Significance of connective tissue growth factor (CTGF) and tumor-stroma interaction in Kras-driven hepatocarcinogenesis and HCC progression

• Project/Area Number: 26670381
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Gastroenterology
• Research Institution: Osaka University
• Principal Investigator: Takehara Tetsuo 大阪大学, 医学(系)研究科(研究院), 教授 (70335355)
• Co-Investigator(Kenkyū-buntansha): Hikita Hayato 大阪大学, 大学院医学系研究科, 助教 (20623044) ; 巽 智秀 大阪大学, 医学(系)研究科(研究院), 講師 (20397699)
• Co-Investigator(Renkei-kenkyūsha): Makino Yuki 大阪大学, 大学院医学系研究科, 医員 (60771334)
• Project Period (FY): 2014-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2015: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2014: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: Kras / CTGF / 発癌 / 肝発癌

Outline of Final Research Achievements

Connective tissue growth factor (CTGF) was found to be up-regulated in tumor area in a Kras-mutated HCC mouse model by the activation of Ras/Mek/Erk pathway. Hepatocyte-specific knockout of CTGF in this mouse model revealed significant decrease of tumor diameter, number, and liver/body weight ratio and better tumor differentiation degrees. In surgically resected human HCC, CTGF was up-regulated in tumor area in the same way as Kras-mutated HCC mouse model and CTGF expression levels were shown to be associated with the malignant grade of HCC. Although forced expression of CTGF in HCC cell lines did not affect the in vitro cell viability or tumor volume of xenograft models, they significantly increased in CTGF-overexpressing HCC cell lines in the coexistence of hepatic stellate cells. From these results, CTGF was proven to be the molecule that promotes HCC progression via tumor-stroma interaction between HCC cells and hepatic stellate cells.

Research Products

• [Presentation] Significance of the up-regulation of connective tissue growth factor in hepatocellular carcinoma (2016)
  • Author(s): Yuki Makino, Hayato Hikita, Takahiro Kodama, Minoru Shigekawa, Tasuku Nakabori, Yoshinobu Saito, Satoshi Tanaka, Ryotaro Sakamori, Tomohide Tatsumi, and Tetsuo Takehara
  • Organizer: The 25th Conference of the Asian Pacific Association for the Study of the Liver
  • Place of Presentation: Tokyo, Japan
  • Year and Date: 2016-02-20
  • Int'l Joint Research
• [Presentation] Significance of connective tissue growth factor in hepatocellular carcinoma and its potential for therapeutic target (2015)
  • Author(s): Yuki Makino, Hayato Hikita, Tsukasa Kawaguchi, Takahiro Kodama, Minoru Shigekawa, Yugo Kai, Yasutoshi Nozaki, Tasuku Nakabori, Yoshinobu Saito, Satoshi Tanaka, Ryotaro Sakamori, Takuya Miyagi, Tomohide Tatsumi, Tetsuo Takehara
  • Organizer: The 66th Annual Meeting of the American Association for the study of Liver Disease
  • Place of Presentation: San Francisco, USA
  • Year and Date: 2015-11-13
  • Int'l Joint Research
• [Presentation] Role of connective tissue growth factor in hepatocellular carcinoma (2015)
  • Author(s): Yuki Makino, Hayato Hikita, Yasutoshi Nozaki, Kenji Ikezawa, Yoshinobu Saito, Satoshi Tanaka, Ryotaro Sakamori, Tomohide Tatsumi, Tetsuo Takehara
  • Organizer: 日本癌学会第74回総会
  • Place of Presentation: 名古屋
  • Year and Date: 2015-10-08
• [Presentation] Significance of connective tissue growth factor with the malignant grade of hepatocellular carcinoma and its potential for therapeutic target (2015)
  • Author(s): Yuki Makino, Hayato Hikita, and Tetsuo Takehara
  • Organizer: 第19回日本肝臓学会大会
  • Place of Presentation: 東京
  • Year and Date: 2015-10-08
• [Presentation] 肝細胞癌におけるRas経路とCTGFの意義・新規治療標的としての可能性 (2015)
  • Author(s): 牧野祐紀 疋田隼人 川口司 甲斐優吾 野崎泰俊 中堀輔 齋藤義修 田中聡司 重川稔 小玉尚宏 阪森亮太郎 宮城琢也 巽智秀 竹原徹郎
  • Organizer: 第51回日本肝臓学会総会
  • Place of Presentation: 熊本
  • Year and Date: 2015-05-21
• [Presentation] Significance of connective tissue growth factor in hepatocellular carcinoma (2015)
  • Author(s): Yuki Makino, Hayato Hikita, Tsukasa Kawaguchi, Takahiro Kodama, Minoru Shigekawa, Yugo Kai, Yasutoshi Nozaki, Tasuku Nakabori, Yoshinobu Saito, Satoshi Tanaka, Ryotaro Sakamori, Takuya Miyagi, Tomohide Tatsumi, Tetsuo Takehara
  • Organizer: The 3rd JSGE International Topic Conference
  • Place of Presentation: Sendai, Japan
  • Year and Date: 2015-04-24
  • Int'l Joint Research
• [Presentation] Significance of Ras pathway and connective tissue growth factor in the development of hepatocellular carcinoma (2014)
  • Author(s): Yuki Makino, Hayato Hikita, Tsukasa Kawaguchi, Takahiro Kodama, Minoru Shigekawa, Yugo Kai, Yasutoshi Nozaki, Tasuku Nakabori, Yoshinobu Saito, Satoshi Tanaka, Ryotaro Sakamori, Takuya Miyagi, Tomohide Tatsumi, Tetsuo Takehara
  • Organizer: Significance of Ras pathway and connective tissue growth factor in the development of hepatocellular carcinoma
  • Place of Presentation: Boston, USA
  • Year and Date: 2014-11-09
• [Presentation] 肝発癌・進展におけるRas経路の活性化とCTGF (2014)
  • Author(s): 牧野祐紀 疋田隼人 竹原徹郎
  • Organizer: 第18回日本肝臓学会大会（JDDW2014）
  • Place of Presentation: 神戸
  • Year and Date: 2014-10-23
• [Presentation] Significance of connective tissue growth factor (CTGF) for the oncogenesis and progression of hepatocellular carcinoma (2014)
  • Author(s): Yuki Makino, Hayato Hikita, Tsukasa Kawaguchi, Yugo Kai, Yasutoshi Nozaki, Tasuku Nakabori, Yoshinobu Saito, Satoshi Tanaka, Ryotaro Sakamori, Takuya Miyagi, Tomohide Tatsumi, Tetsuo Takehara
  • Organizer: 日本癌学会第73回総会
  • Place of Presentation: 横浜
  • Year and Date: 2014-09-26