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Signaling pathways involved in the inhibition of epidermal growth factor receptor by erlotinib in hepatocellular cancer 被引量:7
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作者 Alexander Huether Michael Hpfner +3 位作者 Andreas P Sutter Viola Baradari Detlef Schuppan Hans Scherübl 《World Journal of Gastroenterology》 SCIE CAS CSCD 2006年第32期5160-5167,共8页
AIM: To examine the underlying mechanisms of erlotinib-induced growth inhibition in hepatocellular carcinoma (HCC). METHODS: Erlotinib-induced alterations in gene expression were evaluated using cDNA array technol... AIM: To examine the underlying mechanisms of erlotinib-induced growth inhibition in hepatocellular carcinoma (HCC). METHODS: Erlotinib-induced alterations in gene expression were evaluated using cDNA array technology; changes in protein expression and/or protein activation due to erlotinib treatment as well as IGF-1-induced EGFR transactivation were investigated using Western blotting. RESULTS: Erlotinib treatment inhibited the mitogen activated protein (MAP)-kinase pathway and signal transducer of activation and transcription (STAT)- mediated signaling which led to an altered expression of apoptosis and cell cycle regulating genes as demonstrated by cDNA array technology. Overexpression of proapoptotic factors like caspases and gadds associated with a down-regulation of antiapoptotic factors like Bcl-2, Bcl-XL or jun D accounted for erlotinib's potency to induce apoptosis. Downregulation of cell cycle regulators promoting the G1/S-transition and overexpression of cyclin-dependent kinase inhibitors and gadds contributed to the induction of a G1/G0-arrest in response to erlotinib. Furthermore, we displayed the transactivation of EGFR-mediated signaling by the IGF-1-receptor and showed erlotinib's inhibitory effects on the receptor-receptor cross talk. CONCLUSION: Our study sheds light on the understanding of the mechanisms of action of EGFR-TK- inhibition in HCC-cells and thus might facilitate the design of combination therapies that act additively or synergistically. Moreover, our data on the pathways responding to erlotinib treatment could be helpful in predicting the responsiveness of tumors to EGFR-TKIs in the future. 展开更多
关键词 epidermal growth factor receptor Insulinlike growth factor receptor Tarceva^TM signal transducerof activation and transcription Extracellular regulatedkinase Gene expression
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Effects of (-)-Epigallocatechin gallate on some protein factors involved in the epidermal growth factor receptor signaling pathway
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作者 Yinjiu Huang Ruiqing Xu +3 位作者 Baoan Song Song Yang Li Zhao Shouwei Wu 《Journal of Nanjing Medical University》 2009年第5期293-299,共7页
(-)-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
关键词 (-)-Epigallocatechin gallate (EGCG) epidermal growth factor receptor (EGFR) signaling pathway
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Nexus of signaling and endocytosis in oncogenesis driven by non-small cell lung cancer-associated epidermal growth factor receptor mutants 被引量:3
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作者 Byung Min Chung Eric Tom +3 位作者 Neha Zutshi Timothy Alan Bielecki Vimla Band Hamid Band 《World Journal of Clinical Oncology》 CAS 2014年第5期806-823,共18页
Epidermal growth factor receptor(EGFR) controls a wide range of cellular processes, and aberrant EGFR signaling as a result of receptor overexpression and/or mutation occurs in many types of cancer. Tumor cells in non... Epidermal growth factor receptor(EGFR) controls a wide range of cellular processes, and aberrant EGFR signaling as a result of receptor overexpression and/or mutation occurs in many types of cancer. Tumor cells in non-small cell lung cancer(NSCLC) patients that harbor EGFR kinase domain mutations exhibit oncogene addiction to mutant EGFR, which confers high sensitivity to tyrosine kinase inhibitors(TKIs). As patients invariably develop