Elucidation of regulatory mechanism of cancer microenvironment through stromal cell autophagy in hepatocellular carcinoma

• Project/Area Number: 20K08307
• 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: Osaka University
• Principal Investigator: Hikita Hayato 大阪大学, 大学院医学系研究科, 講師 (20623044)
• Co-Investigator(Kenkyū-buntansha): 阪森 亮太郎 大阪大学, 大学院医学系研究科, 特任講師 (10644685) ; 巽 智秀 大阪大学, 大学院医学系研究科, 准教授 (20397699)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2022: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 肝癌 / 肝癌微小環境 / 細胞間相互作用 / GDF15 / CTGF / IL-6ファミリー分子 / 肝星細胞 / 肝細胞癌

Outline of Research at the Start

星細胞やマクロファージ特異的なオートファジー抑制/促進マウスに発癌させて解析を行うことで、肝星細胞やマクロファージオートファジーを介した多細胞間コミュニケーションが腫瘍進展に与える影響を検討する。また、細胞実験や臨床検体を用いた検討を統合し、癌細胞による間質細胞のオートファジー機構という細胞死機構の制御という観点から腫瘍―間質細胞間の相互作用を明らかにする。腫瘍組織内には様々な細胞が存在しており、２つの細胞間相互作用にとどまらない、微小環境内の複雑な相互作用を紐解くことを目指す。

Outline of Final Research Achievements

Hepatoma cells enhanced autophagy of hepatocytes stellate cells (HSCs). The enhanced autophagy of HSCs increased the expression of GDF15, which promoted the proliferation of hepatoma cells, indicating a mechanism of hepatocarcinoma progression through cell-cell interaction between hepatoma cells and HSCs via enhanced GDF15 secretion.

In hepatoma cells, STAT3 activation enhanced CTGF expression and secretion, and CTGF enhanced secretion of various IL-6 family molecules in HSCs, macrophages, sinusoidal endothelial cells, and T cells; IL-6 family molecules upregulated STAT3 expression and cell proliferation in hepatoma cells. We elucidated the existence of a mechanism of HCC progression by the microenvironment mediated by CTGF-IL-6 family molecules.

Academic Significance and Societal Importance of the Research Achievements

肝癌微小環境による肝癌進展機序が明らかとなった。肝癌細胞だけでなく、間質細胞も肝癌の増殖に大きな影響を与えており、本研究課題の遂行で明らかとなった分子機序を治療標的とすることで、新たな肝癌治療の開発も期待される。本研究成果の社会的な意義は大きいと考える。

