Role of CITED2, a novel ulcerative colitis specific gene, to colitis and carcinogenesis.

• Project/Area Number: 21590405
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Human pathology
• Research Institution: Kitasato University
• Principal Investigator: YOSHIDA Tsutomu 北里大学, 医学部, 講師 (90316943)
• Co-Investigator(Renkei-kenkyūsha): OKAYASU Isao 北里大学, 医学部, 教授 (20014342)
• Project Period (FY): 2009 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2011: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2010: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2009: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 潰瘍性大腸炎 / 分子病理 / UC / CITED2 / 炎症

Research Abstract

In ulcerative colitis, Fusobacterium varium is significantly detected in patients' mucosa, and butyric acid, abundantly produced by the bacterium, induces epithelial apoptosis. Here, we identified a gene induced by butyric acid specifically in ulcerative colitis-associated cancer cell lines. cDNA microarray and the validation study revealed CITED2 to be specifically upregulated. CITED2 could be shown to induce p53 acetylation and p53-dependent apoptosis, accompanied by binding of CBP/p300.In inflammatory foci of ulcerative colitis, histologically evident inflammatory activity and CITED2 expression were significantly correlated. On the other hand, we also found olfactomedin 4(OLFM4) induced in the UC-patients' colonic mucosae, and its expression is correlated to the histological activity of UC. In conclusion, CITED2 was identified as ulcerative colitis-associated protein by cDNA microarray based on the Percellome method under UC-mimicking conditions in vitro. CITED2 activation may induce mucosal apoptosis and erosion by activating p53 and thus play a critical role in linking enteric bacteria with mucosal inflammation in ulcerative colitis. Further study of association of CITED2 and OLFM4 is remains to be clarified.