resistance to TKIs, it is important to delineate the cell biological basis of mutant EGFR-induced cellular transformation since components of these pathways can serve as alternate therapeutic targets to preempt or overcome resistance. NSCLC-associated EGFR mutants are constitutively-active and induce ligandindependent transformation in nonmalignant cell lines. Emerging data suggest that a number of factors are critical for the mutant EGFR-dependent tumorigenicity, and bypassing the effects of TKIs on these pathways promotes drug resistance. For example, activation of downstream pathways such as Akt, Erk, STAT3 and Src is critical for mutant EGFR-mediated biological processes. It is now well-established that the potency and spatiotemporal features of cellular signaling by receptor tyrosine kinases such as EGFR, as well as the specific pathways activated, is determined by the nature of endocytic traffic pathways through which the active receptors traverse. Recent evidence indicates that NSCLCassociated mutant EGFRs exhibit altered endocytic trafficking and they exhibit reduced Cbl ubiquitin ligasemediated lysosomal downregulation. More recent work has shown that mutant EGFRs undergo ligand-independent traffic into the endocytic recycling compartment, a behavior that plays a key role in Src pathway activation and oncogenesis. These studies are beginning to delineate the close nexus between signaling and endocytic traffic of EGFR mutants as a key driver of oncogenicprocesses. Therefore, in this review, we will discuss the links between mutant EGFR signaling and endocytic properties, and introduce potential mechanisms by which altered endocytic properties of mutant EGFRs may alter signaling and vice versa as well as their implications for NSCLC therapy. 展开更多
关键词 NON-SMALL cell lung cancer epidermal growth factor receptor signalING ENDOCYTOSIS Src Cbl UBIQUITINATION
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Effect of hepatocyte growth factor signaling pathway activation on Plasmodium berghei infection 被引量:1
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作者 Nantian Zhong Fengying Huang +8 位作者 Guanghong Tan Jiege Jiao Yingzhi Lin CaichunWang Hua Wang Songlin Zhou Yonghao Huang Fan Chen Yingying Lin 《Asian Pacific Journal of Tropical Medicine》 SCIE CAS 2010年第3期169-172,共4页
Objective:To explore the effect of hepatocyte growth factor signaling pathway activation on Plasmodium berghei infection.Methods:In this study,hepatocyte growth factor was detected by ELISA and Western blotting assay.... Objective:To explore the effect of hepatocyte growth factor signaling pathway activation on Plasmodium berghei infection.Methods:In this study,hepatocyte growth factor was detected by ELISA and Western blotting assay.Hepatocyte injury was detected by FITC-dextran absorption assay,and hepatocyte growth factor expression was shown to be expressed in the same injury cells by immunofluorescence against hepatocyte growth factor.In addition,Activation of hepatocyte growth factor and its receptor signaling pathway was detected with immunoprecipitation and detection of phosphorylation status.Results:It was found that injury of hepatocytes by sporozoite migration induced the secretion of hepatocyte growth factor and it was hepatocyte growth factor that rendered hepatocytes susceptible to Plasmodium sporozoite infection.In addition,hepatocyte infections depended on activation of the hepatocyte growth factor and its receptor signaling pathway.Conclusions:Our results indicate that hepatocyte growth factor and its receptor may possibly be potential targets for new approaches to malaria treatment. 展开更多
关键词 HEPATOCYTE growth factor MALARIA PLASMODIUM SPOROZOITE signaling pathway
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Effects of the Nocth signaling pathway on expression of inflammatory factors and transforming growth factors in diabetic foot ulcers 被引量:1
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作者 Qiang Han Guo-Bin Liu +4 位作者 Ren-Yan Huang Feng Xu Shi-Meng Yan Chen-Yan Shi Jun-Hao Chen 《Journal of Hainan Medical University》 2021年第12期1-1,共1页
