Hepatocellular carcinoma(HCC)is the fourth leading cause of cancer-associated death worldwide.Angiogenesis,the process of formation of new blood vessels,is required for cancer cells to obtain nutrients and oxygen.HCC ...Hepatocellular carcinoma(HCC)is the fourth leading cause of cancer-associated death worldwide.Angiogenesis,the process of formation of new blood vessels,is required for cancer cells to obtain nutrients and oxygen.HCC is a typical hypervascular solid tumor with an aberrant vascular network and angiogenesis that contribute to its growth,progression,invasion,and metastasis.Current anti-angiogenic therapies target mainly tyrosine kinases,vascular endothelial growth factor receptor(VEGFR),and plateletderived growth factor receptor(PDGFR),and are considered effective strategies for HCC,particularly advanced HCC.However,because the survival benefits conferred by these anti-angiogenic therapies are modest,new anti-angiogenic targets must be identified.Several recent studies have determined the underlying molecular mechanisms,including pro-angiogenic factors secreted by HCC cells,the tumor microenvironment,and cancer stem cells.In this review,we summarize the roles of pro-angiogenic factors;the involvement of endothelial cells,hepatic stellate cells,tumor-associated macrophages,and tumor-associated neutrophils present in the tumor microenvironment;and the regulatory influence of cancer stem cells on angiogenesis in HCC.Furthermore,we discuss some of the clinically approved anti-angiogenic therapies and potential novel therapeutic targets for angiogenesis in HCC.A better understanding of the mechanisms underlying angiogenesis may lead to the development of more optimized anti-angiogenic treatment modalities for HCC.展开更多
Background:Circular RNAs(circRNAs)are endogenous non-coding RNAs,some of which have pathological roles.The current study aimed to explore the role of circRNA BTG3-associated nuclear protein(circ-BANP)binding with let-...Background:Circular RNAs(circRNAs)are endogenous non-coding RNAs,some of which have pathological roles.The current study aimed to explore the role of circRNA BTG3-associated nuclear protein(circ-BANP)binding with let-7f-5p and its regulation of the toll-like receptor 4(TLR4)/signal transducer and activator of transcription 3(STAT3)signaling pathway in residual hepatocellular carcinoma(HCC)after insufficient radiofrequency ablation(RFA).Methods:Circ-BANP,let-7f-5p,and TLR4 expressions in HCC samples were assessed using reverse transcription-quantitative polymerase chain reaction(RT-qPCR)and Western blotting.Bioinformatics prediction,RNA pull-down assay,and dual luciferase reporter gene assay were used to analyze the relationships among circ-BANP,let-7f-5p,and TLR4.Huh7 cells were used to generate an in vitro model of residual HCC,defined as Huh7-H cells,which were transfected with either a plasmid or the sequence of circ-BANP,let-7f-5p,or TLR4.Expression of circ-BANP,let-7f-5p,and TLR4 mRNA was determined by RT-qPCR.TLR4,STAT3,p-STAT3,vascular endothelial growth factor A,vascular endothelial growth factor receptor-2,and epithelialmesenchymal transformation(EMT)-related factors proteins were determined by Western blotting.Cell proliferation was determined by cell counting kit-8 and 5-Ethynyl-2’-deoxyuridine(EdU)assay and cell migration and invasion by Transwell assay.Animal studies were performed by inducing xenograft tumors in nude mice.Results:Circ-BANP and TLR4 mRNAs were upregulated in HCC tissues(the fold change for circ-BANP was 1.958 and that for TLR4 was 1.736 relative to para-tumors)and expression further increased following insufficient RFA(fold change for circBANP was 2.407 and that of TLR4 was 2.224 relative to para-tumors).Expression of let-7f-5p showed an opposite tendency(fold change for let-7f-5p in HCC tissues was 0.491 and that in tumors after insufficient RFA was 0.300 relative to paratumors).Competitive binding of circ-BANP to let-7f-5p was demonstrated and TLR4 was identified as a target of let-7f-5p(P<0.01).Knockdown of circ-BANP or elevation of let-7f-5p expression inhibited the TLR4/STAT3 signaling pathway,proliferation,invasion,migration,angiogenesis,and EMT in Huh7 and Huh7-H cells(P<0.01).The effects induced by circBANP knockdown were reversed by let-7f-5p inhibition.Overexpression of TLR4 reversed the impact of let-7f-5p upregulation on the cells(P<0.01).Silencing of circ-BANP inhibited the in vivo growth of residual HCC cells after insufficient RFA(P<0.01).Conclusions:Knockdown of circ-BANP upregulated let-7f-5p to inhibit proliferation,migration,and EMT formation in residual HCC remaining after insufficient RFA.Effects occur via regulation of the TLR4/STAT3 signaling pathway.展开更多
