title: Involvement of Smad3 phosphoisoform-mediated signaling in the development of colonic cancer in IL-10-deficient mice.
abstract: Chronic inflammation predisposes to cancer. Transforming growth factor (TGF)-beta, a multifunctional protein, suppresses the growth of normal colonic epithelial cells, whereas it stimulates the proliferation of cancer cells. Interleukin (IL)-10-deficient mice, which develop colitis and colorectal cancer, show an increased level of plasma TGF-beta. Although TGF-beta may be a key molecule in the development of colon cancer arising from chronic colitis in IL-10-deficient mice, the role of TGF-beta still remains unclear. TGF-beta activates not only TGF-beta type I receptor (TbetaRI) but also c-Jun N-terminal kinase (JNK), which converts the mediator Smad3 into two distinctive phosphoisoforms: C-terminally phosphorylated Smad3 (pSmad3C) and linker-phosphorylated Smad3 (pSmad3L). We studied C57BL/6-IL-10-deficient mice (n=18) at 4 to 32 weeks of age. We investigated histology, and pSmad2/3L, pSmad2/3C, and p53 by immunohistochemistry. pSmad3L staining was detected in the cancer cells in all 10 mice with colonic cancer and in the epithelial cells in 7 of 12 mice with colonic dysplasia, but not in the normal or colitic mice. pSmad3c was detected without any significant difference between stages. p53 was weakly stained in a few cancer cells in 5 out of 10 mice. Smad3L signaling plays an important role in the carcinogenesis of chronic colitis in IL-10-deficient mice.
authors.affiliation: Third Department of Internal Medicine, Kansai Medical University, Moriguchi, Osaka, Japan.
authors.forename: Daisaku
authors.initials: D
authors.lastname: Hachimine
authors.forename: Kazushige
authors.initials: K
authors.lastname: Uchida
authors.forename: Masanori
authors.initials: M
authors.lastname: Asada
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Nishio
authors.forename: Seiji
authors.initials: S
authors.lastname: Kawamata
authors.forename: Go
authors.initials: G
authors.lastname: Sekimoto
authors.forename: Miki
authors.initials: M
authors.lastname: Murata
authors.forename: Hideo
authors.initials: H
authors.lastname: Yamagata
authors.forename: Katsunori
authors.initials: K
authors.lastname: Yoshida
authors.forename: Shigeo
authors.initials: S
authors.lastname: Mori
authors.forename: Yoshiya
authors.initials: Y
authors.lastname: Tahashi
authors.forename: Koichi
authors.initials: K
authors.lastname: Matsuzaki
authors.forename: Kazuichi
authors.initials: K
authors.lastname: Okazaki
mesh_terms: D000818:Animals; D002908:Chronic Disease; D003092:Colitis / Q000378:metabolism*; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000473:pathology; D007124:Immunoenzyme Techniques; D016753:Interleukin-10 / Q000235:genetics; D007420:Intestine, Large / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D051900:Smad3 Protein / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D018125:Receptors, Transforming Growth Factor beta; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D016212:Transforming Growth Factor beta; D016159:Tumor Suppressor Protein p53; D016753:Interleukin-10; D017346:Protein Serine-Threonine Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II