Research Products

• [Journal Article] High expression of L-type amino-acid transporter 1(LAT1) in gastric carcinomas : comparison with non-cancerous lesions (2011)
  • Author(s): Ichinoe, M., Mikami, T., Yoshida, T., Igawa, I., Tsuruta, T., Nakada, N., Anzai, N., Suzuki, Y., Endou, H., Okayasu, I
  • Journal Title: Pathol Int Volume: 61(5) Pages: 281-289
  • NAID: 10031185084
• [Journal Article] Invasive behavior of ulcerative colitis-associated carcinoma is related to reduced expression of CD44 extracellular domain : comparison with sporadic colon carcinoma (2011)
  • Author(s): Mikami, T., Yoshida, T., Numata, Y., Kikuchi, M., Araki, K., Nakada, N., Okayasu, I
  • Journal Title: Diag Pathol Volume: 6 Pages: 30-30
• [Journal Article] CITED2 is activated in ulcerative colitis and induces p53-dependent apoptosis in response to butyric acid (2011)
  • Author(s): Yoshida, T., Sekine, T., Aisaki, K., Mikami, T., Kanno, J., Okayasu I
  • Journal Title: J Gastroenterol Volume: 46(3) Pages: 339-349
  • NAID: 10029027845
• [Journal Article] Cytoglobin expression of rectal subepithelial myofibroblasts : Significant alterations of cytoglobin+stromal cells in long-standing ulcerative colitis (2011)
  • Author(s): Okayasu, I., Mikami, T., Yoshida, T., Hana, K., Yokozawa, M., Sada, M., Fujiwara, M., Kawada, N
  • Journal Title: Hist Histopathol Volume: 26 Pages: 679-688
• [Journal Article] CITED2 is activated in ulcerative colitis and induces p53-dependent apoptosis in response to butyric acid (2011)
  • Author(s): Yoshida, T., et al
  • Journal Title: Journal of Gastroenterology Volume: 46 Issue: 3 Pages: 339-349
  • DOI: 10.1007/s00535-010-0355-9
  • NAID: 10029027845
  • Peer Reviewed
• [Journal Article] High expression of L-type amino-acid transporter 1 (LAT1) in gastric carcinomas : comparison with non-cancerous lesions (2011)
  • Author(s): Ichinoe, M., et al
  • Journal Title: Pathology International Volume: 61 Issue: 5 Pages: 281-289
  • DOI: 10.1111/j.1440-1827.2011.02650.x
  • Peer Reviewed
• [Journal Article] Invasive behavior of ulcerative colitis-associated carcinoma is related to reduced expression of CD44 extracellular domain : comparison with sporadic colon carcinoma (2011)
  • Author(s): Mikami, et al
  • Journal Title: Diag.Pathol Volume: 6 Issue: 1 Pages: 30-38
  • DOI: 10.1186/1746-1596-6-30
  • Peer Reviewed
• [Journal Article] CITED2 is activated in ulcerative colitis and induces p53-dependent apoptosis in responseto butyric acid (2011)
  • Author(s): Yoshida, T., et al.
  • Journal Title: Journal of Gastroenterology Volume: 46(in press)
  • Peer Reviewed
• [Journal Article] Appearance of epithelial and stromal genomic instability in background colorectal mucosa of sporadic colorectal cancer patients. relation to age and gender (2009)
  • Author(s): Umeto, H., Yoshida, T., Araki, K., Yagishita, H., Mikami, T., Okayasu, I
  • Journal Title: J Gastroenterol Volume: 44(10) Pages: 1036-1045
  • NAID: 10025581826
• [Journal Article] Mucosal remodeling in long-standing ulcerative colitis with colorectal neoplasia : Significant alterations of NCAM plus or alpha-SMA plus subepithelial myofibroblasts and interstitial cells (2009)
  • Author(s): Okayasu I, Yoshida, T., Mikami, T., Hana, K., Yokozawa, M., Araki, K., Mitsuhashi, J., Kikuchi, M., Adachi, E., Sada, M
  • Journal Title: Pathol Int Volume: 59(10) Pages: 701-711
• [Journal Article] Commensal bacteria can enter colonic epithelial cells and induce proinflammatory cytokine secretion : a possible pathogenic mechanism of ulcerative colitis (2009)
  • Author(s): Ohkusa, T., Yoshida, T., Sato, N., Watanabe, S., Tajiri, H., Okayasu, I
  • Journal Title: J Med Microbiol Volume: 58(5) Pages: 535-545
• [Journal Article] Appearance of epithelial and stromal genomic instability in background colorectal mucosa of sporadic colorectal cancer patients-relation to age and gender. (2009)
  • Author(s): Umeto, H., Yoshida, T., et al.
  • Journal Title: Journal of Gastroenterology 44 Pages: 1036-1045
  • NAID: 10025581826
  • Peer Reviewed
• [Journal Article] Mucosal remodeling in long-standing ulcerative colitis with colorectal neoplasia : Significant alterations of NCAM plus or alpha-SMA plus subepithelial myofibroblasts (2009)
  • Author(s): Okayasu, I., Yoshida, T., et al.
  • Journal Title: Pathology International 59 Pages: 707-711
  • Peer Reviewed
• [Journal Article] Commensal bacteria can enter colonic epithelial cells and induce proinflammatory cytokine secretion : a possible pathogenic mechanism of ulcerative colitis. (2009)
  • Author(s): Ohkusa, T., Yoshida, T., et al
  • Journal Title: Journal of Medical Microbiology 58 Pages: 535-545
  • Peer Reviewed
• [Presentation] 潰瘍性大腸炎炎症関連蛋白質OLFM4の炎症における役割 (2011)
  • Author(s): 吉田功, 他
  • Organizer: 第99回日本病理学会総会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2011-04-30
• [Presentation] 潰瘍性大腸炎炎症関連蛋白質OLFM4の炎症における役割 (2010)
  • Author(s): 吉田功、三上哲夫、沼田賀子、三枝信、岡安勲
  • Organizer: 第100回日本病理学会総会
  • Place of Presentation: 横浜
  • Year and Date: 2010-04-30
• [Presentation] 網羅的解析によって得られたolfactomedin4の潰瘍性大腸炎及び関連腫瘍における役割 (2010)
  • Author(s): 吉田功、宮前結加、沼田賀子、鶴田智子、三上哲夫、岡安勲
  • Organizer: 第99回日本病理学会総会
  • Place of Presentation: 東京
  • Year and Date: 2010-04-27
• [Presentation] 網羅的解析によって得られたolfactomedin4の潰瘍性大腸炎及び関連腫瘍における役割 (2010)
  • Author(s): 吉田功, 他
  • Organizer: 第99回日本病理学会総会
  • Place of Presentation: 東京都京王プラザホテル
  • Year and Date: 2010-04-27
• [Presentation] Significance of gene expression and localization in active and inactive ulcerative colitis by comprehensive analysis (2009)
  • Author(s): 宮前結加、吉田功、岡安勲
  • Organizer: 第68回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2009-10-03
• [Presentation] 潰瘍性大腸炎発症におけるCITED2-p53系の役割-腸内細菌による新規粘膜上皮細胞死誘導系の可能性 (2009)
  • Author(s): 吉田功、関根司、相崎健一、宮前結加、沼田賀子、三上哲夫、菅野純、岡安勲
  • Organizer: 第98回日本病理学会総会
  • Place of Presentation: 京都
  • Year and Date: 2009-05-02
• [Presentation] 大腸腸内細菌による粘膜上皮性サイトカイン誘導-潰瘍性大腸炎・炎症機序との関連 (2009)
  • Author(s): 丸善明、吉田功、田原あづさ、梅沢敦子、大草敏史、岡安勲
  • Organizer: 第98回日本病理学会総会
  • Place of Presentation: 京都
  • Year and Date: 2009-05-02
• [Presentation] 大腸癌におけるL型アミノ酸トランスポーター発現亢進の証明 (2009)
  • Author(s): 竹之内一政、吉田功、遠藤仁、岡安勲
  • Organizer: 第98回日本病理学会総会
  • Place of Presentation: 京都
  • Year and Date: 2009-05-02
• [Presentation] 潰瘍性大腸炎発症におけるCITED2-p53系の役割-腸内細菌による新規粘膜上皮細胞死誘導系の可能性. (2009)
  • Author(s): 吉田功, 他
  • Organizer: 第98回日本病理学会総会
  • Place of Presentation: 京都国際会館
  • Year and Date: 2009-05-02
• [Book] Mucosal Remodeling and Alteration of Stromal Microenvironment in Ulcerative Colitis as Related to Colorectal Tumorigenesis (2011)
  • Author(s): Isao Okayasu, Tsutomu Yoshida, Tetuo Mikami, Jun Mitsuhashi, Masaaki Ichinoe, Nobuyuki Yanagisawa, Wataru Tokuyama, Kiyomi Hana and Yuichi Ishibashi
  • Publisher: In-Tech
• [Book] Mucosal Remodeling and Alteration of Stromal Microenvironment in Ulcerative Colitis as Related to Colorectal Tumorigenesis(p242-245)(Mortimer B.O'Connor eds.)(In Ulcerative Colitis-Epidemiology, Pathogenesis and Complications) (2011)
  • Author(s): Okayasu, I., et al
  • Total Pages: 280
  • Publisher: In-Tech, Rijeka