大膓がん細胞の悪性形質化を制御する新しい機能性RNAの解明

• Project/Area Number: 18689018
• Research Category: Grant-in-Aid for Young Scientists (A)
• Allocation Type: Single-year Grants
• Research Field: Gastroenterology
• Research Institution: The University of Tokushima
• Principal Investigator: 近藤 茂忠 The University of Tokushima, 大学院・ヘルスバイオサイエンス研究部, 助教 (40304513)
• Project Period (FY): 2006 – 2007
• Project Status: Completed (Fiscal Year 2007)
• Budget Amount: ¥21,320,000 (Direct Cost: ¥16,400,000、Indirect Cost: ¥4,920,000); Fiscal Year 2007: ¥7,930,000 (Direct Cost: ¥6,100,000、Indirect Cost: ¥1,830,000); Fiscal Year 2006: ¥13,390,000 (Direct Cost: ¥10,300,000、Indirect Cost: ¥3,090,000)
• Keywords: VEGF / ノンコーディングRNA / 腫瘍抑制遺伝子p53 / 大腸癌 / RNAサイレンシング / 小分子RNA / 機能性RNA

Research Abstract

本研究では、VEGF遺伝子に内蔵された新規機能性RNAを新たに見出し、このRNAによる「p53腫瘍抑制経路」抑制の分子機構を解明することを目的とし、以下の研究成果を得た。
(1)VEGFmRNA5'UTRの600番目から879番目の塩基から成る、280塩基長の小分子RNAが、ヒトがん細胞株特異的に発現していることを明らかにした。
(2)この小分子RNAは正常型p53をもつがん細胞で高発現していた。
(3)VEGF小分子RNAとp53mRNAは、無細胞実験系でヘテロ二量対を形成できること、さらに細胞内においても複合体を形成していることを明らかにした。
(4)VEGF小分子RNAによるp53mRNAの分解誘導には、processing bodyの形成が必要であることを明らかにした。
(5)VEGF小分子RNAによるp53mRNAの抑制には、microRNA経路は関与しないことを明らかにした。
以上の結果から、mRNA遺伝子には新規の機能性RNAが内蔵されており、がん細胞の悪性形質化に重要な役割を果たしていることが明らかとなった。

Research Products

• [Journal Article] Evidence for cancer-associated expression of NADPH oxidase 1(Noxl)-basedoxidase system in the human stomach. (2007)
  • Author(s): Tominaga K.
  • Journal Title: Free Radic Biol Med. 43 Pages: 1627-1638
  • Peer Reviewed
• [Journal Article] Physical Exercise-Associated Gene Expression Signatures in Peripheral Blood. (2007)
  • Author(s): Kawai T.
  • Journal Title: Clin J Sport Med. 17 Pages: 375-383
  • Peer Reviewed
• [Journal Article] NADPH oxidases in the gastrointestinal tract : a potential role of noxl in innate immune response and carcinogenesis. (2006)
  • Author(s): Rokutan K.
  • Journal Title: Antioxid Redox Signal. 8・9-10 Pages: 1573-1582
• [Journal Article] IRES-dependent regulation of FGF-2 mRNA translation in pathophysiological conditions in the mouse. (2006)
  • Author(s): Gonzalez-Herrera, IG.
  • Journal Title: Biochem Soc Trans. 34・1 Pages: 17-21
• [Journal Article] A role of the adrenal gland in stress-induced up-regulation of cytokines in plasma. (2006)
  • Author(s): Sekiyama A.
  • Journal Title: J Neuroimmunol. 171(1-2) Pages: 38-44
• [Journal Article] Interferon-gamma activates transcription of NADPH oxidase 1 gene and up-regulates production of superoxide anion by human large intestinal epithelial cells. (2006)
  • Author(s): Kuwano, Y.
  • Journal Title: Am. J. Physiol. Cell Physiol. 290(2)
• [Journal Article] A novel tumor-promoting function residing in the 5'non-coding region ofvascular endothelial growth factor mRNA
  • Author(s): Masuda, K.
  • Journal Title: PLoS Medicine (印刷中)
  • Peer Reviewed
• [Presentation] VEGF mRNA 5'非翻訳領域による大腸がん細胞の悪性形質化の誘導 (2008)
  • Author(s): 増田清士
  • Organizer: 第4回日本消化管学会総会
  • Place of Presentation: 大阪
  • Year and Date: 2008-02-07
• [Presentation] 新機能性RNA分子による大腸がん細胞の悪性形質化の誘導 (2007)
  • Author(s): 増田清士
  • Organizer: 第30回日本分子生物学会
  • Place of Presentation: 横浜
  • Year and Date: 2007-12-14
• [Presentation] Cloning of small RNAs that are overlap with 5' terminus of IRES containinggenes. (2007)
  • Author(s): Gunawardane, L.S.
  • Organizer: 第三回COE国際シンポジウム
  • Place of Presentation: 東京
  • Year and Date: 2007-12-03
• [Presentation] THF-a Is a Potent Activator for the Noxl-Based Oxidase System in Large Intestianl Epithelial Cells. (2007)
  • Author(s): Rokutan K,
  • Organizer: Digestive Disease Week 2007
  • Place of Presentation: Washington,D.C.
  • Year and Date: 2007-05-23
• [Presentation] Potential roles of the Nox family in intestinal inflammation in symposium on intestinal inflammation (2007)
  • Author(s): Rokutan K,
  • Organizer: Digestive Disease Week 2007
  • Place of Presentation: Washington,D.C.
  • Year and Date: 2007-05-23
• [Presentation] Novel Function of Stress-Inducible Tra2 Beta mRNA Isoform Including EXON2. (2007)
  • Author(s): Kawai, T
  • Organizer: Digestive Disease Week 2007
  • Place of Presentation: Washington,D.C.
  • Year and Date: 2007-05-22
• [Presentation] 5'-untranslated RNA of the human VEGF transcript is a novel regulatory RNAthat promotes tumor malignancy of human colon cancer cells (2007)
  • Author(s): Masuda, K.
  • Organizer: Digestive Disease Week 2007
  • Place of Presentation: Washington,D.C.
  • Year and Date: 2007-05-21
• [Presentation] IL-18 Regulates Both Constitutive and Stress-Induced Expression of MUC2 Genein the Mouse Colon. (2007)
  • Author(s): Nishida, K.
  • Organizer: Digestive Disease Week 2007
  • Place of Presentation: Washington,D.C.
  • Year and Date: 2007-05-20
• [Patent(Industrial Property Rights)] 特許権 (2007)
  • Inventor(s): 近藤 茂忠
  • Industrial Property Rights Holder: 徳島大学
  • Filing Date: 2007-09-07