Objective:persistent hyperinflammation is an important reason for the development of diabetic foot ulcer.Notch signaling is an important signaling pathway involved in the inflammatory response and cell proliferation i... Objective:persistent hyperinflammation is an important reason for the development of diabetic foot ulcer.Notch signaling is an important signaling pathway involved in the inflammatory response and cell proliferation in diabetic foot ulcer rats.This paper aims to explore the effect of Notch signaling on inflammatory factors,chemokines and growth factors through the intervention of Notch signaling in diabetic foot ulcer rats.Methods:the experimental model was made by using high-fat feed combined with streptozotocin(STZ)to cause diabetes,and the experimental model of diabetic foot ulcer was established by constant temperature and constant pressure scald apparatus.The normal ulcer model was used as a control.The intervention controls of the experimental model included normal saline,western medicine growth factor,Notch agonist Jagged1,Notch signaling inhibitor ly-411575,and the intervention of traditional Chinese medicine Zizhu ointment for 7 days.Serum il-1,il-6,TNF-radiation,and il-17 were detected by ELISA.Real-time PCR was used to detect the inflammatory factors,chemokines,and growth factors associated with Notch signaling in wound tissues:tnf-uum,il-1,il-6,il-17,interleukin-8,ip-10,McP-1,TGF-uum,TGF-livelihood.Results:serum levels of il-1,il-6,TNF-radiation and il-17 in diabetic foot ulcer rats were significantly higher than that in normal ulcer rats.The contents of il-1,il-6,TNF-radiation and il-17a in ly-411575 group and Zizhu ointment group were significantly reduced.Real-time PCR results of wound tissue showed that the levels of inflammatory cytokines il-1,il-6,TNF-radiation,il-17 and chemokines ip-10,il-8 and McP-1 in the wound tissue of diabetic foot ulcer rat model were significantly higher than that of normal ulcer model,and the levels of growth factor TGF-exposure were lower than that of normal ulcer model.LY-411575 significantly reduced il-1,il-6,TNF-maxima,il-17,and the chemokines ip-10,il-8,and McP-1 in diabetic foot ulcer rats,and reduced the expression of TGF-,TGF-earth.Jagged1 can increase the expression of TGF--,TGF---,suggesting that inhibition of the Notch signaling pathway can reduce the expression of the inflammatory factors il-1,il-6,TNF--,il-17a,il-8,and the growth factors TGF--,TGF---.Zizhu ointment can reduce the levels of il-1,il-6,TNF-benand,il-17,and the chemokines ip-10,il-8,and McP-1 on the wound surface of diabetic foot rats,and improve the expression of TGF-benand TGF-SUNS.Ly-411575 inhibited the expression of TGF-bento and TGF-promoting of Zizhu ointment.Conclusion:the expression of inflammatory cytokines and chemokines was higher and the expression of growth factors was lower in diabetic foot ulcer rats than in normal ulcer rats.Inhibition of Notch signaling pathway can reduce the expression of inflammatory factors,chemokines and growth factors in experimental model rats,and Notch signaling pathway can promote inflammation and cell proliferation.Zizhu ointment can reduce the levels of inflammatory cytokines and chemokines in diabetic foot ulcer rats,improve the expression of growth factors,and reduce wound inflammation,which may be related to the inhibition of Nocth signal expression. 展开更多
关键词 Notch signaling pathway Diabetic foot ulcer Inflammatory factor Transforming growth factor
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Inhibition of epidermal growth factor receptor signaling protects human malignant glioma cells from hypoxia - induced cell death 被引量:4
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作者 Steinbach JP Klumpp A +1 位作者 Wolburg H Weller M 《中国神经肿瘤杂志》 2004年第1期22-22,共1页
