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 journalArticle

25 Citations (Scopus)

Abstract

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
Volume17
Issue number3
DOIs
Publication statusPublished - 2011 Mar

Fingerprint

Transforming Growth Factors
Ulcerative Colitis
Carcinogenesis
Inflammation
Mutation
Enterocytes
Cytostatic Agents
Colitis
Neoplasms
ras Genes
Growth Factor Receptors
Oncogene Proteins
Fluorescent Antibody Technique
Phosphotransferases
Stem Cells
Tumor Necrosis Factor-alpha
Cell Proliferation
Growth
Proteins

Keywords

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

ASJC Scopus subject areas

  • Gastroenterology
  • Immunology and Allergy

Cite this

Oncogenic Smad3 signaling induced by chronic inflammation is an early event in ulcerative colitis-associated carcinogenesis. / Kawamata, Seiji; Matsuzaki, Koichi; Murata, Miki; Seki, Toshihito; Matsuoka, Katsuyoshi; Iwao, Yasushi; Hibi, Toshifumi; Okazaki, Kazuichi.

In: Inflammatory Bowel Diseases, Vol. 17, No. 3, 03.2011, p. 683-695.

Research output: Contribution to journalArticle

Kawamata, Seiji ; Matsuzaki, Koichi ; Murata, Miki ; Seki, Toshihito ; Matsuoka, Katsuyoshi ; Iwao, Yasushi ; Hibi, Toshifumi ; Okazaki, Kazuichi. / Oncogenic Smad3 signaling induced by chronic inflammation is an early event in ulcerative colitis-associated carcinogenesis. In: Inflammatory Bowel Diseases. 2011 ; Vol. 17, No. 3. pp. 683-695.
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AU - Matsuoka, Katsuyoshi

AU - Iwao, Yasushi

AU - Hibi, Toshifumi

AU - Okazaki, Kazuichi

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N2 - 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)

AB - 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)

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