(-)-Epigallocatechin gallate (EGCG), a major polyphenolic constituent of green tea, can inhibit activity of specific receptor tyrosine kinases (RTKs) and related downstream signal transduction pathways, resultin...(-)-Epigallocatechin gallate (EGCG), a major polyphenolic constituent of green tea, can inhibit activity of specific receptor tyrosine kinases (RTKs) and related downstream signal transduction pathways, resulting in the control of unwanted cell proliferation. The epidermal growth factor receptor (EGFR) signaling pathway is one of the most important pathways that regulates growth, survival,proliferation and differentiation in mammalian cells. This review addresses the effects of EGCG on some protein factors involved in the EGFR signaling pathway in a direct or indirect manner. Based on our understanding of the interaction between EGCG and these factors, and based on their structures, EGCG could be used as a lead compound for designing and synthesizing novel drugs with significant biological activity.展开更多
BACKGROUND Colorectal cancer(CRC)is an extremely malignant tumor with a high mortality rate.Little is known about the mechanism by which forkhead Box q1(FOXQ1)causes CRC invasion and metastasis through the epidermal g...BACKGROUND Colorectal cancer(CRC)is an extremely malignant tumor with a high mortality rate.Little is known about the mechanism by which forkhead Box q1(FOXQ1)causes CRC invasion and metastasis through the epidermal growth factor receptor(EGFR)pathway.AIM To illuminate the mechanism by which FOXQ1 promotes the invasion and metastasis of CRC by activating the heparin binding epidermal growth factor(HB-EGF)/EGFR pathway.METHODS We investigated the differential expression and prognosis of FOXQ1 and HB-EGF in CRC using the Gene Expression Profiling Interactive Analysis(GEPIA)website(http://gepia.cancer-pku.cn/index.html).Quantitative real-time polymerase chain reaction(qRT-PCR)and Western blotting were used to detect the expression of FOXQ1 and HB-EGF in cell lines and tissues,and we constructed a stable lowexpressing FOXQ1 cell line and verified it with the above method.The expression changes of membrane-bound HB-EGF(proHB-EGF)and soluble HB-EGF(sHB-EGF)in the lowexpressing FOXQ1 cell line were detected by flow cytometry and ELISA.Western blotting was used to detect changes in the expression levels of HB-EGF and EGFR pathway-related downstream genes when exogenous recombinant human HB-EGF was added to FOXQ1 knockdown cells.Proliferation experiments,transwell migration experiments,and scratch experiments were carried out to determine the mechanism by which FOXQ1 activates the EGFR signaling pathway through HB-EGF,and then to evaluate the clinical relevance of FOXQ1 and HB-EGF.RESULTS GEPIA showed that the expression of FOXQ1 in CRC tissues was relatively high and was related to a lower overall survival rate.PCR array results showed that FOXQ1 is related to the HB-EGF and EGFR pathways.Knockdown of FOXQ1 suppressed the expression of HB-EGF,and led to a decrease in EGFR and its downstream genes AKT,RAF,KRAS expression levels.After knockdown of FOXQ1 in CRC cell lines,cell proliferation,migration and invasion were attenuated.Adding HB-EGF restored the migration and invasion ability of CRC,but not the cell proliferation ability.Kaplan–Meier survival analysis results showed that the combination of FOXQ1 and HB-EGF may serve to predict CRC survival.CONCLUSION Based on these collective data,we propose that FOXQ1 promotes the invasion and metastasis of CRC via the HB-EGF/EGFR pathway.展开更多
Objective Leucine-rich repeats and immunoglobulin-like domains 1(LRIG1) is a newly identified human gene that inhibits the epidermal growth factor receptor(EGFR), which on combining with a ligand, can drive tumor grow...Objective Leucine-rich repeats and immunoglobulin-like domains 1(LRIG1) is a newly identified human gene that inhibits the epidermal growth factor receptor(EGFR), which on combining with a ligand, can drive tumor growth. This study investigated the interaction between human LRIG1 and EGFR and attempted to delineate the functions of as well as the mechanisms used by the extracellular(ECD) and cytoplasmic(CPD) domains of the human LRIG1 protein to downregulate human EGFR signaling activity.Methods Two constructed chimeric eukaryotic expression vectors, pIRES2-EGFP-3XFLAG-LRIG1-ET and p3FLAG-LRIG1-TC, encoding the extracellular and transmembrane regions(LRIG1-ET) and the transmembrane and cytoplasmic regions(LRIG1-TC), respectively, and the plasmid p3XFLAG-CMV-9-LRIG1 encoding full-length LRIG1(LRIG1-FL) were transfected into the human glioma cell line U251 or primary astrocytoma cells by using liposomes. The number and affinity of cell surface EGFR on transfected cells was determined by ^(125)I-EGF binding assay. Results The dissociation constant(KD) values for EGFR were higher, and the maximum increase was observed in the cells transfected into LRIG1-ET(1.36 folds). The number of maximal binding sites(Bmax) of the receptors was decreased in all transfected cells; the maximum decrease was noted in the cells transfected into LRIG1-FL(40.05%).Conclusion Both the ECD and CPD of LRIG1 are important to negate EGFR signaling. The ECD may interfere with the binding between EGFR and its ligand and facilitate the functions of CPD. The CPD may, when brought in proximity to EGFR, enhance receptor degradation. These two mechanisms can contribute to the downregulation of EGFR-mediated signaling by LRIG1.展开更多
