Background:Circular RNAs(circRNAs)generated by back-splicing of precursor mRNAs(pre-mRNAs)are often aberrantly expressed in cancer cells.Accumulating evidence has revealed that circRNAs play a critical role in the pro...Background:Circular RNAs(circRNAs)generated by back-splicing of precursor mRNAs(pre-mRNAs)are often aberrantly expressed in cancer cells.Accumulating evidence has revealed that circRNAs play a critical role in the progression of several cancers,including colorectal cancer(CRC).However,the current understandings of the emerging functions of circRNAs in CRC lipid metabolism and the underlying molecular mechanisms are still limited.Here,we aimed to explore the role of circCAPRIN1 in regulating CRC lipid metabolism and tumorigenesis.Methods:circRNA microarray was performed with three pairs of tumor and non-tumor tissues from CRC patients.The expression of circRNAs were determined by quantitative PCR(qPCR)and in situ hybridization(ISH).The endogenous levels of circRNAs in CRC cells were manipulated by transfection with lentiviruses overexpressing or silencing circRNAs.The regulatory roles of circRNAs in the occurrence of CRC were investigated both in vitro and in vivo using gene expression array,RNA pull-down/mass spectrometry,RNA immunoprecipitation assay,luciferase reporter assay,chromatin immunoprecipitation analysis,and fluorescence in situ hybridization(FISH).Results:Among circRNAs,circCAPRIN1 was most significantly upregulated in CRC tissue specimens.circCAPRIN1 expression was positively correlated with the clinical stage and unfavorable prognosis of CRC patients.Downregulation of circCAPRIN1 suppressed proliferation,migration,and epithelial-mesenchymal transition of CRC cells,while circCAPRIN1 overexpression had opposite effects.RNA sequencing and gene ontology analysis indicated that circCAPRIN1 upregulated the expressions of genes involved in CRC lipid metabolism.Moreover,circCAPRIN1 promoted lipid synthesis by enhancing Acetyl-CoA carboxylase 1(ACC1)expression.Further mechanistic assays demonstrated that circCAPRIN1 directly bound signal transducer and activator of transcription 2(STAT2)to activate ACC1 transcription,thus regulating lipid metabolism and facilitating CRC tumorigenesis.Conclusions:These findin展开更多
基金National Natural Science Foundation of China,Grant/Award Numbers:81972260,82103259Shanghai Municipal Natural Science Foundation,Grant/Award Number:21ZR1414400Shanghai Medical Innovation Research Project,Grant/Award Number:22Y11907600。
文摘Background:Circular RNAs(circRNAs)generated by back-splicing of precursor mRNAs(pre-mRNAs)are often aberrantly expressed in cancer cells.Accumulating evidence has revealed that circRNAs play a critical role in the progression of several cancers,including colorectal cancer(CRC).However,the current understandings of the emerging functions of circRNAs in CRC lipid metabolism and the underlying molecular mechanisms are still limited.Here,we aimed to explore the role of circCAPRIN1 in regulating CRC lipid metabolism and tumorigenesis.Methods:circRNA microarray was performed with three pairs of tumor and non-tumor tissues from CRC patients.The expression of circRNAs were determined by quantitative PCR(qPCR)and in situ hybridization(ISH).The endogenous levels of circRNAs in CRC cells were manipulated by transfection with lentiviruses overexpressing or silencing circRNAs.The regulatory roles of circRNAs in the occurrence of CRC were investigated both in vitro and in vivo using gene expression array,RNA pull-down/mass spectrometry,RNA immunoprecipitation assay,luciferase reporter assay,chromatin immunoprecipitation analysis,and fluorescence in situ hybridization(FISH).Results:Among circRNAs,circCAPRIN1 was most significantly upregulated in CRC tissue specimens.circCAPRIN1 expression was positively correlated with the clinical stage and unfavorable prognosis of CRC patients.Downregulation of circCAPRIN1 suppressed proliferation,migration,and epithelial-mesenchymal transition of CRC cells,while circCAPRIN1 overexpression had opposite effects.RNA sequencing and gene ontology analysis indicated that circCAPRIN1 upregulated the expressions of genes involved in CRC lipid metabolism.Moreover,circCAPRIN1 promoted lipid synthesis by enhancing Acetyl-CoA carboxylase 1(ACC1)expression.Further mechanistic assays demonstrated that circCAPRIN1 directly bound signal transducer and activator of transcription 2(STAT2)to activate ACC1 transcription,thus regulating lipid metabolism and facilitating CRC tumorigenesis.Conclusions:These findin