基金supported by the National Key Research and Development Program of China(Grant No.2020YFA0803700)the National Natural Science Foundation of China(Grant Nos.91639108,81770272,and 81970425)+1 种基金the Beijing Natural Science Foundation(Grant No.7212044)the Beijing Hospital Authority Youth Program(Grant No.QML20190306)。
文摘Hepatocellular carcinoma(HCC)is the fourth leading cause of cancer-associated death worldwide.Angiogenesis,the process of formation of new blood vessels,is required for cancer cells to obtain nutrients and oxygen.HCC is a typical hypervascular solid tumor with an aberrant vascular network and angiogenesis that contribute to its growth,progression,invasion,and metastasis.Current anti-angiogenic therapies target mainly tyrosine kinases,vascular endothelial growth factor receptor(VEGFR),and plateletderived growth factor receptor(PDGFR),and are considered effective strategies for HCC,particularly advanced HCC.However,because the survival benefits conferred by these anti-angiogenic therapies are modest,new anti-angiogenic targets must be identified.Several recent studies have determined the underlying molecular mechanisms,including pro-angiogenic factors secreted by HCC cells,the tumor microenvironment,and cancer stem cells.In this review,we summarize the roles of pro-angiogenic factors;the involvement of endothelial cells,hepatic stellate cells,tumor-associated macrophages,and tumor-associated neutrophils present in the tumor microenvironment;and the regulatory influence of cancer stem cells on angiogenesis in HCC.Furthermore,we discuss some of the clinically approved anti-angiogenic therapies and potential novel therapeutic targets for angiogenesis in HCC.A better understanding of the mechanisms underlying angiogenesis may lead to the development of more optimized anti-angiogenic treatment modalities for HCC.
基金supported by a grant from the National Natural Science Foundation of China(No.8157110423).
文摘Background:Circular RNAs(circRNAs)are endogenous non-coding RNAs,some of which have pathological roles.The current study aimed to explore the role of circRNA BTG3-associated nuclear protein(circ-BANP)binding with let-7f-5p and its regulation of the toll-like receptor 4(TLR4)/signal transducer and activator of transcription 3(STAT3)signaling pathway in residual hepatocellular carcinoma(HCC)after insufficient radiofrequency ablation(RFA).Methods:Circ-BANP,let-7f-5p,and TLR4 expressions in HCC samples were assessed using reverse transcription-quantitative polymerase chain reaction(RT-qPCR)and Western blotting.Bioinformatics prediction,RNA pull-down assay,and dual luciferase reporter gene assay were used to analyze the relationships among circ-BANP,let-7f-5p,and TLR4.Huh7 cells were used to generate an in vitro model of residual HCC,defined as Huh7-H cells,which were transfected with either a plasmid or the sequence of circ-BANP,let-7f-5p,or TLR4.Expression of circ-BANP,let-7f-5p,and TLR4 mRNA was determined by RT-qPCR.TLR4,STAT3,p-STAT3,vascular endothelial growth factor A,vascular endothelial growth factor receptor-2,and epithelialmesenchymal transformation(EMT)-related factors proteins were determined by Western blotting.Cell proliferation was determined by cell counting kit-8 and 5-Ethynyl-2’-deoxyuridine(EdU)assay and cell migration and invasion by Transwell assay.Animal studies were performed by inducing xenograft tumors in nude mice.Results:Circ-BANP and TLR4 mRNAs were upregulated in HCC tissues(the fold change for circ-BANP was 1.958 and that for TLR4 was 1.736 relative to para-tumors)and expression further increased following insufficient RFA(fold change for circBANP was 2.407 and that of TLR4 was 2.224 relative to para-tumors).Expression of let-7f-5p showed an opposite tendency(fold change for let-7f-5p in HCC tissues was 0.491 and that in tumors after insufficient RFA was 0.300 relative to paratumors).Competitive binding of circ-BANP to let-7f-5p was demonstrated and TLR4 was identified as a target of let-7f-5p(P<0.01).Knockdown of circ-BANP or elevation of let-7f-5p expression inhibited the TLR4/STAT3 signaling pathway,proliferation,invasion,migration,angiogenesis,and EMT in Huh7 and Huh7-H cells(P<0.01).The effects induced by circBANP knockdown were reversed by let-7f-5p inhibition.Overexpression of TLR4 reversed the impact of let-7f-5p upregulation on the cells(P<0.01).Silencing of circ-BANP inhibited the in vivo growth of residual HCC cells after insufficient RFA(P<0.01).Conclusions:Knockdown of circ-BANP upregulated let-7f-5p to inhibit proliferation,migration,and EMT formation in residual HCC remaining after insufficient RFA.Effects occur via regulation of the TLR4/STAT3 signaling pathway.
