Development of Therapies against Hepatocellular Carcinoma Stem Cells via Regulation of Autophagy Activity

• Project/Area Number: 18K16364
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 55020:Digestive surgery-related
• Research Institution: Okayama University of Science (2019-2020); Yamaguchi University (2018)
• Principal Investigator: Nobuyuki Fujiwara 岡山理科大学, 獣医学部, 助教 (30805875)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2020: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2019: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: cancer stem cell / autophagy / PP6 / がん幹細胞 / オートファジー / がん肝細胞 / Protein phosphatase / 肝細胞がん / Beclin 1

Outline of Final Research Achievements

Initially, our plan was to develop an anticancer strategy to specifically inhibit autophagy in cancer stem cells by focusing on the regulatory mechanism of autophagy, which we had previously elucidated. However, as the expression of PP6, a protein phosphatase, was found to be up-regulated in cancer stem cells, I changed the goal of the project, thinking that clarifying the regulatory mechanism would lead to drug discovery targeting cancer stem cells. As a result, we found that PP6 is regulated by autophagy and that PP6 suppresses autophagy.

Academic Significance and Societal Importance of the Research Achievements

これまでにProtein phosphatase 6　(PP6)は、様々ながん種で遺伝子が変異していることや
発現が変化することが報告されており、がんにおいて重要な因子であることは認識されているがPP6発現がどのように制御されているかは全く明らかになっていなかった。本研究によりPP6の発現制御機構の一端が明らかにできたことにより、様々ながん種の発生メカニズムの解明や治療法の開発の一助となることが期待される。

