Sorafenib resistance and c-Jun in hepatocellular carcinoma

• Project/Area Number: 17K09404
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Nihon University
• Principal Investigator: KANDA Tatsuo 日本大学, 医学部, 准教授 (20345002)
• Co-Investigator(Kenkyū-buntansha): 森山 光彦 日本大学, 医学部, 教授 (50191060) ; 松岡 俊一 日本大学, 医学部, 准教授 (80307842) ; 山本 敏樹 日本大学, 医学部, 准教授 (50409009) ; 楡井 和重 日本大学, 医学部, 准教授 (70350014)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2017: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: ソラフェニブ耐性 / 肝細胞癌 / TLR4 / c-Fos / c-Jun / AP-1 / レンバチニブ / レゴラフェニブ / Fos / 自然免疫 / Toll-like receptor / 進行肝細胞癌 / ソラフェニブ / GRP78 / AR / 肝癌細胞株 / 膵癌細胞株

Outline of Final Research Achievements

Sorafenib has been used as an oral systemic chemotherapeutic agent for patients with advanced hepatocellular carcinoma (HCC). It is important to elucidate the mechanism of sorafenib resistance and improve the treatment efficacy. 1) Phosphorylation of c-Jun is involved in the sorafenib resistance of human hepatoma cell lines. 2) We examined whether oral tyrosine kinase inhibitors (TKIs) affect innate immunity including Toll-like receptor (TLR) signaling pathway, by real-time PCR arrays and cytotoxic assays. 3) Regorafenib upregulated C-X-C motif chemokine ligand (CXCL10) mRNA expression and downregulated Fos proto-oncogene, AP-1 transcription factor subunit (c-Fos) and ubiquitin conjugating enzyme E2 N (UBE2N) mRNAs in both HepG2 and Huh7 cells. 4) Lenvatinib upregulated interleukin 1 alpha and TLR4 mRNAs.
TLR signaling pathway plays a role in the treatment response of TKIs. Modulation of TLR pathway may be important in the treatment of sorafenib-resistant patients with advanced HCC.

Academic Significance and Societal Importance of the Research Achievements

c-Junの肝硬変、肝細胞癌における関与は多様性に富む。肝細胞癌のソラフェニブ耐性機序に関わる複雑なc-Jun/AP-1シグナル伝達経路の解明は重要である。本研究ではソラフェニブ耐性の2次治療薬剤レゴラフェニブがCXCL10発現増加やc-FosおよびUBE2N発現低下を介して作用し、レンバチニブはIL1AやToll-like receptor (TLR) 4発現増加を介して作用することを解明した。これら薬剤はTLRシグナル伝達に影響を与えて作用することを明らかにした。TLRシグナル伝達経路修飾がソラフェニブ耐性進行肝癌患者の治療に重要であることを解明した。新規薬剤開発に繋がる可能性がある。