Epidermal growth factor receptor(EGFR)signaling has become an importanttarget for drug development becauseEGFR signaling enhances tumor cell proliferation,migration,and invasion and inhibits apoptosis.However,theresul... Epidermal growth factor receptor(EGFR)signaling has become an importanttarget for drug development becauseEGFR signaling enhances tumor cell proliferation,migration,and invasion and inhibits apoptosis.However,theresults of clinical trials using EGFR inhibitors in patients with solid tumors have been disappointing.Here,wereport a protective effect of the EGFR inhibitors AG1478 and PD153035 against cell death induced by acute hy-poxia,which contrasts with their proapoptotic effects under normoxia.Under hypoxic conditions,both agents re- 展开更多
关键词 EGFR Inhibition of epidermal growth factor receptor signaling protects human malignant glioma cells from hypoxia induced cell death
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Forkhead Box q1 promotes invasion and metastasis in colorectal cancer by activating the epidermal growth factor receptor pathway
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作者 Jin-Jin Zhang Chang-Xiong Cao +5 位作者 Li-Lan Wan Wen Zhang Zhong-Jiang Liu Jin-Li Wang Qiang Guo Hui Tang 《World Journal of Gastroenterology》 SCIE CAS 2022年第17期1781-1797,共17页
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
关键词 Colorectal cancer Forkhead Box Q1 Heparin binding epidermal growth factor epidermal growth factor receptor pathway Migration Invasion
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Epidermal growth factor receptor:a key manipulator in molecular pathways of malignant glioma
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作者 Changshu Ke 《Oncology and Translational Medicine》 2016年第2期99-103,共5页
The epidermal growth factor receptor (EGFR) is a member of the ErbB/EGFR family, including EGFR/Herl, ErbB2/Her2, ErbB-3/Her3, and ErbB-4/Her4. EGFR exerts its effects through the receptor tyrosine kinase phosphoryl... The epidermal growth factor receptor (EGFR) is a member of the ErbB/EGFR family, including EGFR/Herl, ErbB2/Her2, ErbB-3/Her3, and ErbB-4/Her4. EGFR exerts its effects through the receptor tyrosine kinase phosphorylation and activation of important downstream signaling pathways in normal and neoplastic cells, mainly the Ras GTPase/MAP kinase (MAPK), STAT3, and phosphatidylinositide 3 kinase-AKT pathways. EGFR deregulation is common in malignant glioma, especially primary glioblastoma, and exists in three forms: gene overexpression (amplification), autocrine effects of EGFR activation, and activating receptor mutation (EGFRvlII). However, some EGFR abnormalities have also been found in low-grade gliomas, including the nuclear localization of EGFR, expression in the microfoci of anaplastic transformation, and association with neovascularization in the mesenchyma of the glioma, which suggests that some unknown EGFR-related mechanisms are possibly responsible for its central role in the initiation and progression of malignant glioma. Uncovering these mechanisms will have potential value in the development of radio- therapy, chemotherapy, and EGFR-targeted therapy for glioma. 展开更多
关键词 epidermal growth factor receptor (EGFR) molecular pathways malignant glioma
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Fibroblast growth factor receptor signaling as therapeutic targets in gastric cancer 被引量:9
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作者 Masakazu Yashiro Tasuku Matsuoka 《World Journal of Gastroenterology》 SCIE CAS 2016年第8期2415-2423,共9页
Fibroblast growth factor receptors(FGFRs) regulate a variety of cellular functions, from embryogenesis to adult tissue homeostasis. FGFR signaling also plays significant roles in the proliferation, invasion, and survi... Fibroblast growth factor receptors(FGFRs) regulate a variety of cellular functions, from embryogenesis to adult tissue homeostasis. FGFR signaling also plays significant roles in the proliferation, invasion, and survival of several types of tumor cells. FGFR-induced alterations, including gene amplification, chromosomal translocation, and mutations, have been shown to be associated with the tumor initiation and progression of gastric cancer, especially in diffuse-type cancers. Therefore, the FGFR signaling pathway might be one of the therapeutic targets in gastric cancer. This review aims to provide an overview of the role of FGFR signaling in tumorigenesis, tumor progression, proliferation, and chemoresistance. We also discuss the accumulating evidence that demonstrates the effectiveness of using clinical therapeutic agents to inhibit FGFR signaling for the treatment of gastric cancer. 展开更多