Research Products

• [Journal Article] STAT3 is Activated by CTGF-mediated Tumor-stroma Cross Talk to Promote HCC Progression (2023)
  • Author(s): Makino Yuki、Hikita Hayato、Kato Seiya、Sugiyama Masaya、Shigekawa Minoru、Sakamoto Tatsuya、Sasaki Yoichi、Murai Kazuhiro、Sakane Sadatsugu、Kodama Takahiro、Sakamori Ryotaro、Kobayashi Shogo、Eguchi Hidetoshi、Takemura Nobuyuki、Kokudo Norihiro、Yokoi Hideki、Mukoyama Masashi、Tatsumi Tomohide、Takehara Tetsuo
  • Journal Title: Cellular and Molecular Gastroenterology and Hepatology Volume: 15 Issue: 1 Pages: 99-119
  • DOI: 10.1016/j.jcmgh.2022.09.006
  • Peer Reviewed
• [Journal Article] White Adipose Tissue Autophagy and Adipose-Liver Crosstalk Exacerbate Nonalcoholic Fatty Liver Disease in Mice (2021)
  • Author(s): Sakane Sadatsugu、Hikita Hayato、Shirai Kumiko、Myojin Yuta、Sasaki Youichi、Kudo Shinnosuke、Fukumoto Kenji、Mizutani Naoki、Tahata Yuki、Makino Yuki、Yamada Ryoko、Kodama Takahiro、Sakamori Ryotaro、Tatsumi Tomohide、Takehara Tetsuo
  • Journal Title: Cellular and Molecular Gastroenterology and Hepatology Volume: 12 Issue: 5 Pages: 1683-1699
  • DOI: 10.1016/j.jcmgh.2021.07.008
  • Peer Reviewed
• [Journal Article] Hepatic Stellate Cells in Hepatocellular Carcinoma Promote Tumor Growth Via Growth Differentiation Factor 15 Production (2021)
  • Author(s): Myojin Y, Hikita H, Sugiyama M, Sasaki Y, Fukumoto K, Sakane S, Makino Y, Takemura N, Yamada R, Shigekawa M, Kodama T, Sakamori R, Kobayashi S, Tatsumi T, Suemizu H, Eguchi H, Kokudo N, Mizokami M, Takehara T.
  • Journal Title: Gastroenterology . Volume: 160 Issue: 5 Pages: 1741-1754
  • DOI: 10.1053/j.gastro.2020.12.015
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Persistent hepatocyte apoptosis promotes tumorigenesis from diethylnitrosamine-transformed hepatocytes through increased oxidative stress, independent of compensatory liver regeneration (2021)
  • Author(s): Nozaki Y, Hikita H, Tanaka S, Fukumoto K, Urabe M, Sato K, Myojin Y, Doi A, Murai K, Sakane S, Saito Y, Kodama T, Sakamori R, Tatsumi T, Takehara T.
  • Journal Title: Sci Rep Volume: 11 Issue: 1 Pages: 3363-3363
  • DOI: 10.1038/s41598-021-83082-7
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Gab1 in livers with persistent hepatocyte apoptosis has an antiapoptotic effect and reduces chronic liver injury, fibrosis and tumorigenesis (2021)
  • Author(s): Mizutani N, Hikita H, Saito Y, Myojin Y, Sato K, Urabe M, Kurahashi T, Shiode Y, Sakane S, Murai K, Nozaki Y, Kodama T, Sakamori R, Yoshida Y, Tatsumi T, Takehara T.
  • Journal Title: Am J Physiol Gastrointest Liver Physiol. Volume: in press Issue: 6 Pages: G958-G968
  • DOI: 10.1152/ajpgi.00370.2020
  • Peer Reviewed / Int'l Joint Research
• [Presentation] 肝癌細胞のSTAT3活性化における間質細胞とのクロストーク (2023)
  • Author(s): 疋田隼人、加藤聖也、竹原徹郎
  • Organizer: 第109回日本消化器病学会総会
• [Presentation] 癌微小環境による肝癌癌進展機序に着目した新規肝発癌バイオマーカー (2022)
  • Author(s): 疋田隼人、竹原徹郎
  • Organizer: 第42回日本分子腫瘍マーカー研究会
• [Presentation] 慢性肝疾患における肝細胞のp53活性化による肝前駆細胞の出現と肝発癌 (2021)
  • Author(s): 牧野祐紀 疋田隼人 竹原徹郎
  • Organizer: 第57回日本肝臓学会総会
• [Presentation] 肝星細胞と肝癌細胞の細胞間相互作用の解明 (2021)
  • Author(s): 明神悠太、疋田隼人、竹原徹郎
  • Organizer: 第57回日本肝臓学会総会
• [Presentation] CTGFとIL-6ファミリー分子を介した腫瘍-間質クロストークによるSTAT3活性化と肝癌の増大進展 (2021)
  • Author(s): 牧野祐紀 疋田隼人 竹原徹郎
  • Organizer: 第28回肝細胞研究会
• [Presentation] 血清GDF15はＣ型慢性肝疾患の新規発癌予測バイオマーカーである (2021)
  • Author(s): 明神悠太、疋田隼人、竹原徹郎
  • Organizer: 第25回日本肝臓学会大会
• [Presentation] 肝癌微小環境における肝星細胞のオートファジーを介したGDF15の意義 (2020)
  • Author(s): 明神悠太、疋田隼人、竹原徹郎
  • Organizer: 第56回日本肝臓学会総会
• [Presentation] 肝星細胞がオートファジー依存的に分泌するGDF15は肝細胞癌の進展に寄与する (2020)
  • Author(s): 明神悠太、疋田隼人、小玉尚宏、牧野祐紀、阪森亮太郎、巽智秀、溝上雅史、江口英利、竹原徹郎
  • Organizer: 第79回日本癌学会学術総会
• [Presentation] Hepatic stellate cell autophagy promotes HCC progression via GDF15 (2020)
  • Author(s): Yuta Myojin, Hayato Hikita, Masaya Sugiyama, Takahiro Kodama, Yuki Makino, Ryoko Yamada, Tasuku Nakabori, Ryotaro Sakamori, Tomohide Tatsumi, Masashi Mizokami, Tetsuo Takehara
  • Organizer: The Digital International Liver Congress of the European Association for the Study of the Liver
  • Int'l Joint Research
• [Presentation] GDF15 secreted by hepatic stellate cells accelerates HCC progression in an autophagy-dependent manner (2020)
  • Author(s): Yuta Myojin, Hayato Hikita , Masaya Sugiyama, Takahiro Kodama, Yuki Makino, Ryoko Yamada, Ryotaro Sakamori, Tomohide Tatsumi, Masashi Mizokami, Tetsuo Takehara
  • Organizer: The Liver Meeting Digital Experience
  • Int'l Joint Research
• [Remarks] 肝がん進展に関わる新たな分子を発見
  • URL: https://resou.osaka-u.ac.jp/ja/research/2020/20201224_2