Retinoid-Mediated Suppression of Hepatocellular Carcinoma Invasion through a Novel Regulatory Mechanism of Gene Expression

2018 Fiscal Year Final Research Report

• Project/Area Number: 16K09359
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Tottori University
• Principal Investigator: Tsuchiya Hiroyuki 鳥取大学, 医学(系)研究科(研究院), 准教授 (00403402)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: 肝細胞癌 / レチノイド / 癌細胞浸潤 / RAR / TFPI2 / MAFファミリー

Outline of Final Research Achievements

Retinoids exert antitumor effects mainly through retinoic acid receptor α (RARα). In the present study, I identified the factors involved in the RARα-mediated transcriptional regulation of the tumor suppressor gene, tissue factor pathway inhibitor 2 (TFPI2), in hepatocellular carcinoma (HCC). All-trans-retinoic acid (ATRA) significantly increased TFPI2 expression through RARα in a human HCC cell line. TFPI2 was vital in the ATRA-mediated suppression of HCC cell invasion. Musculoaponeurotic fibrosarcoma oncogene homolog B (MAFB) significantly enhanced the activation of the TFPI2 promoter via RARα, while MAFF inhibited it. Patients with HCC expressing low MAFB and high MAFF levels showed the shortest disease-free survival time. These results suggest that MAFB and MAFF play critical roles in the antitumor effects of retinoids by regulating the expression of retinoid target genes, such as TFPI2, and can be promising in the development of therapies to combat HCC invasion.

Free Research Field

肝臓学

Academic Significance and Societal Importance of the Research Achievements

これまでレチノイドとTFPI2が癌細胞浸潤を阻害することは知られていたが、両者を関係づけた本研究が初めてである。またMAFファミリーについても同様である。これによってレチノイドによる新たな抗腫瘍作用とそのメカニズムが明らかになった。さらに、これまで申請者を含め数多くの研究グループがレチノイドの優れた有効性を報告してきたが、レチノイドに伴う許容しがたい副作用はその有効性を損なう大きな障害となっている。そのため本研究で明らかになったメカニズムを利用し、レチノイドに伴う副作用を回避したより特異性の高い治療薬の開発への展開が可能となる。