关键词 FIBROBLAST growth factor RECEPTOR GASTRIC cancer signalING pathway TARGETED therapy
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Effect of Calmodulin and Voltage-dependent Ca^(2+) Channel on the Proliferation of Heptoma Cells Induced by Epidermal Growth Factor
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作者 吴斌文 王家 +1 位作者 袁顺玉 崔武任 《Journal of Huazhong University of Science and Technology(Medical Sciences)》 SCIE CAS 2003年第1期26-28,共3页
The effect of thyrosine kinase, calmodulin and voltage-dependent Ca 2+ channel on the proliferation of hepatoma cells induced by EGF was studied. Hepatoma cell line SMMC7721 was cultured in RPMI1640 serum-free me... The effect of thyrosine kinase, calmodulin and voltage-dependent Ca 2+ channel on the proliferation of hepatoma cells induced by EGF was studied. Hepatoma cell line SMMC7721 was cultured in RPMI1640 serum-free medium. DNA synthesis rate of hepatoma cells was measured by 3H-TdR incorporation. 10 -9 mol/L EGF could significantly stimulate the proliferation of hepatoma cells (P<0.05), and this effect might be significantly inhibited by tyrosine kinase inhibitor (P<0.001). Calmodulin inhibitor W-7 had no effect on the basic phase of cultured hepatoma cells (P> 0.05), but it had very significantly inhibitory effect on the proliferation of hepatoma cells induced by EGF (P<0.001). Voltage-dependent Ca 2+ channel inhibitor Varapamil had no inhibition on the proliferation of hepatoma cells induced by EGF (P>0.05). It had no effect on the basic phase of cultured hepatoma cells (P>0.05). It is suggested that tyrosine kinase and Ca 2+-calmodulin-dependent pathway may play a critical role on the proliferation of heptoma cells induced by EGF, and voltage-dependent Ca 2+ channel is independent of the effect of EGF. 展开更多
关键词 epidermal growth factor human hepatoma cell line Ca 2+-calmodulin-dependent pathway tyrosine kinase voltage-dependent Ca 2+ channel
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Effect of miR-124 Overexpression under Wnt/β-catenin Signaling Pathway on Inflammatory Factor and Epidermal Growth Factor in Rats with Precancerous Gastric Lesions
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作者 ZHOU Li-jiang 《Chinese Journal of Biomedical Engineering(English Edition)》 CAS 2024年第1期17-26,共10页
Objective:To investigate the effects of miR-124 overexpression on inflammatory factors and epidermal growth factor in rats with gastric precancerous lesions by modulating the Wnt/β-catenin signaling pathway.Methods:E... Objective:To investigate the effects of miR-124 overexpression on inflammatory factors and epidermal growth factor in rats with gastric precancerous lesions by modulating the Wnt/β-catenin signaling pathway.Methods:Eighty SPF-grade Wistar rats were selected as the research subjects.After adaptive feeding,they were divided into 4 groups using a random number table method.The control group was fed a regular diet,while the model group,low expression group,and overexpression group of rats were treated with N-methyl-N’-nitro-N-nitrosoguanidine to establish a model of gastric cancer precancerous lesions.After successful modeling,the control group and model group rats were injected intraperitoneally with 0.9%sodium chloride solution,the low-expression group rats were injected intraperitoneally with miR-124-5p inhibitor,and the over-expression group rats were injected intraperitoneally with miR-124-5p mimic.After 8 weeks of continuous injection,the levels of miR-124,Wnt/β-catenin signaling pathway-related proteins,inflammatory factors,and epidermal growth factor