The role of ER stress and PERK for chronic liver injury and hepatocarcinogenesis

• Project/Area Number: 18K08007
• 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: Ehime University
• Principal Investigator: Hiasa Yoichi 愛媛大学, 医学系研究科, 教授 (70314961)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: PERK / ERストレス / 肝細胞がん / RMRP / long noncoding RNA / アポトーシス / Bcl-2 / cleaved カスパーゼ3 / Protein kinase R (PKR) / MAPKシグナル / c-Fos / c-Jun / eIF2-alpha / PKR / 肝細胞癌 / MAPK / 慢性肝障害 / 肝癌

Outline of Final Research Achievements

Endoplasmic reticulum (ER) stress plays an important role in chronic liver injury by inducing hepatocyte degeneration and inflammation, which contributes liver carcinogenesis and tumor progression. Protein kinase R-like endoplasmic reticulum kinase (PERK) is one of the major ER stress molecules, and is known to induce apoptosis, however, the role in the hepatocellular carcinoma is controversial. In this study, a long non-coding RNA, RNA component of mitochondrial RNA processing endoribonuclease (RMRP), was identified as the most upregulated molecule by knocking down of the PERK. The expression of RMRP was correlated with the expression of PERK in experiments with the siRNA and PERK plasmid in both HCC cell lines and human HCC tissue. Furthermore, RMRP downregulation induced apoptotic cell death. RMRP is downregulated by PERK, which induces apoptosis in HCC. RMRP could be a new therapeutic target to regulate HCC in patients with chronic liver diseases associated with ER stress.

Academic Significance and Societal Importance of the Research Achievements

小胞体ストレス(ERストレス)は発がんおよびがん進展に関わりうる重要な細胞内ストレスの一つである。これまで、ERストレスにより誘導されるPERKの肝細胞がんにおける役割は不明確であり、本研究ではその役割を明らかにするとともに、PERKと最も関連するlong noncoding RNAであるRMRPを同定した。またRMRPがPERKにより発現が抑制され、内因性経路を介したアポトーシス誘導促進に寄与としていることを解明した。RMRPは、PERK経路をコントロールしてがんの進展を阻害できる可能性があり、新たな治療標的となりうるとともに、肝細胞がん制御の新たなストラテジーにつながる可能性がある。