Research Products

• [Journal Article] Molecular Mechanisms: Connections between Nonalcoholic Fatty Liver Disease, Steatohepatitis and Hepatocellular Carcinoma (2020)
  • Author(s): Kanda Tatsuo、Goto Taichiro、Hirotsu Yosuke、Masuzaki Ryota、Moriyama Mitsuhiko、Omata Masao
  • Journal Title: International Journal of Molecular Sciences Volume: 21 Issue: 4 Pages: 1525-1525
  • DOI: 10.3390/ijms21041525
  • Peer Reviewed / Open Access
• [Journal Article] APASL HCV guidelines of virus-eradicated patients by DAA on how to monitor HCC occurrence and HBV reactivation. (2019)
  • Author(s): Kanda T, Lau GKK, Wei L, Moriyama M, Yu ML, Chuang WL, Ibrahim A, Lesmana CRA, Sollano J, Kumar M, Jindal A, Sharma BC, Hamid SS, Kadir Dokmeci A, Mamun-Al-Mahtab, McCaughan GW, Wasim J, Crawford DHG, Kao JH, Ooka Y, Yokosuka O, Sarin SK, Omata M.
  • Journal Title: Hepatology International Volume: 13 Issue: 6 Pages: 649-661
  • DOI: 10.1007/s12072-019-09988-7
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Possible association of arrestin domain-containing protein 3 and progression of non-alcoholic fatty liver disease. (2019)
  • Author(s): Ogawa M, Kanda T, Higuchi T, Takahashi H, Kaneko T, Matsumoto N, Nirei K, Yamagami H, Matsuoka S, Kuroda K, Moriyama M.
  • Journal Title: International Journal of Medical Sciences Volume: 16 Issue: 7 Pages: 909-921
  • DOI: 10.7150/ijms.34245
  • Peer Reviewed / Open Access
• [Journal Article] Follow-up Results of HCV GT2 Patients After Sofosbuvir/Ribavirin Therapy: Careful Attention to Occurrence of HCC (2019)
  • Author(s): KANEKO TOMOHIRO、KANDA TATSUO、NIREI KAZUSHIGE、MATSUMOTO NAOKI、YAMAZAKI MOTOMI、SHIBATA TOSHIKATSU、TAMURA AKINORI、OGAWA MASAHIRO、NAKAJIMA NORIKO、MATSUOKA SHUNICHI、KURODA KAZUMICHI、KOMORIYA TOMOE、YAMAMOTO TATSUO、TAKAYAMA TADATOSHI、MORIYAMA MITSUHIKO
  • Journal Title: Anticancer Research Volume: 39 Issue: 7 Pages: 3855-3862
  • DOI: 10.21873/anticanres.13535
  • Peer Reviewed / Open Access
• [Journal Article] Molecular Mechanisms Driving Progression of Liver Cirrhosis towards Hepatocellular Carcinoma in Chronic Hepatitis B and C Infections: A Review (2019)
  • Author(s): Kanda Tatsuo、Goto Taichiro、Hirotsu Yosuke、Moriyama Mitsuhiko、Omata Masao
  • Journal Title: International Journal of Molecular Sciences Volume: 20 Issue: 6 Pages: 1358-1358
  • DOI: 10.3390/ijms20061358
  • Peer Reviewed / Open Access
• [Journal Article] Exosomes and Hepatocellular Carcinoma: From Bench to Bedside (2019)
  • Author(s): Sasaki Reina、Kanda Tatsuo、Yokosuka Osamu、Kato Naoya、Matsuoka Shunichi、Moriyama Mitsuhiko
  • Journal Title: International Journal of Molecular Sciences Volume: 20 Issue: 6 Pages: 1406-1406
  • DOI: 10.3390/ijms20061406
  • Peer Reviewed / Open Access
• [Journal Article] Exosomes and Hepatocellular Carcinoma: From Bench to Bedside. (2019)
  • Author(s): Reina Sasaki、Kanda Tatsuo、Yokosuka Osamu、Kato Naoya、Matsuoka Shunichi、Moriyama Mitsuhiko
  • Journal Title: International Journal of Molecular Sciences Volume: 20 Pages: 2416-2416
  • Peer Reviewed / Open Access
• [Journal Article] Early occurrence and recurrence of hepatocellular carcinoma in hepatitis C virus-infected patients after sustained virological response (2018)
