Biological significance of crosstalk between TGF-beta and Hippo pathway in HCC progression

• Project/Area Number: 25462098
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Digestive surgery
• Research Institution: Kumamoto University
• Principal Investigator: KURAMOTO Kunitaka 熊本大学, 医学部附属病院, 非常勤診療医師 (10646441)
• Co-Investigator(Kenkyū-buntansha): IMAI Katsunori 熊本大学, 医学部附属病院, 助教 (60555746) ; BEPPU Toru 熊本大学, 医学部附属病院, 特任教授 (70301372) ; HASHIMOTO Daisuke 熊本大学, 医学部附属病院, 助教 (80508507) ; HAYASHI Hiromitsu 熊本大学, 医学部附属病院, 非常勤診療医師 (80625773)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2013: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: TAZ / YAP / Chemoresistance / TGF-β / 肝細胞癌 / Hippo-pathway / 浸潤・転移 / TGF-beta

Outline of Final Research Achievements

TAZ expression was associated with worse prognostic outcomes in patients after hepatectomy for hepatocellular carcinoma. TAZ inhibition reduced cell growth and phosphorylation of Akt. Overexpression of TAZ increased phosphorylation of Akt. Under the treatment with 5-FU, TAZ inhibition enhanced chemoresistance accompanying with YAP expression. Double knockdown of TAZ/YAP diminished the enhanced chemoresistance. Thus, dual targeting of TAZ/YAP is required for effective anti-cancer strategy in HCC. On the other hand, the downregulation or overexpression of TAZ did not show any significant changes in TGF-β-Smad signal. The crosstalk between Hippo-pathway and TGF-β-Smad signal may not be in HCC.

Research Products

• [Journal Article] An Imbalance in TAZ and YAP Expression in Hepatocellular Carcinoma Confers Cancer Stem Cell-like Behaviors Contributing to Disease Progression. (2015)
  • Author(s): Hayashi H, Higashi T, Yokoyama N, Kaida T, Sakamoto K, Fukushima Y, Ishimoto T, Kuroki H, Nitta H, Hashimoto D, Chikamoto A, Oki E, Beppu T, Baba H.
  • Journal Title: Cancer Res. Volume: 75(22) Issue: 22 Pages: 4985-97
  • DOI: 10.1158/0008-5472.can-15-0291
  • Peer Reviewed / Open Access
• [Journal Article] miR-9-3p plays a tumour-suppressor role by targeting TAZ (WWTR1) in hepatocellular carcinoma cells. (2015)
  • Author(s): Higashi, T., Hayashi, H., Ishimoto, T., Takeyama, H., Kaida, T., Arima, K., Taki, K., Sakamoto, K., Kuroki, H., Okabe, H., Nitta, H., Hashimoto, D., Chikamoto, A., Beppu, T., Baba, H.
  • Journal Title: Br J Cancer Volume: 14;113(2) Issue: 2 Pages: 252-8
  • DOI: 10.1038/bjc.2015.170
  • Peer Reviewed
• [Presentation] TAZ (WWTR1), a key transcription co-activator of hippo-pathway, promotes hepatocellular carcinoma progression via PI3K/Akt/mTOR pathway (2014)
  • Author(s): Hiromitsu Hayashi, Hideyuki Kuroki, Shigeki Nakagawa, Takaaki Higashi, Keita Sakamoto, Naomi Yokoyama, Takatoshi Ishiko, Toru Beppu, Hideo Baba.
  • Organizer: AACR 2014
  • Place of Presentation: San Diego