Inhibiting cholesterol de novo synthesis promotes hepatocellular carcinoma progression by upregulating prostaglandin E synthase 2-mediated arachidonic acid metabolism under high fatty acid conditions

作者全名："Zhao, Zhibo; Liu, Xinyi; Xiang, Yue; Hou, Zhengping; He, Kun; Zhong, Guochao; Hu, Jiejun; Cai, Dong; Liu, Yan; Ren, Jihua; Gong, Jianping; Zhao, Lei"

作者地址："[Zhao, Zhibo; Liu, Xinyi; Xiang, Yue; Hou, Zhengping; He, Kun; Zhong, Guochao; Hu, Jiejun; Cai, Dong; Liu, Yan; Ren, Jihua; Gong, Jianping; Zhao, Lei] Chongqing Med Univ, Affiliated Hosp 2, Ctr Lipid Res, Dept Hepatobiliary Surg, 1 Med Rd, Chongqing, Peoples R China; [Zhao, Zhibo; Liu, Xinyi; Xiang, Yue; Hou, Zhengping; He, Kun; Zhong, Guochao; Hu, Jiejun; Cai, Dong; Liu, Yan; Ren, Jihua; Gong, Jianping; Zhao, Lei] Chongqing Med Univ, Affiliated Hosp 2, Minist Educ, Key Lab Mol Biol Infect Dis, 1 Med Rd, Chongqing, Peoples R China; [Liu, Xinyi] Peoples Hosp Jianyang City, Dept Gen Surg, Jianyang, Peoples R China; [Liu, Yan] Chengdu Univ Tradit Chinese Med, Affiliated Peoples Hosp 5, Chengdu, Peoples R China"

通信作者："Ren, JH; Gong, JP; Zhao, L (通讯作者)，Chongqing Med Univ, Affiliated Hosp 2, Ctr Lipid Res, Dept Hepatobiliary Surg, 1 Med Rd, Chongqing, Peoples R China.; Ren, JH; Gong, JP; Zhao, L (通讯作者)，Chongqing Med Univ, Affiliated Hosp 2, Minist Educ, Key Lab Mol Biol Infect Dis, 1 Med Rd, Chongqing, Peoples R China."

来源：CANCER SCIENCE

ESI学科分类：CLINICAL MEDICINE

WOS号：WOS:001120097000001

JCR分区：Q1

影响因子：4.5

年份：2023

卷号：　

期号：　

开始页：　

结束页：　

文献类型：Article; Early Access

关键词：arachidonic acid metabolism; cholesterol DNS; HCC; PTGES2; statin

摘要："Inhibition of cholesterol de novo synthesis (DNS) by statins has controversial effects on the treatment of hepatocellular carcinoma (HCC). High fatty acid conditions have been reported to limit the effect of statins on metabolism diseases. Whether high fatty acid conditions interfere with the effect of statins on HCC remains unclear. Here, we reported that inhibiting cholesterol DNS with atorvastatin promoted the oncogenic capabilities of diethylnitrosamine (DEN) in mice fed high fatty acid diets (HFD). The combined analysis of metabolomics and transcriptomics revealed that arachidonic acid (AA) metabolism was the most significant changed pathway between mice with and without atorvastatin treatment. In vitro, in the presence of AA precursor linoleic acid (LA), atorvastatin promoted the proliferation and migration ability of HCC cell lines. However, in the absence of LA, these phenomena disappeared. TCGA and tissue microarray examination revealed that prostaglandin e synthase 2 (PTGES2), a key enzyme in AA metabolism, was associated with the poor outcome of HCC patients. Overexpression of PTGES2 promoted the proliferation and migration of HCC cell lines, and knockdown of PTGES2 inhibited the proliferation and migration of cells. Additionally, atorvastatin upregulated PTGES2 expression by enhancing Sterol-regulatory element binding protein 2 (SREBP2)-mediated transcription. Knockdown of PTGES2 reversed the proliferation and migration ability enhanced by atorvastatin. Overall, our study reveals that a high fatty acid background is one of the possible conditions limiting the application of statins in HCC, under which statins promote the progression of HCC by enhancing SREBP2-mediated PTGES2 transcription. Inhibition of cholesterol DNS promotes nuclear transposition of SREBP2, which activates the transcription of PTGES2. In the presence of high fatty acids, LA or AA provides abundant substrate for PTGES2, which catalyzes the production of PGE2. The upregulated PGE2 is a well-studied risk factor that promotes the proliferation and metastasis of HCC.image"

基金机构：National Natural Science Foundation of China

基金资助正文：We appreciate Professor Ruan Xiongzhong and Chen Yaxi for sharing their experimental platform.