Inhibiting HMGCR represses stemness and metastasis of hepatocellular carcinoma via Hedgehog signaling  

作　　者：Zhirong Zhang Jiayao Yang Rui Liu Jing Ma Kai Wang Xiaojun Wang Ni Tang 

机构地区：[1]Key Laboratory of Molecular Biology for Infectious Diseases(Ministry of Education),Institute for Viral Hepatitis,Department of Infectious Diseases,The Second Affiliated Hospital,Chongqing Medical University,Chongqing 400016,China [2]Institute of Hepatobiliary Surgery,Southwest Hospital,Third Military Medical University(Army Medical University),Chongqing 400038,China

出　　处：《Genes & Diseases》2024年第5期470-483,共14页基因与疾病（英文）

基　　金：the National Key Research and Development Program of China(No.2023YFC2306803);the China National Natural Science Foundation(No.82273238,82272975,82072286);the Innovative and Entrepreneurial Team of Chongqing Talents Plan,Chongqing Medical Scientific Research Project(Joint Project of Chongqing Health Commission and Science and Technology Bureau;No.2023DBXM007);Senior Medical Talents Program of Chongqing for Young and Middle-aged,the Kuanren Talents and DengFeng program of the Second Affiliated Hospital of Chongqing Medical University(China),the Future Medical Youth Innovation Team of Chongqing Medical University(China)(No.W0036,W0101);the Postdoctoral Fellowship Program of China Postdoctoral Science Foundation(No.GZC20233349).

摘　　要：Cancer stem cells(CSCs)play a crucial role in tumor initiation,recurrence,metastasis,and drug resistance.However,the current understanding of CSCs in hepatocellular carcinoma(HCC)remains incomplete.Through a comprehensive analysis of the database,it has been observed that 3-hydroxy-3-methylglutaryl-coenzyme A reductase(HMGCR),a critical enzyme involved in cholesterol synthesis,is up-regulated in HCC tissues and liver CSCs.Moreover,high expression of HMGCR is associated with a poor prognosis in patients with HCC.Functionally,HMGCR promotes the stemness and metastasis of HCC both in vitro and in vivo.By screening various signaling pathway inhibitors,we have determined that HMGCR regulates stemness and metastasis by activating the Hedgehog signaling in HCC.Mechanistically,HMGCR positively correlates with the expression of the Smoothened receptor and facilitates the nuclear translocation of the transcriptional activator GLI family zinc finger 1.Inhibition of the Hedgehog pathway can reverse the stimulatory effects of HMGCR on stemness and metastasis in HCC.Notably,simvastatin,an FDA-approved cholesterol-lowering drug,has been shown to inhibit stemness and metastasis of HCC by targeting HMGCR.Taken together,our findings suggest that HMGCR promotes the regeneration and metastasis of HCC through the activation of Hedgehog signaling,and simvastatin holds the potential for clinical suppression of HCC metastasis.

关 键 词：Cancer stem cells HEDGEHOG Hepatocellular carcinoma METASTASIS STATIN 

分 类 号：R735.7[医药卫生—肿瘤]