were observed and compared among the four groups of rats.Results:The differences in the relative expression of miR-124 among the four groups of rats were statistically significant(P<0.05);the differences in the expression of Wnt protein andβ-catenin protein among the four groups of rats were statistically significant(P<0.05),and the expression of Wnt protein andβ-catenin protein in the overexpression group was significantly higher than that of the control group,and significantly lower than that in the model group and the low-expression group;the levels of IL-1β,IL-6,and TNF-αof rats in the four groups of rats IL-1β,IL-6 and TNF-αlevels were statistically different(P<0.05),and the levels of IL-1β,IL-6 and TNF-αin rats in the overexpression group were higher than those in the model group and significantly lower than those in the model group and the low-expression group(P<0.05);the differences in the levels of EGF,HER1 and HER2 among the four groups of rats were statistically different(P<0.05),and the levels of EGF levels were higher than those of the control group,and EGF and HER1 were significantly lower than those of the model and low expression groups(P<0.05).Conclusion:Mi R-124 overexpression helps to reduce gastric mucosal damage and inflammatory response in rats with gastric precancerous lesions,and its mechanism of action may be linked to the inhibition of the Wnt/β-catenin signaling pathway. 展开更多
关键词 precancerous lesions of the stomach Wnt/β-catenin signal pathway miR-124 inflammatory factor epidermal growth factor
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TGF-β1 signal pathway in the regulation of inflammation in patients with atrial fibrillation 被引量:15
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作者 Ye Erbo lati.Ali Mira Muhuyati +3 位作者 Wu-Hong Lu Peng-Yi He Zhi-Qiang Liu Yu-Chun Yang 《Asian Pacific Journal of Tropical Medicine》 SCIE CAS 2013年第12期999-1003,共5页
Objective:To observe the expression changes of inflammatory markers TGF-β1,Smad3 and IL-6 in patients with atrial fibrillation(AF),and to explore the significance of TGF-β1 signaling pathway in the structural remode... Objective:To observe the expression changes of inflammatory markers TGF-β1,Smad3 and IL-6 in patients with atrial fibrillation(AF),and to explore the significance of TGF-β1 signaling pathway in the structural remodeling of AF.Methods:The expression of TGF-β1,Smad3 and IL-6 in 50 cases with AF and 30 normal cases were detected by RT-PCR and ELISA.Results:The TGF-β1,Smad3 and IL-6 mRNA and protein expression levels in patients with AF were significantly higher than that in the control group(P<0.05),but there was no significantly different between the paroxysmal AF group and the persistent AF group(P>0.05).The TGF-β1mRNA expression in the≥50 years subgroup was significantly higher than that in the<50years subgroups,and it was higher in the NYHAⅢsubgroup than in theⅠ/Ⅱgrade subgroup.It was also higher in the left ventricular ejection fraction(LVEF)<50%subgroup than in LVEF≥50%group,and it was significantly higher in the AF time≥36 months subgroup than that in<36months subgroup(P<0.05).The Smad3 and IL-6 expressions in the in the LVEF<50%subgroup were both high that than that in LVEF≥50%group,and higher in the AF time≥36 months subgroup than that in<36 months subgroup(P<0.05).There were a positive correlation between TGF-β1,Smad3 and IL-6(r=0.687,r=0.547).There were also a positive correlation between Smad3 and IL-6 mRNA(r=0.823).Conclusions:AF is associated with inflammation,and the inflammation is also involved in the fibrillation and sustain of AF.The TGF-β1 signal pathway may be involved in the process of atrial structural remodeling in patients with AF,and iss related with the occurrence and maintenance of AF. 展开更多
关键词 ATRIAL FIBRILLATION TRANSFORMING growth factor β1 signal transduction INFLAMMATION
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Insulin-like growth factor binding protein related protein 1 knockdown attenuates hepatic ?brosis via the regulation of MMPs/TIMPs in mice 被引量:11