  • Author(s): Kanda T, Matsuoka S, Moriyama M
  • Journal Title: Hepatology International Volume: 12 Issue: 2 Pages: 90-93
  • DOI: 10.1007/s12072-018-9862-1
  • Peer Reviewed / Open Access
• [Journal Article] Persistent Hepatic Inflammation Plays a Role in Hepatocellular Carcinoma After Sustained Virological Response in Patients with HCV Infection (2018)
  • Author(s): Nirei K, Kanda T, Nakamura H, Matsuoka S, Takayama T, Sugitani M, Moriyama M
  • Journal Title: Int J Med Sci Volume: 15 Issue: 5 Pages: 466-474
  • DOI: 10.7150/ijms.23147
  • Peer Reviewed
• [Journal Article] Interferon-free treatment for patients with chronic hepatitis C and autoimmune liver disease: higher SVR rates with special precautions for deterioration of autoimmune hepatitis (2018)
  • Author(s): Kanda T, Yasui S, Nakamura M, Nakamoto S, Takahashi K, Wu S, Sasaki R, Haga Y, Ogasawara S, Saito T, Kobayashi K, Kiyono S, Ooka Y, Suzuki E, Chiba T, Maruyama H, Imazeki F, Moriyama M, Kato N
  • Journal Title: Oncotarget Volume: 9 Issue: 14 Pages: 11631-11637
  • DOI: 10.18632/oncotarget.24391
  • Peer Reviewed / Open Access
• [Journal Article] Retreatment of patients with treatment failure of direct-acting antivirals: Focus on hepatitis C virus genotype 1b (2017)
  • Author(s): Kanda T, Nirei K, Matsumoto N, Higuchi T, Nakamura H, Yamagami H, Matsuoka S, Moriyama M
  • Journal Title: World J Gastroenterol Volume: 23 Issue: 46 Pages: 8120-8127
  • DOI: 10.3748/wjg.v23.i46.8120
  • Peer Reviewed / Open Access
• [Journal Article] Direct-acting antiviral agents against hepatitis C virus and lipid metabolism (2017)
  • Author(s): Kanda T, Moriyama M
  • Journal Title: World J Gastroenterol Volume: 23 Issue: 31 Pages: 5645-5649
  • DOI: 10.3748/wjg.v23.i31.5645
  • Peer Reviewed / Open Access
• [Presentation] レゴラフェニブの肝癌細胞Toll-like receptor関連シグナルに対する影響. (2019)
  • Author(s): 神田達郎, 高橋央, 金子朋弘, 本田真之, 有間修平, 上村慎也, 金澤芯依,山名陽一郎, 水谷卓, 松本直樹, 中村仁美, 石井大雄, 楡井和重, 山上裕晃, 小川眞広, 松岡俊一, 森山光彦.
  • Organizer: 第55回日本肝臓学会総会
• [Presentation] レンバチニブが肝癌細胞Toll-like receptor関連シグナルに与える影響. (2019)
  • Author(s): 神田達郎, 松岡俊一, 小川眞広, 松本直樹, 上村慎也, 水谷卓, 有間修平, 本田真之, 金澤芯依, 金子朋弘, 高橋央, 山名陽一郎, 石井大雄, 樋口晃久, 山上裕晃, 中村仁美, 楡井和重, 森山光彦.
  • Organizer: 第55回日本肝癌研究会
• [Presentation] レンバチニブを使用し著効した後, 再増悪をきたした肝細胞癌の2例. (2019)
  • Author(s): 有間修平, 高橋央, 金子朋弘, 本田真之, 石井大雄, 山名陽一郎, 水谷卓, 上村慎也, 松本直樹, 中村仁美, 山上裕晃, 神田達郎, 松岡俊一, 森山光彦.
  • Organizer: 第55回日本肝癌研究会
• [Presentation] 各種分子標的薬が肝癌細胞株自然免疫シグナル伝達経路に与える影響に関する検討. (2019)
  • Author(s): 神田達郎, 松本直樹, 森山光彦.
  • Organizer: 第23回日本肝臓学会大会
• [Presentation] Effects of regorafenib on the toll-like receptor signaling pathways in HCC. (2019)
  • Author(s): Tatsuo Kanda, Naoki Matsumoto, Hiroaki Yamagami, Shunichi Matsuoka, Mitsuhiko Moriyama.
  • Organizer: APASL Single Topic Conference on Liver Immunology and Genetics
  • Int'l Joint Research
• [Presentation] Different mechanism of action of regorafenib and lenvatinib on toll-like receptor-signaling pathways in human hepatoma cell lines. (2019)
  • Author(s): Kanda T, Moriyama M.
  • Organizer: AASLD The Liver Meeting 2019, John B. Hynes Memorial Convention Center, Boston, MA, USA.
  • Int'l Joint Research