Overexpression of wild-type HRAS drives non-alcoholic steatohepatitis to hepatocellular carcinoma in mice  

作　　者：Chen Ling Su-Su Liu Yu-Ya Wang Gui-Tao Huo Yan-Wei Yang Nan Xu Hong Wang Yong Wu Yu-Fa Miao Rui Fu Yu-Wei Zhao Chang-Fa Fan 

机构地区：[1]College of Life Sciences,Northwest University,Provincial Key Laboratory of Biotechnology of Shaanxi Province,Xi’an,Shaanxi 710069,China [2]Division of Animal Model Research,Institute for Laboratory Animal Resources,National Institutes for Food and Drug Control(NIFDC),Beijing 102629,China [3]National Center for Safety Evaluation of Drugs,National Institutes for Food and Drug Control(NIFDC),Beijing 100176,China [4]Division of HIV/AIDS and Sexually Transmitted Virus Vaccines,Institute for Biological Products Control,National Institutes for Food and Drug Control(NIFDC),Beijing 102629,China [5]Division of Laboratory Animal Monitoring,Institute for Laboratory Animal Resources,National Institutes for Food and Drug Control(NIFDC),Beijing 102629,China

出　　处：《Zoological Research》2024年第3期551-566,共16页动物学研究（英文）

基　　金：supported by the National Institutes for Food and Drug Control,State Key Laboratory of Drug Regulatory Science。

摘　　要：Hepatocellular carcinoma(HCC),a prevalent solid carcinoma of significant concern,is an aggressive and often fatal disease with increasing global incidence rates and poor therapeutic outcomes.The etiology and pathological progression of non-alcoholic steatohepatitis(NASH)-related HCC is multifactorial and multistage.However,no single animal model can accurately mimic the full NASH-related HCC pathological progression,posing considerable challenges to transition and mechanistic studies.Herein,a novel conditional inducible wild-type human HRAS overexpressed mouse model(HRAS-HCC)was established,demonstrating 100%morbidity and mortality within approximately one month under normal dietary and lifestyle conditions.Advanced symptoms of HCC such as ascites,thrombus,internal hemorrhage,jaundice,and lung metastasis were successfully replicated in mice.In-depth pathological features of NASH-related HCC were demonstrated by pathological staining,biochemical analyses,and typical marker gene detections.Combined murine anti-PD-1 and sorafenib treatment effectively prolonged mouse survival,further confirming the accuracy and reliability of the model.Based on protein-protein interaction(PPI)network and RNA sequencing analyses,we speculated that overexpression of HRAS may initiate the THBS1-COL4A3 axis to induce NASH with severe fibrosis,with subsequent progression to HCC.Collectively,our study successfully duplicated natural sequential progression in a single murine model over a very short period,providing an accurate and reliable preclinical tool for therapeutic evaluations targeting the NASH to HCC continuum.

关 键 词：HRAS THBS1 HCC driver factor NASH FIBROSIS Cirrhosis HCC Treatment evaluation 

分 类 号：R575[医药卫生—消化系统] R735.7[医药卫生—内科学]