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作者 Jun-Jie Ren Ting-Juan Huang +5 位作者 Qian-Qian Zhang Hai-Yan Zhang Xiao-Hong Guo Hui-Qin Fan Ren-Ke Li Li-Xin Liu 《Hepatobiliary & Pancreatic Diseases International》 SCIE CAS CSCD 2019年第1期38-47,共10页
Background: Previous research suggested that insulin-like growth factor binding protein related protein 1(IGFBPrP1), as a novel mediator, contributes to hepatic fibrogenesis. Matrix metalloproteinases(MMP) and tissue ... Background: Previous research suggested that insulin-like growth factor binding protein related protein 1(IGFBPrP1), as a novel mediator, contributes to hepatic fibrogenesis. Matrix metalloproteinases(MMP) and tissue inhibitors of metalloproteinases(TIMP) play an essential role in hepatic fibrogenesis by regulating homeostasis and remodeling of the extracellular matrix(ECM). However, the interaction between IGFBPrP1 and MMP/TIMP is not clear. The present study was to knockdown IGFBPrP1 to investigate the correlation between IGFBPrP1 and MMP/TIMP in hepatic fibrosis. Methods: Hepatic fibrosis was induced by thioacetamide(TAA) in mice. Knockdown of IGFBPrP1 expression by ultrasound-targeted microbubble destruction-mediated CMB-shRNA-IGFBPrP1 delivery, or inhibition of the Hedgehog(Hh) pathway by cyclopamine treatment, was performed in TAA-induced liver fibrosis mice. Hepatic fibrosis was determined by hematoxylin and eosin and Sirius red staining. Hepatic expression of IGFBPrP1, α-smooth muscle actin( α-SMA), transforming growth factor β 1(TGF β1), collagen I, MMPs/TIMPs, Sonic Hedgehog(Shh), and glioblastoma family transcription factors(Gli1) were investigated by immunohistochemical staining and Western blotting analysis. Results: We found that hepatic expression of IGFBPrP1, TGF β1, α-SMA, and collagen I were increased longitudinally in mice with TAA-induced hepatic fibrosis, concomitant with MMP2/TIMP2 and MMP9/TIMP1 imbalance and Hh pathway activation. Knockdown of IGFBPrP1 expression, or inhibition of the Hh pathway, reduced the hepatic expression of IGFBPrP1, TGF β1, α-SMA, and collagen I and re-established MMP2/TIMP2 and MMP9/TIMP1 balance. Conclusions: Our findings suggest that IGFBPrP1 knockdown attenuates liver fibrosis by re-establishing MMP2/TIMP2 and MMP9/TIMP1 balance, concomitant with the inhibition of hepatic stellate cell activation, down-regulation of TGF β1 expression, and degradation of the ECM. Furthermore, the Hh pathway mediates IGFBPrP1 knockdown-induced attenuation of hepatic fibrosis through the regulation of MMPs/TIMPs balance. 展开更多
关键词 HEPATIC fibrosis INSULIN-LIKE growth factor binding PROTEIN RELATED PROTEIN 1 Matrix METALLOPROTEINASE Tissue inhibitor of METALLOPROTEINASE Ultrasound-targeted microbubble destruction Hedgehog signaling pathway
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Targeting key signalling pathways in oesophageal adenocarcinoma:A reality for personalised medicine? 被引量:6
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作者 Richard R Keld Yeng S Ang 《World Journal of Gastroenterology》 SCIE CAS CSCD 2011年第23期2781-2790,共10页
Cancer treatments are rapidly changing.Curative treatment for oesophageal adenocarcinoma currently involves surgery and cytotoxic chemotherapy or chemoradiotherapy.Outcomes for both regimes are generally poor as a res... Cancer treatments are rapidly changing.Curative treatment for oesophageal adenocarcinoma currently involves surgery and cytotoxic chemotherapy or chemoradiotherapy.Outcomes for both regimes are generally poor as a result of tumor recurrence.We have reviewed the key signalling pathways associated with oesophageal adenocarcinomas and discussed the recent trials of novel agents that attempt to target these pathways.There are many trials underway with the aim of improving survival in oesophageal cancer.Currently,phase 2 and 3 trials are focused on MAP kinase inhibition,either through inhibition of growth factor receptors or signal transducer proteins.In order to avoid tumor resistance,it appears to be clear that targeted therapy will be needed to combat the multiple signalling pathways that are in operation in oesophageal adenocarcinomas.This may be achievable in the future with the advent of gene signatures and a combinatorial approach. 展开更多