Research Products

• [Journal Article] The long noncoding RNA of RMRP is downregulated by PERK, which induces apoptosis in hepatocellular carcinoma cells (2021)
  • Author(s): Yukimoto Atsushi、Watanabe Takao、Sunago Kotaro、Nakamura Yoshiko、Tanaka Takaaki、Koizumi Yohei、Yoshida Osamu、Tokumoto Yoshio、Hirooka Masashi、Abe Masanori、Hiasa Yoichi
  • Journal Title: Scientific Reports Volume: 11 Issue: 1 Pages: 7926-7926
  • DOI: 10.1038/s41598-021-86592-6
  • Peer Reviewed / Open Access
• [Journal Article] Development of a method for measuring spleen stiffness by transient elastography using a new device and ultrasound-fusion method (2021)
  • Author(s): Tanaka Takaaki、Hirooka Masashi、Koizumi Yohei、Watanabe Takao、Yoshida Osamu、Tokumoto Yoshio、Nakamura Yoshiko、Sunago Koutarou、Yukimoto Atsushi、Abe Masanori、Hiasa Yoichi
  • Journal Title: PLOS ONE Volume: 16 Issue: 2 Pages: e0246315-e0246315
  • DOI: 10.1371/journal.pone.0246315
  • Peer Reviewed / Open Access
• [Journal Article] Therapeutic Effects of the PKR Inhibitor C16 Suppressing Tumor Proliferation and Angiogenesis in Hepatocellular Carcinoma in Vitro and in Vivo. (2020)
  • Author(s): Watanabe T, Ninomiya H, Saitou T, Takanezawa S, Yamamoto S, Imai Y, Yoshida O, Kawakami R, Hirooka M, Abe M, Imamura T, Hiasa Y.
  • Journal Title: Scientific Reports Volume: 20;10(1) Issue: 1 Pages: 5133-5133
  • DOI: 10.1038/s41598-020-61579-x
  • Peer Reviewed / Open Access
• [Journal Article] Advanced fibrosis of non-alcoholic steatohepatitis affects the significance of lipoprotein(a) as a cardiovascular risk factor (2020)
  • Author(s): Konishi K, Miyake T, Furukawa S, Senba H, Kanzaki S, Nakaguchi H, Yukimoto A, Nakamura Y, Watanabe T, Koizumi Y, Yoshida O, Tokumoto Y, Hirooka M, Kumagi T, Abe M, Matsuura B, Hiasa Y.
  • Journal Title: Atherosclerosis Volume: 299 Pages: 32-37
  • DOI: 10.1016/j.atherosclerosis.2020.02.026
  • Peer Reviewed
• [Journal Article] Treatment on the spleen prevents the progression of secondary sarcopenia in patients with liver cirrhosis (2020)
  • Author(s): Hirooka M, Koizumi Y, Tanaka T, Nakamura Y, Sunago K, Yukimoto A, Watanabe T, Yoshida O, Miyake T, Tokumoto Y, Matsuura B, Abe M, Hiasa Y
  • Journal Title: Hepatol Commun Volume: 4 Issue: 12 Pages: 1812-1823
  • DOI: 10.1002/hep4.1604
  • Peer Reviewed / Open Access
• [Journal Article] Zinc deficiency as an independent prognostic factor for patients with early hepatocellular carcinoma due to hepatitis virus. (2020)
  • Author(s): Hiraoka A, Nagamatsu K, Izumoto H, Adachi T, Yoshino T, Tsuruta M, Aibiki T, Okudaira T, Yamago H, Iwasaki R, Suga Y, Mori K, Miyata H, Tsubouchi E, Ninomiya T, Kawasaki H, Hirooka M, Matsuura B, Abe M, Hiasa Y, Michitaka K.
  • Journal Title: Hepatol Res. Volume: 50 Issue: 1 Pages: 92-100
  • DOI: 10.1111/hepr.13430
  • Peer Reviewed
• [Journal Article] Safety and efficacy of lenvatinib in elderly patients with unresectable hepatocellular carcinoma: A multicenter analysis with propensity score matching. (2020)
  • Author(s): Tada T, Kumada T, Hiraoka A, Michitaka K, Atsukawa M, Hirooka M, Tsuji K, Ishikawa T, Takaguchi K, Kariyama K, Itobayashi E, Tajiri K, Shimada N, Shibata H, Ochi H, Toyoda H, Nouso K, Tsutsui A, Nagano T, Itokawa N, Hayama K, Imai M, Joko K, Koizumi Y, Hiasa Y.
  • Journal Title: Hepatol Res. Volume: 50 Issue: 1 Pages: 75-83
  • DOI: 10.1111/hepr.13427
  • Peer Reviewed
• [Journal Article] Post-Progression Treatment Eligibility of Unresectable Hepatocellular Carcinoma Patients Treated with Lenvatinib. (2020)
  • Author(s): Hiraoka A, Kumada T, Fukunishi S, Atsukawa M, Hirooka M, Tsuji K, Ishikawa T, Takaguchi K, Kariyama K, Itobayashi E, Tajiri K, Shimada N, Shibata H, Ochi H, Tada T, Toyoda H, Yokohama K, Nouso K, Tsutsui A, Nagano T, Itokawa N, Hayama K, Arai T, Imai M, Joko K, Koizumi Y, Hiasa Y, Michitaka K, Kudo M.
  • Journal Title: Liver Cancer Volume: 9 Issue: 1 Pages: 73-83
  • DOI: 10.1159/000503031
  • Peer Reviewed / Open Access
• [Journal Article] Stimulated hepatic stellate cell promotes progression of hepatocellular carcinoma due to protein kinase R activation (2019)
  • Author(s): Imai Y, Yoshida O, Watanabe T, Yukimoto A, Koizumi Y, Ikeda Y, Tokumoto Y, Hirooka M, Abe M, Hiasa Y
  • Journal Title: PLos One Volume: 14 Issue: 2 Pages: e0212589-e0212589