Research Products

• [Journal Article] Pancreatic Cancer Stem-Like Cells With High Calreticulin Expression Associated With Immune Surveillance (2021)
  • Author(s): Fujiwara Yasuhiro、Tsunedomi Ryouichi、Yoshimura Kiyoshi、Matsukuma Satoshi、Fujiwara Nobuyuki、Nishiyama Mitsuo、Kanekiyo Shinsuke、Matsui Hiroto、Shindo Yoshitaro、Tokumitsu Yukio、Yoshida Shin、Iida Michihisa、Suzuki Nobuaki、Takeda Shigeru、Ioka Tatsuya、Hazama Shoichi、Nagano Hiroaki
  • Journal Title: Pancreas Volume: 50 Issue: 3 Pages: 405-413
  • DOI: 10.1097/mpa.0000000000001772
  • Peer Reviewed / Open Access
• [Journal Article] Protein phosphatase 6 dissociates the Beclin 1/Vps34 complex and inhibits autophagy (2021)
  • Author(s): Fujiwara Nobuyuki、Shibutani Shusaku、Ohama Takashi、Sato Koichi
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 552 Pages: 191-195
  • DOI: 10.1016/j.bbrc.2021.02.136
  • Peer Reviewed
• [Journal Article] Cathepsin B is highly expressed in pancreatic cancer stem-like cells and is associated with patients' surgical outcomes (2020)
  • Author(s): Fujimoto Takuya、Tsunedomi Ryouichi、Matsukuma Satoshi、Yoshimura Kiyoshi、Oga Atsunori、Fujiwara Nobuyuki、Fujiwara Yasuhiro、Matsui Hiroto、Shindo Yoshitaro、Tokumitsu Yukio、Suzuki Nobuaki、Kobayashi Shogo、Hazama Shoichi、Eguchi Hidetoshi、Nagano Hiroaki
  • Journal Title: Oncology Letters Volume: 21 Issue: 1 Pages: 1-1
  • DOI: 10.3892/ol.2020.12291
  • Peer Reviewed / Open Access
• [Journal Article] Siglec-7 is a predictive biomarker for the efficacy of cancer vaccination against metastatic colorectal cancer (2020)
  • Author(s): Yamada Kensuke、Hazama Shoichi、Suzuki Nobuaki、Xu Ming、Nakagami Yuki、Fujiwara Nobuyuki、Tsunedomi Ryouichi、Yoshida Shin、Tomochika Shinobu、Matsukuma Satoshi、Matsui Hiroto、Tokumitsu Yukio、Kanekiyo Shinsuke、Shindo Yoshitaro、Watanabe Yusaku、Iida Michihisa、Takeda Shigeru、Ioka Tatsuya、Ueno Tomio、et al.
  • Journal Title: Oncology Letters Volume: 21 Issue: 1 Pages: 1-1
  • DOI: 10.3892/ol.2020.12271
  • Peer Reviewed / Open Access
• [Journal Article] Autophagy regulates levels of tumor suppressor enzyme protein phosphatase 6. (2020)
  • Author(s): Nobuyuki Fujiwara, Shusaku Shibutani, Yusuke Sakai, Toshio Watanabe, Issei Kitabayashi, Hiroko Oshima, Masanobu Oshima, Hisashi Hoshida, Rinji Akada, Tatsuya Usui, Takashi Ohama*, Koichi Sato.
  • Journal Title: Cancer Science Volume: 111 Issue: 12 Pages: 4371-4380
  • DOI: 10.1111/cas.14662
  • Peer Reviewed / Open Access
• [Journal Article] Serum LOX-1 is a novel prognostic biomarker of colorectal cancer. (2020)
  • Author(s): Nakashima-Nakasuga C, Hazama S, Suzuki N, Nakagami Y, Xu M, Yoshida S, Tomochika S, Fujiwara N, Matsukuma S, Matsui H, Tokumitsu Y, Kanekiyo S, Shindo Y, Maeda N, Tsunedomi R, Iida M, Takeda S, Yoshino S, Ueno T, Hamamoto Y, Ogihara H, Hoshii Y, Nagano H.
  • Journal Title: Int J Clin Oncol. Volume: - Issue: 7 Pages: 1308-1317
  • DOI: 10.1007/s10147-020-01673-2
  • Peer Reviewed
• [Presentation] Protein phosphatase 6 regulates neurite outgrowth through the activating of mTORC2/Akt/CREB signaling in N2a cells (2021)
  • Author(s): Kitamura N, Fujiwara N, Hayakawa K, Ohama T, Sato K
  • Organizer: The 5th symposium Association of Japan-Indonesia Veterinary Education
  • Int'l Joint Research
• [Presentation] Protein phosphatase 6は大腸がん細胞の幹細胞性を制御する (2020)
  • Author(s): 藤原信行、恒富亮一、硲彰一、友近忍、鈴木伸明、大浜剛、佐藤晃一、永野浩昭
  • Organizer: 第163回日本獣医学会
• [Presentation] Protein phosphatase 6は大腸癌細胞の幹細胞性を制御する (2019)
  • Author(s): 藤原信行、恒富亮一、硲彰一、友近忍、鈴木伸明、大浜剛、佐藤晃一、永野浩昭
  • Organizer: 第9回日本プロテインホスファターゼ研究会 学術集会
• [Presentation] Protein phosphatase 6 controls tumor malignancy of colon cancer through regulation of cancer stemness. (2019)
  • Author(s): Nobuyuki Fujiwara, Ryouichi Tsunedomi, Shoichi Hazama, Nobuaki Suzuki, Takashi Ohama, Shigefumi Yoshino, Hiroaki Nagano
  • Organizer: 第78回日本癌学会学術総会
• [Presentation] Protein phosphatase 6は大腸癌細胞の幹細胞性を制御する (2019)
  • Author(s): 藤原 信行、恒富 亮一、硲 彰一、友近 忍、鈴木 伸明、大浜 剛、佐藤 晃一、永野 浩昭
  • Organizer: 第42回日本分子生物学会年会
• [Presentation] Protein phosphatase 6は大腸癌の悪性化に関与する (2018)
  • Author(s): 藤原信行、硲彰一、友近忍、鈴木伸明、 武田茂、 吉野茂文、大浜剛、佐藤晃一、上野富雄、永野浩昭
  • Organizer: 第73回日本消化器外科学会総会
• [Presentation] Protein phosphatase 6 controls tumor progression of colon cancer. (2018)
  • Author(s): 藤原信行、恒富亮一、硲彰一、友近忍、鈴木伸明、 武田茂、大浜剛、佐藤晃一、吉野茂文、上野富雄、永野浩昭
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] Elucidation of control mechanism of type 2A protein phosphatase by autophagy (2018)
  • Author(s): Nobuyuki Fujiwara, Shusaku T. Shibutani, Yusuke Sakai, Hiroshi Shima, Toshio Watanabe, Hiroko Ohshima, Masanobu Ohshima, Tathuya Saito, Shizuo Akira, Hiroaki Nagano, Tathuya Usui, Takashi Ohama, Koichi Sato
  • Organizer: 第13回プロテインホスファターゼ国際カンファレンス Workshop on Frontiers in Phosphatase Research and Drug Discovery
  • Int'l Joint Research
• [Presentation] オートファジーによるtype 2A protein phosphataseの制御機構の解明 (2018)
  • Author(s): 藤原 信行、渋谷 周作、坂井 祐介、島 礼、渡邊 利雄、大島 浩子、大島 正伸、齋藤 達哉、審良 静男、永野 浩昭、臼井 達哉、大浜 剛、佐藤 晃一
  • Organizer: 第41回日本分子生物学会総会
• [Presentation] がん幹細胞様細胞と臨床サンプルとの統合解析により同定されたがん幹細胞関連遺伝子 (2018)
  • Author(s): 恒富亮一、西山光郎、藤原信行、松隈 聰、兼清信介、友近 忍、徳光幸生、飯田通久、鈴木伸明、武田茂、山本 滋、吉野茂文、上野富雄、硲 彰一、永野浩昭
  • Organizer: 第26回日本消化器関連学会週間 (JDDW2018)
• [Presentation] RAB3B was identified as a gene involved in characteristics of induced cancer stem-like sphere cells (2018)
  • Author(s): Ryouichi Tsunedomi, Kiyoshi Yoshimura, Satoshi Matsukuma, Nobuyuki Fujiwara, Shinsuke Kanekiyo, Michihisa Iida, Nobuaki Suzuki, Shigeru Takeda, Shigefumi Yoshino, Shoichi Hazama, Tomio Ueno, Hiroaki Nagano
  • Organizer: 第77回日本癌学会学術総会