC). CRCs accompanied by ulcerative colitis, chronic inflammation in the colon, often have elevated Src activity, and ulcerative colitis-related CRCs are more likely to become invasive, whereas Ras activation is rarely associated with this disease. The aim of this study was to investigate the effects of a proinflammatory cytokine, tumor necrosis factor α (TNF-α), on the invasive properties of epithelial cells constitutively expressing activated Ras or Src. Methods: A cell line derived from intestinal epithelia was transfected with a v-src- or v-H-ras-expressing vector. The effect of TNF-α on morphologic changes in colonies cultured in soft agar was determined. Src protein kinase activity, peroxide production, E-cadherin expression levels, and the phosphorylation status of β-catenin and E-cadherin were determined. The invasive potential of these cells was determined by measuring cell motility and using an in vitro invasion assay. Results: TNF-α altered the colony morphology of src-, but not ras-expressing cells. TNF-α increased peroxide production, leading to Src protein expression as well as Src activity in src transfectants. Activation of Src by TNF-α led to reduced E-cadherin levels and enhanced invasion of src transfectants. Pyrrolidine dithiocarbamate and herbimycin A inhibited these effects. Conclusion: These results indicate that Src kinase activation enhances the response of epithelial cells to TNF-α leading to increased invasion through mechanisms that involve production of reactive oxygen intermediates.

Original languageEnglish (US)
Pages (from-to)331-339
Number of pages9
Issue number2
StatePublished - 2002
Externally publishedYes

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology


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