Integrin-beta 6 is required for TGF-beta-mediated EMT and promotes the disease progression of intrahepatic cholangiocellular carcinoma

• Project/Area Number: 26861088
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Digestive surgery
• Research Institution: Kumamoto University
• Principal Investigator: HAYASHI Hiromitsu 熊本大学, 医学部附属病院, 非常勤診療医師 (80625773)
• Research Collaborator: HIGASHI Takaaki 熊本大学, 大学院生命科学研究部, 大学院生 ; KUROKI Hideyuki 熊本大学, 医学部附属病院, 非常勤診療医師 ; BEPPU toru 熊本大学, 医学部附属病院, 特任助教
• Project Period (FY): 2014-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2015: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2014: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 肝内胆管癌 / 上皮間葉転換 / Integrin-β6 / 癌細胞浸潤 / 癌細胞増殖 / TGF-β-Smadシグナル / EMT / cholangiocarcinoma / TGF-β

Outline of Final Research Achievements

ICC is characterized as a poor prognostic disease represented by the highly invasiveness. EMT plays a pivotal role in cancer invasion and metastasis, and then TGF-β signaling is a potent inducible factor of EMT. Integrin-β6, which is an epithelial restricted trans-membrane protein, promotes binding to extracellular matrix proteins. In this study, we investigated the role of integrin-β6 during TGF-β-mediated EMT using ICC cell lines, and examined the clinic-pathological significance of Integrinβ6 expression in ICC patients.
Addition of TGF-β to ICC cells successfully induced EMT, spindle-shaped morphology, and high invasiveness, with the integrin-β6 induction. The inhibition of integrin-β6 expression using RNAi abolished TGF-β-mediated EMT induction. In clinical setting, high integrin-β6 expression was significantly associated with Stage IV, lymph node metastasis, and then resulted in worse prognosis compared with low expression group.

Research Products

• [Journal Article] Functional assessment versus conventional volumetric assessment in the prediction of operative outcomes after major hepatectomy. (2015)
  • Author(s): Hayashi H, Beppu T, Okabe H, Kuroki H, Nakagawa S, Imai K, Nitta H, Chikamoto A, Ishiko T, Baba H
  • Journal Title: Surgery Volume: 157(1) Pages: 20-6
  • DOI: 10.1016/j.surg.2014.06.013
  • Peer Reviewed
• [Journal Article] Tumor Shrinkage in Response to Vitamin K2 in Hepatocellular Carcinoma with Multiple Lung Metastases: A Case Report (2014)
  • Author(s): Hayashi H, Higashi T, Takeyama H, Sakamoto K, Kuroki H, Nitta H, Hashimoto D, Chikamoto A, Beppu T, Baba H
  • Journal Title: AJCC Rep Volume: 2(2) Pages: 20140548-554
  • Peer Reviewed
• [Presentation] TSP-1 を介したTGF－β活性化機構抑制による肝切除術後の肝再生促進療法 (2015)
  • Author(s): 黒木秀幸、林洋光、中川茂樹、東孝暁、橋本大輔、新田英利、近本亮、石河隆敏、別府透、馬場秀夫
  • Organizer: 第27回日本肝胆膵外科学会・学術集会
  • Place of Presentation: ホテルグランパシフィック LE DAIBA（東京都）
  • Year and Date: 2015-06-12
• [Presentation] スタチン内服による肝細胞癌に対する肝切除後再発抑制効果に関する検討 (2015)
  • Author(s): 東 孝暁、林洋光、武山秀晶、有馬浩太、甲斐田剛圭、高城克暢、坂本慶太、坂田和也、岡部弘尚、新田英利、橋本大輔、近本亮、別府透、馬場秀夫
  • Organizer: 第115回日本外科学会定期学術集会
  • Place of Presentation: 名古屋国際会議場（愛知県）
  • Year and Date: 2015-04-18
• [Presentation] Integrin-β6 is correlated with transforming growth factor (TGF)-β-mediated epithelial-mesenchymal transition (EMT) and promotes the disease (2014)
  • Author(s): Higashi T
  • Organizer: AACR Annual Meeting 2014
  • Place of Presentation: San Diego, California
  • Year and Date: 2014-04-05 – 2014-04-09
• [Presentation] Integrin beta6 はTGFbeta による上皮間葉転換を促進し肝内胆管癌の進展に関与する (2014)
  • Author(s): 東 孝暁
  • Organizer: 第114回日本外科学会定期学術集会
  • Place of Presentation: 京都
  • Year and Date: 2014-04-03 – 2014-04-05