Investigation of markers and mechanisms of NASH-associated liver cancer

2019 Fiscal Year Final Research Report

• Project/Area Number: 17K07177
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Tumor biology
• Research Institution: Osaka City University
• Principal Investigator: Kakehashi Anna 大阪市立大学, 大学院医学研究科, 講師 (60382222)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: 発がん / 発がんマーカー / 動物モデル / NASH

Outline of Final Research Achievements

In obese diabetes/NASH model TSOD mice, a large number of altered foci (AF) and liver tumors were developed. Metabolome analysis revealed significant elevation of glucose metabolites and L-Arg in HCCs of TSOD mice. Furthermore, immunohistochemistry demonstrated rise in phosphokinases, P-mTOR and inhibition of arginase 1 (ARG1) in HCCs. It was concluded that elevation of glucose metabolites and L-Arg, decreased ARG1 expression and activation of mTOR pathway are main characteristics of NASH HCCs. In NASH model STAM mice, significant overexpression of CACHD1 was found in AF and tumors. Significant decrease of autophagy marker Atg12 and increase of p62 were detected in CACHD1+ precancerous lesions and tumors of STAM mice.In human NASH HCCs, the survival rate of ARG1- and CACHD1+ HCC patients was significantly reduced compared to ARG1+ and CACHD1- patients. It is suggested that ARG1 and CACHD1 are potential markers of NASH liver carcinogenesis.

Free Research Field

発がん

Academic Significance and Societal Importance of the Research Achievements

肥満、糖尿病、脂質異常症などを伴ったいわゆるメタボリックシンドロームでみられるインスリン抵抗性が病因の一つとされている非アルコール性脂肪肝炎は、ウイルス性の慢性肝炎同様、肝細胞癌を発生することが明らかとなり、肝癌発症の背景疾患として注目が高まっている。本研究で発見した新規NASH関連肝発がんマーカーCACHD1およびARG1がメタボリックシンドロームおよびNASHに由来肝細胞癌の早期発見、癌の予後、治療のために新規マーカーとして使用される可能性が示され、発がんメカニズムは明らかにするためにも重要である。