Search for new therapeutic targets for obesity-induced liver cancer focusing on mRNA degradation regulation

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K16309
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 50010:Tumor biology-related
• Research Institution: Osaka Metropolitan University (2022); Osaka City University (2020-2021)
• Principal Investigator: Yamagishi Ryota 大阪公立大学, 大学院医学研究科, 助教 (30793145)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: 肥満誘導性肝がん / SASP / 細胞老化

Outline of Final Research Achievements

In recent years, the number of patients with obesity-induced hepatocellular carcinoma (HCC) based on fatty liver has been increasing steadily, and the development of preventive and treatment methods is urgently needed. In this study, as a result of analyzing the SASP factors related to the development of obesity-induced liver cancer, we found that the cytokine IL-33 is a SASP factor that is particularly highly expressed in hepatic stellate cells (HSCs) in the obesity-induced liver tumor. Furthermore, as a mechanism for the extracellular release of SASP factors, the SASP factor IL-33 is released outside the HSCs through pores formed on the cell membrane by the pyroptosis-executing factor gasdermin D. The released IL-33 promoted HCC development through activating ST2-positive Treg cells. Our findings could lead to new insights for understanding obesity-induced HCC progression.

Free Research Field

腫瘍生物学

Academic Significance and Societal Importance of the Research Achievements

肝がんは、5年生存率が35.8％程度(がん腫別統計2021）と低い。そのため、肝がんの原因遺伝子を探るためのゲノム解析が、世界的に進められているが、発症に結び付く特定の原因遺伝子変異は見つかっていない。その中で、これまで肝がんの半数以上を占めてきたウイルス性肝がんは有効な抗ウイルス薬の開発により減少傾向となっている。一方で、脂肪肝を背景とする肥満誘導性肝がんは著しい増加傾向にあり、その予防法・治療法の開発は喫緊の課題となっている。そのため、肝がん微小環境に着目した本研究の成果は、肥満誘導性肝がんの治療法開発に繋がる有用な成果であると考えられる。