Regulation of pancreatic cancer progression by targeting Hic-5, a TGF-beta-inducible adaptor expressed in cancer-stroma.

• Project/Area Number: 19K08404
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: Showa University
• Principal Investigator: Kaneyama Shuri 昭和大学, 医学部, 准教授 (10338535)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
• Keywords: 膵がん / 膵線維化 / がん微小環境 / がん関連線維芽細胞 / 微小環境制御 / Hic-5 / TGF-b / 細胞接着班分子

Outline of Research at the Start

がん間質はがん細胞増殖作用を持ち、発がん・がん進展に重要な役割を持つことが認識されている。申請者らは近年、活性酸素応答性アダプター分子 Hic-5 ががん間質にのみ高発現し細胞外マトリックス (ECM)を制御していること、および自作した Hic-5 欠損マウスで大腸がんの発症がほぼ完全に抑制されることを報告した。本研究では間質の豊富な膵がん発症へのHic-5 の関与を明らかにすると共に、がん組織の硬い ECM 構造の実態解析に着手する。最終的に既存抗がん剤とは異なる難治性がんの間質機能抑制という新しい作用機序を持つ新規がん治療ターゲット分子の提唱を目指す。

Outline of Final Research Achievements

Alteration in the density of extracellular matrix (ECM) occurs in the tumor stroma. We have previously demonstrated that Hydrogen peroxide-inducible clone-5 (Hic-5) was strongly induced in CAFs found in human colorectal cancer and responsible for generating a tumor-promoting stroma. In this study, we focused on pancreatic cancer which is characterized by a dense stromal response, and investigated the contribution of Hic-5 to pancreatic cancer development through regulation of cancer stromal phenotype using a mouse model of pancreatic cancer. Furthermore, we clarified the involvement of Hic-5 in pancreatic fibrosis, which is considered to be one of the causes of pancreatic cancer resistance to treatment.

Academic Significance and Societal Importance of the Research Achievements

膵線維化は難治癌である膵がんの治療抵抗性の一因と考えられており、本研究により膵線維化制御メカニズムの一因が明らかにされた。がん組織中の線維化を標的とした新たな膵がんの治療戦略開発につながるデータである。

Research Products

• [Journal Article] STING, a cytosolic DNA sensor, plays a critical role in atherogenesis: a link between innate immunity and chronic inflammation caused by lifestyle-related diseases (2021)
  • Author(s): Pham Phuong Tran、Fukuda Daiju、Nishimoto Sachiko、Kim-Kaneyama Joo-Ri、Lei Xiao-Feng、Takahashi Yutaka、Sato Tomohito、Tanaka Kimie、Sata Masataka et al.
  • Journal Title: European Heart Journal Volume: 42 Issue: 42 Pages: 4336-4348
  • DOI: 10.1093/eurheartj/ehab249
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Hic-5 is required for activation of pancreatic stellate cells and development of pancreatic fibrosis in chronic pancreatitis (2020)
  • Author(s): Gao Lin、Lei Xiao-Feng、Miyauchi Aya、Noguchi Masahito、Omoto Tomokatsu、Haraguchi Shogo、Miyazaki Takuro、Miyazaki Akira、Kim-Kaneyama Joo-ri
  • Journal Title: Scientific Reports Volume: 10 Issue: 1 Pages: 19105-19105
  • DOI: 10.1038/s41598-020-76095-1
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Toll‐Like Receptor 9 Plays a Pivotal Role in Angiotensin II Induced Atherosclerosis (2019)
  • Author(s): Fukuda Daiju、Nishimoto Sachiko、Aini Kunduziayi、Tanaka Atsushi、Nishiguchi Tsuyoshi et al.
  • Journal Title: Journal of the American Heart Association Volume: 8 Issue: 7
  • DOI: 10.1161/jaha.118.010860
  • NAID: 120006602927
  • Peer Reviewed / Open Access
• [Journal Article] Excessive mechanical loading promotes osteoarthritis through the gremlin-1?NF-κB pathway (2019)
  • Author(s): Chang Song Ho、Mori Daisuke、Kobayashi Hiroshi、Mori Yoshifumi、Nakamoto Hideki、Okada Keita、Taniguchi Yuki、Sugita Shurei、Yano Fumiko、Chung Ung-il、Kim-Kaneyama Joo-ri、Yanagita Motoko、Economides Aris、Canalis Ernesto、Chen Di、Tanaka Sakae、Saito Taku
  • Journal Title: Nature Communications Volume: 10 Issue: 1 Pages: 1442-1442
  • DOI: 10.1038/s41467-019-09491-5
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Adamts17 is involved in skeletogenesis through modulation of BMP-Smad1/5/8 pathway (2019)
  • Author(s): Oichi Takeshi、Taniguchi Yuki、Soma Kazuhito、Oshima Yasushi、Yano Fumiko、Mori Yoshifumi、Chijimatsu Ryota、Kim-Kaneyama Joo-ri、Tanaka Sakae、Saito Taku
  • Journal Title: Cellular and Molecular Life Sciences Volume: 76 Issue: 23 Pages: 4795-4809
  • DOI: 10.1007/s00018-019-03188-0
  • Peer Reviewed / Open Access
• [Journal Article] Light-at-night exposure affects brain development through pineal allopregnanolone-dependent mechanisms (2019)
  • Author(s): Haraguchi S, Kamata M, Tokita T, Tashiro KI, Sato M, Nozaki M, Okamoto-Katsuyama M, Shimizu I, Han G, Chowdhury VS, Lei XF, Miyazaki T, Kim-Kaneyama JR, Nakamachi T, Matsuda K, Ohtaki H, Tokumoto T, Tachibana T, Miyazaki A, Tsutsui K.
  • Journal Title: eLife Volume: 8
  • DOI: 10.7554/elife.45306
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Alleviation of murine osteoarthritis by deletion of the focal adhesion mechanosensitive adapter, Hic-5 (2019)
  • Author(s): Miyauchi Aya、Kim-Kaneyama Joo-ri、Lei Xiao-Feng、Chang Song Ho、Saito Taku、Haraguchi Shogo、Miyazaki Takuro、Miyazaki Akira
  • Journal Title: Scientific Reports Volume: 9 Issue: 1 Pages: 15770-15770
  • DOI: 10.1038/s41598-019-52301-7
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] 細胞接着斑メカニカルストレス応答性アダプター分子 Hic-5欠損による変形性膝関節症発症抑 (2021)
  • Author(s): 宮内彩, 雷小峰, 張成虎, 齋藤琢, 宮崎章, 金山朱里
  • Organizer: 第39回日本骨代謝学会学術集会
• [Presentation] レドックス感受性アダプター分子の疾患発症における役割 (2021)
  • Author(s): 金山朱里
  • Organizer: 第30回昭和大学学士会シンポジウム
  • Invited
• [Presentation] Stromal Hic-5 expression contributes to colorectal tumorigenesis through stromal remodeling (2020)
  • Author(s): Joo-ri Kim-kaneyama, Tomokatsu Omoto, Xiao-Feng Lei, Aya Miyauchi, Lin Gao, Shogo Haraguchi, Takuro Miyazaki and Akira Miyazaki
  • Organizer: Stromal Cells in Immunity and Disease, Keystone Symposia
  • Int'l Joint Research
• [Presentation] レドックス感受性アダプター分子の動脈硬化性疾患発症における役割 (2019)
  • Author(s): 金山 朱里、雷 小峰、宮内 彩、宮崎 章
  • Organizer: 第51回日本動脈硬化学会総会・学術集会(シンポジウム)