Signaling pathway via TNF-α/NF-κB in intestinal epithelial cells may be directly involved in colitis-associated carcinogenesis

Michio Onizawa, Takashi Nagaishi, Takanori Kanai, Ken Ichi Nagano, Shigeru Oshima, Yasuhiro Nemoto, Atsushi Yoshioka, Teruji Totsuka, Ryuichi Okamoto, Tetsuya Nakamura, Naoya Sakamoto, Kiichiro Tsuchiya, Kazuhiro Aoki, Keiichi Ohya, Hideo Yagita, Mamoru Watanabe

Research output: Contribution to journalArticle

104 Citations (Scopus)

Abstract

Treatment with anti-TNF-α MAb has been accepted as a successful maintenance therapy for patients with inflammatory bowel diseases (IBD). Moreover, it has been recently reported that blockade of TNF receptor (TNFR) 1 signaling in infiltrating hematopoietic cells may prevent the development of colitis-associated cancer (CAC). However, it remains unclear whether the TNF-α signaling in epithelial cells is involved in the development of CAC. To investigate this, we studied the effects of anti-TNF-α MAb in an animal model of CAC by administration of azoxymethane (AOM) followed by sequential dextran sodium sulfate (DSS) ingestion. We observed that the NF-κB pathway is activated in colonic epithelia from DSS-administered mice in association with upregulation of TNFR2 rather than TNFR1. Immunoblot analysis also revealed that the TNFR2 upregulation accompanied by the NF-κB activation is further complicated in CAC tissues induced in AOM/DSS-administered mice compared with the nontumor area. Such NF-κB activity in the epithelial cells is significantly suppressed by the treatment of MP6-XT22, an anti-TNF-α MAb. Despite inability to reduce the severity of colitis, sequential administration of MP6-XT22 reduced the numbers and size of tumors in association with the NF-κB inactivation. Taken together, present studies suggest that the TNFR2 signaling in intestinal epithelial cells may be directly involved in the development of CAC with persistent colitis and imply that the maintenance therapy with anti-TNF-α MAb may prevent the development of CAC in patients with long-standing IBD.

Original languageEnglish
Pages (from-to)G850-G859
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume296
Issue number4
DOIs
Publication statusPublished - 2009 Apr

Keywords

  • Carcinogenesis
  • Colitis-associated cancer
  • Intestinal epithelial cells
  • TNFR2
  • Tumor necrosis factor-α

ASJC Scopus subject areas

  • Physiology
  • Hepatology
  • Gastroenterology
  • Physiology (medical)

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