Objective To eoplore ulhether or not growth factors are involved in the restenosis afterangioplasty .Methods A rabbit model of atherosclerosis was established with cholesterol feeding after iliacartery injury made wit...Objective To eoplore ulhether or not growth factors are involved in the restenosis afterangioplasty .Methods A rabbit model of atherosclerosis was established with cholesterol feeding after iliacartery injury made with an inflated balloon catheter. Then balloon angioplasty was made. Expression oftransforming growth factor /β1(TGF-β1), epidermal growth factor receptor (EGFR), and basic fibroblast growthfactor (bFGF) mRNA was observed in rabbit iliac artery before and after balloon angioplasty with hybridization ofNorthern blot and reverse transcription polymerase chain reaction. Results Expression of TGF- β1. EGFR andbFGF mRNA in rabbit iliac artery was significantly increased 1 week and 2 weeks after angioplasty in comparisonwith that before angioplasty, Conclusion TGF-β1, EGFR and bFGF may be involved in the restenosis afterangioplasts.展开更多
We produced low-molecular-weight heparin/protamine micro (nano) particles (LMW-H/P MPs·NPs) as a carrier for heparin-binding growth factors (GFs), such as fibroblast growth factor (FGF)-2 and various GFs in plate...We produced low-molecular-weight heparin/protamine micro (nano) particles (LMW-H/P MPs·NPs) as a carrier for heparin-binding growth factors (GFs), such as fibroblast growth factor (FGF)-2 and various GFs in platelet-rich plasma (PRP). A mixture of LMW-H (MW: approximately 5000 Da, 6.4 mg/ml) and protamine (MW: approximately 3000 Da, 10 mg/ml) at a ratio of 7:3 (vol:vol) yields a dispersion of micro (nano) particles (200 nm - 3 μm in diameter). The diluted LMW-H solution in saline (0.32 mg/ml) mixed with diluted protamine (0.5 mg/ml) at a ratio at 7:3 (vol:vol) resulted in soluble nanoparticles (approximately 100 nm in diameter). The generated NPs could be then stabilized by adding 2 mg/ml dextran (MW: 178-217 kDa) and remained soluble after lyophilization of dialyzed LMW-H /P NPs solution. The LMW-H/P MPs·NPs adsorb GFs, control their release, protect GFs and activate their biological activities. Furthermore, administration of GFs-containing F/P MPs·NPs exhibited significantly higher inductions of vascularization and fibrous tissue formation in vivo than GFs alone. LMW-H/P MPs·NPs can also efficiently bind to tissue culture plates and retain the binding of GFs. The LMW-H/P MPs·NP-coated matrix with various GFs or cytokines provided novel biomaterials that could control cellular activity such as proliferation and differentiation. Thus, LMW-H/P MPs·NPs are an excellent carrier for GFs and are a functional coating matrix for various kinds of cell cultures.展开更多
Background ^11C-4-N-(3-bromoanilino)-6,7-dimethoxyquinazoline (1^11C-PD153035) has been reported as a tracer for imaging human tumors that overexpress epidermal growth factor receptor (EGFR). However it is still...Background ^11C-4-N-(3-bromoanilino)-6,7-dimethoxyquinazoline (1^11C-PD153035) has been reported as a tracer for imaging human tumors that overexpress epidermal growth factor receptor (EGFR). However it is still unclear whether ^11C-PD153035 uptake correlates with EGFR expression levels. The objective of this study was to investigate the relationship between ^11C-PD153035 accumulation and EGFR expression levels. Methods Synthesis of ^11C-PD153035 was performed in the Tracerlab FXc system. Accumulation of ^11C-PD153035 by MDA-MB-468, A549 and MDA-MB-231 cells was measured in vitro. There were six tumor-bearing mice in each group. ^11C-PD153035 uptake in tumors was determined by positron emission tomography/computed tomography (PET/CT). Tumor/normal muscle tissue (TINT) analysis in PET images was applied to quantify the PET data. Sixty minutes after PET/CT scanning, the nude mice were sacrificed and the tumors were excised. The ^11C-PD153035 accumulation in different tumors was determined by a gamma counter. Results Close correlation existed between the uptake and the level of EGFR expression both in vitro and ex vivo (r^2=0.72, P〈0.001; r^2=0.63, P=0.003). When the static TINT analysis method was applied to analyze the PET data, the observed correlation was again excellent (^2=0.70, P=-0.001). Conclusions The uptake of PET tracer ^11C-PD153035 closely correlates with the EGFR expression levels in tumor cells. ^11C-PD153035 has the potential to yield useful information for both cancer diagnosis and therapy.展开更多
文摘(-)-Epigallocatechin gallate (EGCG), a major polyphenolic constituent of green tea, can inhibit activity of specific receptor tyrosine kinases (RTKs) and related downstream signal transduction pathways, resulting in the control of unwanted cell proliferation. The epidermal growth factor receptor (EGFR) signaling pathway is one of the most important pathways that regulates growth, survival,proliferation and differentiation in mammalian cells. This review addresses the effects of EGCG on some protein factors involved in the EGFR signaling pathway in a direct or indirect manner. Based on our understanding of the interaction between EGCG and these factors, and based on their structures, EGCG could be used as a lead compound for designing and synthesizing novel drugs with significant biological activity.
