Explore new therapies targeting endoplasmic reticulumn stress response for Hepatocellular Carcinoma

• Project/Area Number: 16K19346
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Gastroenterology
• Research Institution: Hiroshima University
• Principal Investigator: Zhang Yizhou 広島大学, 医歯薬保健学研究科(医), 研究員 (70711117)
• Project Period (FY): 2016-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 肝細胞癌 / 小胞体ストレス / BBF2H7 / 分子標的治療 / ER stress response / CRISPR-CAS9 / cancer targeted therapy / ゲノム編集

Outline of Final Research Achievements

Using genome-wide transcriptome profiles and in vitro validation, we elucidated the mechanism of how ER stress transducer CREB3L2/BBF2H7 promotes hepatocarcinogenesis. BBF2H7 is over-activated in hepatocellular carcinoma (HCC), and is associated with an aggressive HCC subtype correlating with poor clinical outcome. At the molecular level, we found a partial fragment of BBF2H7 to be competitively bound to a subunit of AP-1, thus blocking AP-1 transcriptional activity and indirectly suppressing the stability of p53. In rescue experiments, we demonstrated that this fragment is indispensable to the proliferation of HCC, suggesting a potential target for the treatment of this common cancer.

Research Products

• [Journal Article] Serum HMGB1 concentrations at 4 weeks is a useful predictor of extreme poor prognosis for advanced hepatocellular carcinoma treated with sorafenib and hepatic arterial infusion chemotherapy. (2018)
  • Author(s): Masuda K, Ono A, Aikata H, Kawaoka T, Nelson Hayes C, Teraoka Y, Daijo K, Nakamura-Inagaki Y, Morio K, Fujino H, Kan H, Uchida T, Masaki K, Kobayashi T, Nakahara T, Makokha GN, Zhang Y, Nagaoki Y, Miki D, Tsuge M, Hiramatsu A, Imamura M, Abe-Chayama H, Kawakami Y, Ochi H, Chayama K.
  • Journal Title: J Gastroenterol. Volume: 53 Issue: 1 Pages: 107-118
  • DOI: 10.1007/s00535-017-1348-8
  • Peer Reviewed
• [Journal Article] The association between serum cytokine and chemokine levels and antiviral response by entecavir treatment in chronic hepatitis B patients (2017)
  • Author(s): Kurihara M, Tsuge M, Murakami E, Mori N, Ohishi W, Uchida T, Fujino H, Nakahara T, Abe-Chayama H, Kawaoka T, Miki D, Hiramatsu A, Imamura M, Kawakami Y, Aikata H, Ochi H, Zhang Y, Makokha GN, Hayes CN, Chayama K.
  • Journal Title: Antivir Ther Volume: Epub ahead of print Issue: 3 Pages: 239-248
  • DOI: 10.3851/imp3196
  • Peer Reviewed
• [Journal Article] Persistent loss of HBV markers in serum without cellular immunity by combination of PEG-IFN plus ETV therapy in humanized mice (2017)
  • Author(s): Uchida T, Imamura M, Hayes CN, Hiraga N, Kan H, Tsuge M, Abe-Chayama H, Zhang Y, Makokha GN, Aikata H, Miki D, Ochi H, Ishida Y, Tateno C, Chayama K
  • Journal Title: Antimicrob Agents Chemother Volume: 61 Issue: 9
  • DOI: 10.1128/aac.00725-17
  • Peer Reviewed / Open Access
• [Journal Article] Antiviral effects of anti-HBs immunoglobulin and vaccine on HBs antigen seroclearance for chronic hepatitis B infection. (2016)
  • Author(s): Tsuge M, Hiraga N, Uchida T, Kan H, Miyaki E, Masaki K, Ono A, Nakahara T, Abe-Chayama H, Zhang Y, Naswa MG, Kawaoka T, Miki D, Imamura M, Kawakami Y, Aikata H, Ochi H, Hayes CN, Chayama K.
  • Journal Title: Journal of Gastroenterology Volume: In press Issue: 11 Pages: 1073-1080
  • DOI: 10.1007/s00535-016-1189-x
  • Peer Reviewed / Open Access
• [Presentation] New insights on the role of endoplasmic reticulum stress response in development of hepatocellular carcinoma (2017)
  • Author(s): Yizhou Zhang, C Nelson Hayes, Tadahiko Yoshima, Masataka Tsuge, Hiromi Abe-Chayama, Kazuaki Chayama
  • Organizer: AASLD
  • Int'l Joint Research
• [Presentation] Hepatocellular Carcinoma Promotion by Endoplasmic Reticulum Stress Transducer BBF2H7. (2016)
  • Author(s): Yizhou Zhang, Nelson Hayes, Masataka Tsuge, Takuro Uchida, Daiki Miki, Hiromi Abe, Kazuaki Chayama
  • Organizer: AASLD 2016.
  • Place of Presentation: Boston, USA.
  • Int'l Joint Research