Hepatocellular carcinoma differentiation by reactivating HNF-4a

• Project/Area Number: 18K19538
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 53:Organ-based internal medicine and related fields
• Research Institution: Kanazawa University
• Principal Investigator: Yamashita Taro 金沢大学, 附属病院, 准教授 (90377432)
• Project Period (FY): 2018-06-29 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000); Fiscal Year 2019: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000); Fiscal Year 2018: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000)
• Keywords: 肝細胞がん / 肝細胞分化 / HNF-4α / 肝発がん

Outline of Final Research Achievements

Hepatocellular carcinoma is one of the most common deadly cancer in Japan, and approximately 30,000 patients die each year. HNF4A is a nuclear receptor known to regulate lipid, carbohydrate, amino acid, and drug metabolism, but it also work as a tumor suppressor to regulate cell cycle. In this study, we evaluated the potential candidate molecules to regulated HNF4A gene expression or HNF4A transcriptional activation. We found that regorafenib and HDAC inhibitor enhanced the expression of HNF4A in Huh7 HCC cell lines. We further found that polyprenoic acid induced the transcriptional activation of HNF4A, and lauric acid additively activate the function of polyprenoic acid to induce transcriptional activation of HNF4A.

Academic Significance and Societal Importance of the Research Achievements

肝細胞がんにおいてHNF4Aは遺伝子変異を認めない転写因子であり、かつ活性化されることで細胞増殖を呈しさせる、薬物標的として有用な核内受容体と考えられる。しかしその制御機構や活性化リガンドは未だ十分明らかになっていない。本研究では新たなHNF4A遺伝子発現を活性化させる分子標的薬やHNF4A転写活性を制御する脂質を見出しており、新しい機序に基づく肝細胞がん治療への応用が期待される。

Research Products

• [Journal Article] Inactivation of Transcriptional Repressor Capicua Confers Sorafenib Resistance in Human Hepatocellular Carcinoma (2020)
  • Author(s): Hashiba Tomomi、Yamashita Taro、et al
  • Journal Title: Cellular and Molecular Gastroenterology and Hepatology Volume: 20 Issue: 2 Pages: 30039-4
  • DOI: 10.1016/j.jcmgh.2020.02.009
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The osteopontin-CD44 axis in hepatic cancer stem cells regulates IFN signaling and HCV replication. (2018)
  • Author(s): Shirasaki T, Honda M, Yamashita T, Nio K, Shimakami T, Shimizu R, Nakasyo S, Murai K, Shirasaki N, Okada H, Sakai Y, Sato T, Suzuki T, Yoshioka K, Kaneko S.
  • Journal Title: Sci Rep. Volume: 8 Issue: 1 Pages: 13143-13143
  • DOI: 10.1038/s41598-018-31421-6
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] 1.Dickkopf-1 is a new molecular target for the treatment of hepatocellular carcinoma (2018)
  • Author(s): Tsuyoshi Suda, Taro Yamashita, Shuichi Kaneko,
  • Organizer: AASLD Annual Meeting
  • Int'l Joint Research