基金Supported by National Natural Science Foundation of China,No. 81502556Yunnan Digestive Endoscopy Clinical Medical Center Foundation for Health Commission of Yunnan Province,No. 2X2019-01-02
文摘BACKGROUND Colorectal cancer(CRC)is an extremely malignant tumor with a high mortality rate.Little is known about the mechanism by which forkhead Box q1(FOXQ1)causes CRC invasion and metastasis through the epidermal growth factor receptor(EGFR)pathway.AIM To illuminate the mechanism by which FOXQ1 promotes the invasion and metastasis of CRC by activating the heparin binding epidermal growth factor(HB-EGF)/EGFR pathway.METHODS We investigated the differential expression and prognosis of FOXQ1 and HB-EGF in CRC using the Gene Expression Profiling Interactive Analysis(GEPIA)website(http://gepia.cancer-pku.cn/index.html).Quantitative real-time polymerase chain reaction(qRT-PCR)and Western blotting were used to detect the expression of FOXQ1 and HB-EGF in cell lines and tissues,and we constructed a stable lowexpressing FOXQ1 cell line and verified it with the above method.The expression changes of membrane-bound HB-EGF(proHB-EGF)and soluble HB-EGF(sHB-EGF)in the lowexpressing FOXQ1 cell line were detected by flow cytometry and ELISA.Western blotting was used to detect changes in the expression levels of HB-EGF and EGFR pathway-related downstream genes when exogenous recombinant human HB-EGF was added to FOXQ1 knockdown cells.Proliferation experiments,transwell migration experiments,and scratch experiments were carried out to determine the mechanism by which FOXQ1 activates the EGFR signaling pathway through HB-EGF,and then to evaluate the clinical relevance of FOXQ1 and HB-EGF.RESULTS GEPIA showed that the expression of FOXQ1 in CRC tissues was relatively high and was related to a lower overall survival rate.PCR array results showed that FOXQ1 is related to the HB-EGF and EGFR pathways.Knockdown of FOXQ1 suppressed the expression of HB-EGF,and led to a decrease in EGFR and its downstream genes AKT,RAF,KRAS expression levels.After knockdown of FOXQ1 in CRC cell lines,cell proliferation,migration and invasion were attenuated.Adding HB-EGF restored the migration and invasion ability of CRC,but not the cell proliferation ability.Kaplan–Meier survival analysis results showed that the combination of FOXQ1 and HB-EGF may serve to predict CRC survival.CONCLUSION Based on these collective data,we propose that FOXQ1 promotes the invasion and metastasis of CRC via the HB-EGF/EGFR pathway.
基金Supported by the grants of the National Natural Science Foundation of China(No.30973073 and 81172402)
文摘Objective Leucine-rich repeats and immunoglobulin-like domains 1(LRIG1) is a newly identified human gene that inhibits the epidermal growth factor receptor(EGFR), which on combining with a ligand, can drive tumor growth. This study investigated the interaction between human LRIG1 and EGFR and attempted to delineate the functions of as well as the mechanisms used by the extracellular(ECD) and cytoplasmic(CPD) domains of the human LRIG1 protein to downregulate human EGFR signaling activity.Methods Two constructed chimeric eukaryotic expression vectors, pIRES2-EGFP-3XFLAG-LRIG1-ET and p3FLAG-LRIG1-TC, encoding the extracellular and transmembrane regions(LRIG1-ET) and the transmembrane and cytoplasmic regions(LRIG1-TC), respectively, and the plasmid p3XFLAG-CMV-9-LRIG1 encoding full-length LRIG1(LRIG1-FL) were transfected into the human glioma cell line U251 or primary astrocytoma cells by using liposomes. The number and affinity of cell surface EGFR on transfected cells was determined by ^(125)I-EGF binding assay. Results The dissociation constant(KD) values for EGFR were higher, and the maximum increase was observed in the cells transfected into LRIG1-ET(1.36 folds). The number of maximal binding sites(Bmax) of the receptors was decreased in all transfected cells; the maximum decrease was noted in the cells transfected into LRIG1-FL(40.05%).Conclusion Both the ECD and CPD of LRIG1 are important to negate EGFR signaling. The ECD may interfere with the binding between EGFR and its ligand and facilitate the functions of CPD. The CPD may, when brought in proximity to EGFR, enhance receptor degradation. These two mechanisms can contribute to the downregulation of EGFR-mediated signaling by LRIG1.
