Functional analysis of the cancer development from fatty acid metabolism and oxidative phosphorylation of HCC based on NAFLD/NASH

• Project/Area Number: 16K19939
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Digestive surgery
• Research Institution: Kumamoto University
• Principal Investigator: NAKAGAWA Shigeki 熊本大学, 医学部附属病院, 寄附講座教員 (10594872)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2017: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 肝細胞癌 / 非アルコール性脂肪肝 / 遺伝子発現 / TM6SF2 / NAFLD / NASH / 癌代謝 / 脂肪肝 / NAFLD/NASH肝細胞癌 / 脂肪酸代謝 / 酸化ストレス / 薬剤感受性予測因子

Outline of Final Research Achievements

Recently, Non-alcoholic fatty liver disease: NAFLD is increasing as a cause of hepatocellular carcinoma: HCC in Japan. We focused on the gene named TM6SF2, as an oncogene which is strongly associated with the development of HCC, and we analyzed the functional role of this gene in the process of cancer development. We used the exhaustive gene expression database and analyzed the association between TM6SF2 expression and molecular pathways, we revealed that the TM6SF2 expression is strongly associated with fatty acid metabolism, oxidative phosphorylation, suggesting that the TM6SF2 regulate the fatty acid metabolism and associated with the development of HCC.

Academic Significance and Societal Importance of the Research Achievements

今回の研究においてTM6SF2が非アルコール性脂肪肝炎を背景とした肝細胞癌の発癌に関わっている事が明らかとなった。これにより非アルコール性脂肪肝炎患者の中でも発癌リスクの高い群を同定する事が可能であり、更にはTM6SF2を標的とした発癌予防へと発展する事が期待される。

