Oncogenic Smad3 signaling induced by chronic inflammation is an early event in ulcerative colitis-associated carcinogenesis

Seiji Kawamata, Koichi Matsuzaki, Miki Murata, Toshihito Seki, Katsuyoshi Matsuoka, Yasushi Iwao, Toshifumi Hibi, Kazuichi Okazaki

Research output: Contribution to journalArticlepeer-review

32 Citations (Scopus)


Background: Both chronic inflammation and somatic mutations likely contribute to the pathogenesis of ulcerative colitis (UC)-associated dysplasia and cancer. On the other hand, both tumor suppression and oncogenesis can result from transforming growth factor (TGF)-β signaling. TGF-β type I receptor (TβRI) and Ras-associated kinases differentially phosphorylate a mediator, Smad3, to become C-terminally phosphorylated Smad3 (pSmad3C), linker phosphorylated Smad3 (pSmad3L), and both C-terminally and linker phosphorylated Smad3 (pSmad3L/C). The pSmad3C/p21WAF1 pathway transmits a cytostatic TGF-β signal, while pSmad3L and pSmad3L/C promote cell proliferation by upregulating c-Myc oncoprotein. The purpose of this study was to clarify the alteration of Smad3 signaling during UC-associated carcinogenesis. Methods: By immunostaining and immunofluorescence, we compared pSmad3C-, pSmad3L-, and pSmad3L/C-mediated signaling in colorectal specimens representing colitis, dysplasia, or cancer from eight UC patients with signaling in normal colonic crypts. We also investigated p53 expression and mutations of p53 and K-ras genes. We further sought functional meaning of the phosphorylated Smad3-mediated signaling in vitro. Results: As enterocytes in normal crypts migrated upward toward the lumen, cytostatic pSmad3C/p21WAF1 tended to increase, while pSmad3L/c-Myc shown by progenitor cells gradually decreased. Colitis specimens showed prominence of pSmad3L/C/c-Myc, mediated by TGF-β and tumor necrosis factor (TNF)-α, in all enterocyte nuclei throughout entire crypts. In proportion with increases in frequency of p53 and K-ras mutations during progression from dysplasia to cancer, the oncogenic pSmad3L/c-Myc pathway came to be dominant with suppression of the pSmad3C/p21WAF1 pathway. Conclusions: Oncogenic Smad3 signaling, altered by chronic inflammation and eventually somatic mutations, promotes UC-associated neoplastic progression by upregulating growth-related protein. (Inflamm Bowel Dis 2011)

Original languageEnglish
Pages (from-to)683-695
Number of pages13
JournalInflammatory bowel diseases
Issue number3
Publication statusPublished - 2011 Mar
Externally publishedYes


  • Smad
  • TGF-β
  • TNF-α
  • biomarker
  • c-Jun N-terminal kinase

ASJC Scopus subject areas

  • Immunology and Allergy
  • Gastroenterology


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