文摘Objective To eoplore ulhether or not growth factors are involved in the restenosis afterangioplasty .Methods A rabbit model of atherosclerosis was established with cholesterol feeding after iliacartery injury made with an inflated balloon catheter. Then balloon angioplasty was made. Expression oftransforming growth factor /β1(TGF-β1), epidermal growth factor receptor (EGFR), and basic fibroblast growthfactor (bFGF) mRNA was observed in rabbit iliac artery before and after balloon angioplasty with hybridization ofNorthern blot and reverse transcription polymerase chain reaction. Results Expression of TGF- β1. EGFR andbFGF mRNA in rabbit iliac artery was significantly increased 1 week and 2 weeks after angioplasty in comparisonwith that before angioplasty, Conclusion TGF-β1, EGFR and bFGF may be involved in the restenosis afterangioplasts.
文摘We produced low-molecular-weight heparin/protamine micro (nano) particles (LMW-H/P MPs·NPs) as a carrier for heparin-binding growth factors (GFs), such as fibroblast growth factor (FGF)-2 and various GFs in platelet-rich plasma (PRP). A mixture of LMW-H (MW: approximately 5000 Da, 6.4 mg/ml) and protamine (MW: approximately 3000 Da, 10 mg/ml) at a ratio of 7:3 (vol:vol) yields a dispersion of micro (nano) particles (200 nm - 3 μm in diameter). The diluted LMW-H solution in saline (0.32 mg/ml) mixed with diluted protamine (0.5 mg/ml) at a ratio at 7:3 (vol:vol) resulted in soluble nanoparticles (approximately 100 nm in diameter). The generated NPs could be then stabilized by adding 2 mg/ml dextran (MW: 178-217 kDa) and remained soluble after lyophilization of dialyzed LMW-H /P NPs solution. The LMW-H/P MPs·NPs adsorb GFs, control their release, protect GFs and activate their biological activities. Furthermore, administration of GFs-containing F/P MPs·NPs exhibited significantly higher inductions of vascularization and fibrous tissue formation in vivo than GFs alone. LMW-H/P MPs·NPs can also efficiently bind to tissue culture plates and retain the binding of GFs. The LMW-H/P MPs·NP-coated matrix with various GFs or cytokines provided novel biomaterials that could control cellular activity such as proliferation and differentiation. Thus, LMW-H/P MPs·NPs are an excellent carrier for GFs and are a functional coating matrix for various kinds of cell cultures.
文摘Background ^11C-4-N-(3-bromoanilino)-6,7-dimethoxyquinazoline (1^11C-PD153035) has been reported as a tracer for imaging human tumors that overexpress epidermal growth factor receptor (EGFR). However it is still unclear whether ^11C-PD153035 uptake correlates with EGFR expression levels. The objective of this study was to investigate the relationship between ^11C-PD153035 accumulation and EGFR expression levels. Methods Synthesis of ^11C-PD153035 was performed in the Tracerlab FXc system. Accumulation of ^11C-PD153035 by MDA-MB-468, A549 and MDA-MB-231 cells was measured in vitro. There were six tumor-bearing mice in each group. ^11C-PD153035 uptake in tumors was determined by positron emission tomography/computed tomography (PET/CT). Tumor/normal muscle tissue (TINT) analysis in PET images was applied to quantify the PET data. Sixty minutes after PET/CT scanning, the nude mice were sacrificed and the tumors were excised. The ^11C-PD153035 accumulation in different tumors was determined by a gamma counter. Results Close correlation existed between the uptake and the level of EGFR expression both in vitro and ex vivo (r^2=0.72, P〈0.001; r^2=0.63, P=0.003). When the static TINT analysis method was applied to analyze the PET data, the observed correlation was again excellent (^2=0.70, P=-0.001). Conclusions The uptake of PET tracer ^11C-PD153035 closely correlates with the EGFR expression levels in tumor cells. ^11C-PD153035 has the potential to yield useful information for both cancer diagnosis and therapy.