  • DOI: 10.1371/journal.pone.0212589
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Combination of Resection and Ablative Treatment for Hepatocellular Carcinoma: Usefulness of Complementary Radiofrequency Ablation. (2019)
  • Author(s): Hiraoka A, Hirooka M, Ochi H, Koizumi Y, Izumoto H, Ueki H, Tsuruta M, Ono A, Yoshino T, Aibiki T, Okudaira T, Yamago H, Suga Y, Iwasaki R, Mori K, Miyata H, Kishida M, Tsubouchi E, Abe M, Matsuura B, Ninomiya T, Joko K, Kawasaki H, Hiasa Y, Michitaka K.
  • Journal Title: Oncology Volume: 96 Issue: 5 Pages: 242-251
  • DOI: 10.1159/000496225
  • Peer Reviewed
• [Journal Article] Prognostic factor of lenvatinib for unresectable hepatocellular carcinoma in real‐world conditions?Multicenter analysis (2019)
  • Author(s): Ｈｉｒａｏｋａ Ａｔｓｕｓｈｉ、Ｈｉｒｏｏｋａ Ｍａｓａｓｈｉ、ｅｔ ａｌ．
  • Journal Title: Cancer Medicine Volume: 8 Issue: 8 Pages: 3719-3728
  • DOI: 10.1002/cam4.2241
  • Peer Reviewed / Open Access
• [Journal Article] Clinical features of lenvatinib for unresectable hepatocellular carcinoma in real-world conditions: Multicenter analysis. (2019)
  • Author(s): Hiraoka A, Kumada T, Kariyama K, Takaguchi K, Atsukawa M, Itobayashi E, Tsuji K, Tajiri K, Hirooka M, Shimada N, Shibata H, Ishikawa T, Ochi H, Tada T, Toyoda H, Nouso K, Tsutsui A, Itokawa N, Imai M, Joko K, Hiasa Y, Michitaka K.
  • Journal Title: Cancer Med. Volume: 8 Issue: 1 Pages: 137-146
  • DOI: 10.1002/cam4.1909
  • Peer Reviewed / Open Access
• [Journal Article] Lenvatinib-induced thyroid abnormalities in unresectable hepatocellular carcinoma (2019)
  • Author(s): Koizumi Yohei、Hirooka Masashi、Hiraoka Atsushi、Ochi Hironori、Tanaka Takaaki、Yukimoto Atsushi、Imai Yuusuke、Watanabe Takao、Yoshida Osamu、Miyake Teruki、Matsuura Bunzo、Michitaka Kojiro、Joko Kouji、Abe Masanori、Hiasa Yoichi
  • Journal Title: Endocrine Journal Volume: 66 Issue: 9 Pages: 787-792
  • DOI: 10.1507/endocrj.EJ19-0140
  • NAID: 130007719421
  • ISSN: 0918-8959, 1348-4540
  • Peer Reviewed / Open Access
• [Journal Article] Early Relative Change in Hepatic Function with Lenvatinib for Unresectable Hepatocellular Carcinoma (2019)
  • Author(s): Ｈｉｒａｏｋａ Ａｔｓｕｓｈｉ、Ｈｉｒｏｏｋａ Ｍａｓａｓｈｉ、ｅｔ ａｌ．
  • Journal Title: Oncology Volume: 97 Issue: 6 Pages: 334-340
  • DOI: 10.1159/000502095
  • Peer Reviewed
• [Journal Article] Important Clinical Factors in Sequential Therapy Including Lenvatinib against Unresectable Hepatocellular Carcinoma (2019)
  • Author(s): Ｈｉｒａｏｋａ Ａｔｓｕｓｈｉ、Ｈｉｒｏｏｋａ Ｍａｓａｓｈｉ、ｅｔ ａｌ．
  • Journal Title: Oncology Volume: 97 Issue: 5 Pages: 277-285
  • DOI: 10.1159/000501281
  • Peer Reviewed
• [Journal Article] Impact of ALBI grade on survival in patients with HCC who received sorafenib: an analysis using time‐dependent ROC (2018)
  • Author(s): Tada Toshifumi、Kumada Takashi、Toyoda Hidenori、Tsuji Kunihiko、Hiraoka Atsushi、Michitaka Kojiro、Deguchi Akihiro、Ishikawa Toru、Imai Michitaka、Ochi Hironori、Joko Koji、Shimada Noritomo、Tajiri Kazuto、Hirooka Masashi、Koizumi Yohei、Hiasa Yoichi、Tanaka Junko
  • Journal Title: Journal of Gastroenterology and Hepatology Volume: - Issue: 6 Pages: 1066-1073
  • DOI: 10.1111/jgh.14564
  • Peer Reviewed
• [Journal Article] Roles of protein kinase R in cancer: Potential as a therapeutic target. (2018)
  • Author(s): Watanabe T, Imamura T, Hiasa Y.
  • Journal Title: Cancer Sci. Volume: 109 Issue: 4 Pages: 919-925
  • DOI: 10.1111/cas.13551
  • Peer Reviewed / Open Access
• [Presentation] The long noncoding RNA of RMRP induces apoptosis via PERK by ER stress in hepatocellular carcinoma. (2020)
  • Author(s): Yukimoto Atsushi, Watanabe Takao, Sunago Kotaro, Tanaka Takaaki, Nakamura Yoshiko, Koizumi Yohei, Yoshida Osamu, Tokumoto Yoshio, Hirooka Masashi, Abe Masanori, Hiasa Yoichi.
  • Organizer: The Liver Meeting of American Association for the Study of Liver disease
  • Int'l Joint Research
• [Presentation] 肝細胞癌進展における小胞体ストレス関連遺伝子PERKの役割 (2020)
  • Author(s): 行本敦、渡辺崇夫、日浅陽一
  • Organizer: 第56回日本肝臓学会総会
• [Presentation] 肝細胞癌におけるProtein kinase R (PKR)の組織バイオマーカーとしての役割と標的治療の可能性 (2020)
  • Author(s): 渡辺崇夫、徳本良雄、日浅陽一
  • Organizer: 第56回日本肝臓学会総会
• [Presentation] 肝細胞癌におけるprotein kinase R (PKR)の治療標的としての可能性 (2020)
  • Author(s): 渡辺崇夫、二宮寛子、日浅陽一
  • Organizer: 第79回日本癌学会学術集会
• [Presentation] 肝細胞癌における Protein kinase R (PKR)の役割と、治療標的としての可能性 (2020)
  • Author(s): 渡辺崇夫、今村健志、日浅陽一
  • Organizer: 第24回日本がん分子標的治療学会学術集会