Research Products

• [Journal Article] Lysyl oxidase induces epithelial‐mesenchymal transition and predicts intrahepatic metastasis of hepatocellular carcinoma (2019)
  • Author(s): Umezaki Naoki、Nakagawa Shigeki、Yamashita Yo‐ichi、Kitano Yuki、Arima Kota、Miyata Tatsunori、Hiyoshi Yukiharu、Okabe Hirohisa、Nitta Hidetoshi、Hayashi Hiromitsu、Imai Katsunori、Chikamoto Akira、Baba Hideo
  • Journal Title: Cancer Science Volume: 110(6) Pages: 2033-2043
  • DOI: 10.1111/cas.14010
  • Peer Reviewed / Open Access
• [Journal Article] Cell type-specific pharmacological kinase inhibition for cancer chemoprevention (2018)
  • Author(s): Deshmukh M, Nakagawa S, Higashi T, Vincek A, Venkatesh A, Ruiz de Galarreta M, Koh AP, Goossens N, Hirschfield H, Bian CB, Fujiwara N, Ono A, Hoshida H, El-Abtah M, Ahmad NB, Lujambio A, Sanchez R, Fuchs BC, Poelstra K, Prakash J, Hoshida Y.
  • Journal Title: Nanomedicine: Nanotechnology, Biology and Medicine Volume: 14(2) Pages: 317-325
  • DOI: 10.1016/j.nano.2017.11.004
  • Peer Reviewed
• [Journal Article] Enhancer of zeste homolog 2 (EZH2) regulates tumor angiogenesis and predicts recurrence and prognosis of intrahepatic cholangiocarcinoma. (2018)
  • Author(s): Nakagawa Shigeki、Okabe Hirohisa、Ouchi Mayuko、Tokunaga Ryuma、Umezaki Naoki、Higashi Takaaki、Kaida Takatoshi、Arima Kota、Kitano Yuki、Kuroki Hideyuki、Mima Kosuke、Nitta Hidetoshi、Imai Katsunori、Hashimoto Daisuke、Yamashita Yo-ichi、Chikamoto Akira、Baba Hideo
  • Journal Title: HPB (Oxford) Volume: 20 Pages: 939-948
  • DOI: 10.1016/j.hpb.2018.03.018
  • Peer Reviewed
• [Journal Article] Preoperative platelet-to-lymphocyte ratio can predict recurrence beyond the Milan criteria after hepatectomy for patients with hepatocellular carcinoma. (2017)
  • Author(s): Kaida T, Nitta H, Kitano Y, Yamamura K, Arima K, Higashi T, Taki K, Nakagawa S, Okabe H, Hayashi H, Imai K, Hashimoto D, Yamashita YI, Chikamoto A, Ishiko T, Beppu T, Baba H.
  • Journal Title: Hepatol Res Volume: Epub ahead of print Pages: 991-999
  • DOI: 10.1111/hepr.12835
  • Peer Reviewed
• [Journal Article] Selective Venous Occlusions for Reducing Blood Loss During Right Anterior Sectionectomy of the Liver for Hepatocellular Carcinoma. (2017)
  • Author(s): Yamashita Y, Imai K, Tsujita E, Kaida T, Yamao T, Umezaki N, Nakagawa S, Hashimoto D, Chikamoto A, Baba H.
  • Journal Title: J Am Coll Surg Volume: 224(2)
  • DOI: 10.1016/j.jamcollsurg.2016.10.035
  • Peer Reviewed
• [Journal Article] Pre-treatment double- or triple-positive tumor markers are predictive of a poor outcome for patients undergoing radiofrequency ablation for hepatocellular carcinoma. (2017)
  • Author(s): itta H, Nakagawa S, Kaida T, Arima K, Higashi T, Taki K, Okabe H, Hayashi H, Hashimoto D, Chikamoto A, Ishiko T, Beppu T, Baba H.
  • Journal Title: Surg Today Volume: 47(3) Pages: 375-384
  • DOI: 10.1007/s00595-016-1385-6
  • Peer Reviewed
• [Journal Article] Molecular Liver Cancer Prevention in Cirrhosis by Organ Transcriptome Analysis and Lysophosphatidic Acid Pathway Inhibition. (2016)
  • Author(s): Nakagawa S, Higashi T, Goossens N, Bain G, Lauwers GY, Koh AP, El-Abtah M, Ahmad NB, Hoshida H, Erstad DJ, Gunasekaran G, Lee Y, Yu ML, Chuang WL, Dai CY, Baba H, Mahajan M, Nair VD, Lanuti M, Iavarone M, Colombo M, Llovet JM, Tager AM, Schwarz ME, Chung RT, Tanabe KK, Zhang B, Fuchs BC, Hoshida Y, et al.
  • Journal Title: Cancer cell. Volume: 30(6) Pages: 879-890
  • DOI: 10.1016/j.ccell.2016.11.004
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Palbociclib (PD-0332991), a selective CDK4/6 inhibitor, restricts tumour growth in preclinical models of hepatocellular carcinoma. (2016)
  • Author(s): Bollard J, Miguela V, Ruiz de Galarreta M, Venkatesh A, Bian CB, Roberto MP, Tovar V, Sia D, Molina-Sanchez P, Nguyen CB, Nakagawa S, Llovet JM, Hoshida Y, Lujambio A.
  • Journal Title: Gut Volume: Epub ahead of print
  • DOI: 10.1136/gutjnl-2016-312268
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Nonalcoholic Steatohepatitis Is Associated With Increased Mortality in Obese Patients Undergoing Bariatric Surgery. (2016)
  • Author(s): Goossens N, Hoshida Y, Song WM, Jung M, Morel P, Nakagawa S, Zhang B, Frossard JL, Spahr L, Friedman SL, Negro F, Rubbia-Brandt L, Giostra E
  • Journal Title: Clin Gastroenterol Hepatol. Volume: 14(11) Pages: 1619-1628
  • DOI: 10.1016/j.cgh.2015.10.010
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Statin attenuates cell proliferative ability via TAZ (WWTR1) in hepatocellular carcinoma. (2016)
  • Author(s): Higashi T, Hayashi H, Kitano Y, Yamamura K, Kaida T, Arima K, Taki K, Nakagawa S, Okabe H, Nitta H, Imai K, Hashimoto D, Chikamoto A, Beppu T, Baba H.
  • Journal Title: Medical oncology Volume: 33(11) Pages: 123-123
  • DOI: 10.1007/s12032-016-0845-6
  • Peer Reviewed
• [Presentation] A stromal liver gene signature predictive of HCC risk across all liver disease etiologies (2018)
  • Author(s): Shigeki Nakagawa, Naoki Umesaki, Takanobu Yamao Yuki Kitano, Kensuke Yamamura, Kota Arima, Tatsunori Miyata, Takayoshi Kaida, Yujin Hoshida, Katsunori Imai,Daisuke Hashimoto, Yoichi Yamashita, Akira Chikamoto, Hideo Baba
  • Organizer: AACR 2018
  • Int'l Joint Research
• [Presentation] 肝細胞癌における多中心性及び肝内転移再発予測の為のMolecular gene signatureの検討 (2018)
  • Author(s): 中川茂樹、梅崎直紀、北野雄希、今井克憲、山下洋市、近本亮、馬場秀夫
  • Organizer: 第118回日本外科学会定期学術集会
• [Presentation] Lymphocitye 25-gene signature can predict the prognosis of the patients who underwent surgery for pancreatic cancer (2018)
  • Author(s): Shigeki Nakagawa、Yo-ichi Yamashita, Hirohisa Okabe, Katsunori Imai, Hidetoshi Nitta, Akira Chikamoto, Hideo Baba
  • Organizer: 第30回日本肝胆膵外科学会学術集会
• [Presentation] Molecular gene signature predictibe HCC recurrence for the precision medicine of HCC patients (2018)
  • Author(s): Shigeki Nakagawa、Yo-ichi Yamashita, Naoki Umezaki, Yuki Kitano, Tatsunori Miyata, Hirohisa Okabe, Katsunori Imai, Hidetoshi Nitta, Akira Chikamoto, Hideo Baba
  • Organizer: 第73回日本消化器外科学会総会
• [Presentation] 肝細胞癌のモレキュラーサブクラスと再発、腫瘍マーカーの検討 (2018)
  • Author(s): 中川茂樹、山下洋市、岡部弘尚、林洋光、今井克憲、近本亮、馬場秀夫
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] 末梢血リンパ球数と膵癌根治切除術後再発の相関の検討 (2018)
  • Author(s): 中川茂樹、山下洋市、岡部弘尚、林洋光、今井克憲、近本亮、馬場秀夫
  • Organizer: 第56回日本癌治療学会学術集会
• [Presentation] 肝細胞癌初回切除例におけるBALAD scoreによるMolecular Subtype予測と臨床的意義の検討 (2018)
  • Author(s): 中川茂樹、山下洋市、岡部弘尚、新田英利、今井克憲、林洋光、近本亮、石河隆敏、馬場秀夫
  • Organizer: JDDW 2018