PTPRO represses colorectal cancer tumorigenesis and progression by reprogramming fatty acid metabolism  

作　　者：Weixing Dai Wenqiang Xiang Lingyu Han Zixu Yuan Renjie Wang Yanlei Ma Yongzhi Yang Sanjun Cai Ye Xu Shaobo Mo Qingguo Li Guoxiang Cai 

机构地区：[1]Department of Colorectal Surgery,Fudan University Shanghai Cancer Center,Shanghai 200032,P.R.China [2]Department of Oncology,Shanghai Medical College,Fudan University,Shanghai 200032,P.R.China [3]Department of Surgery,Sixth Affiliated Hospital of Sun Yat-sen University,Guangzhou,Guangdong 528406,P.R.China

出　　处：《Cancer Communications》2022年第9期848-867,共20页癌症通讯（英文）

基　　金：National Natural Science Foundation of China,Grant/Award Numbers:81871958,82103554;Science and Technology Commission of Shanghai Municipality,Grant/Award Numbers:19140902100,16401970502,17411951100。

摘　　要：Background:Abnormal expression of protein tyrosine phosphatases(PTPs)has been reported to be a crucial cause of cancer.As a member of PTPs,protein tyrosine phosphatase receptor type O(PTPRO)has been revealed to play tumor suppressive roles in several cancers,while its roles in colorectal cancer(CRC)remains to be elucidated.Hence,we aimed to explore the roles and mechanisms of PTPRO in CRC initiation and progression.Methods:The influences of PTPRO on the growth and liver metastasis of CRC cells and the expression patterns of different lipid metabolism enzymes were evaluated in vitro and in vivo.Molecular and biological experiments were conducted to uncover the underpinning mechanisms of dysregulated de novo lipogenesis and fatty acidβ-oxidation.Results:PTPRO expression was notably downregulated in CRC liver metastasis compared to the primary cancer,and such a downregulation was associated with poor prognosis of patients with CRC.PTPRO silencing significantly promoted cell growth and liver metastasis.Compared with PTPRO wild-type mice,PTPROknockout mice developed more tumors and harbored larger tumor loads under treatment with azoxymethane and dextran sulfate sodium.Gene set enrichment analysis revealed that PTPRO downregulation was significantly associated with the fatty acid metabolism pathways.Blockage of fatty acid synthesis abrogated the effects of PTPRO silencing on cell growth and liver metastasis.Further experiments indicated that PTPRO silencing induced the activation of the AKT serine/threonine kinase(AKT)/mammalian target of rapamycin(mTOR)signaling axis,thus promoting de novo lipogenesis by enhancing the expression of sterol regulatory element-binding protein 1(SREBP1)and its target lipogenic enzyme acetyl-CoA carboxylase alpha(ACC1)by activating the AKT/mTOR signaling pathway.Furthermore,PTPRO attenuation decreased the fatty acid oxidation rate by repressing the expression of peroxisome proliferator-activated receptor alpha(PPARα)and its downstream enzyme peroxisomal acyl-coenzyme A oxidase 1(ACOX1)v

关 键 词：AKT colorectal cancer fatty acid oxidation fatty acid synthesis lipid metabolism liver metastasis MTOR PTPRO TUMORIGENESIS 

分 类 号：R735.3[医药卫生—肿瘤]