关键词 Oesophageal adenocarcinoma signallingpathways MAP and PI3 Kinase pathways Wnt signalling Transforming growth factor-13 pathway Nuclear factor-KBpathways Transcription factors Tyrosine kinase receptors
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Interplay between micro RNA-17-5p, insulin-like growth factor-Ⅱ through binding protein-3 in hepatocellular carcinoma 被引量:3
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作者 Danira Ashraf Habashy Hend Mohamed El Tayebi +3 位作者 Injie Omar Fawzy Karim Adel Hosny Gamal Esmat Ahmed Ihab Abdelaziz 《World Journal of Hepatology》 CAS 2016年第23期976-984,共9页
AIM: To investigate the effect of microR NA on insulinlike growth factor binding protein-3(IGFBP-3) and hence on insulin-like growth factor-Ⅱ(IGF-Ⅱ) bioavailability in hepatocellular carcinoma(HCC).METHODS: Bioinfor... AIM: To investigate the effect of microR NA on insulinlike growth factor binding protein-3(IGFBP-3) and hence on insulin-like growth factor-Ⅱ(IGF-Ⅱ) bioavailability in hepatocellular carcinoma(HCC).METHODS: Bioinformatic analysis was performed using microrna.org, DIANA lab and Segal lab softwares. Total RNA was extracted from 23 HCC and 10 healthy liver tissues using mir Vana mi RNA Isolation Kit. microR NA-17-5p(miR-17-5p) expression was mimicked and antagonized in Hu H-7 cell lines using Hi Per Fect Transfection Reagent, then total RNA was extracted using Biozol reagent then reverse transcribed into cD NA followed by quantification of mi R-17-5p and IGFBP-3 expression using Taq Man real-time quantitative PCR. Luciferase reporter assay was performed to validate the binding of miR-17-5p to the 3'UTR of IGFBP-3. Free IGF-Ⅱ protein was measured in transfected Hu H-7 cells using IGF-Ⅱ ELISA kit. RESULTS: Bioinformatic analysis revealed IGFBP-3 as a potential target for miR-17-5p. Screening of miR-17-5p and IGFBP-3 revealed a moderate negative correlation in HCC patients, where mi R-17-5p was extensively underexpressed in HCC tissues(P = 0.0012), while IGFBP-3 showed significant upregulation in the same set of patients(P = 0.0041) compared to healthy donors. Forcing mi R-17-5p expression in Hu H-7 cell lines showed a significant downregulation of IGFBP-3 mR NA expression(P = 0.0267) and a significant increase in free IGF-Ⅱ protein(P = 0.0339) compared to mock untransfected cells using unpaired t-test. Luciferase assay validated IGFBP-3 as a direct target of mi R-17-5p; luciferase activity was inhibited by 27.5% in cells co-transfected with miR-17-5p mimics and the construct harboring the wild-type binding region 2 of IGFBP-3 compared to cells transfected with this construct alone(P = 0.0474).CONCLUSION: These data suggest that regulating IGF-Ⅱ bioavailability and hence HCC progression can be achieved through targeting IGFBP-3 via manipulating the expression of miR NAs. 展开更多
关键词 INSULIN-LIKE growth factor BINDING protein-3 INSULIN-LIKE growth factor signaling pathway MicroR NA INSULIN-LIKE growth factor-Ⅱ HEPATOCELLULAR carcinoma
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TGF-β1/SMAD SIGNALING PATHWAY MEDIATES p53-DEPENDENT APOPTOSIS IN HEPATOMA CELL LINES 被引量:2
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作者 Chun-lei Wang Yuan-lian Wan +1 位作者 Yu-cun Liu Zhi-qiang Huang 《Chinese Medical Sciences Journal》 CAS CSCD 2006年第1期33-35,共3页
Objective To determine whether transforming growth factor betal (TGF-β1)/Smad signaling pathway mediates p53-dependent apoptosis in hepatoma cell lines.Methods Three human hepatic carcinoma cell lines, HepG2, Huh-7, ... Objective To determine whether transforming growth factor betal (TGF-β1)/Smad signaling pathway mediates p53-dependent apoptosis in hepatoma cell lines.Methods Three human hepatic carcinoma cell lines, HepG2, Huh-7, and Hep3B, were used in this study.TGF-β1-induced apoptosis in hepatic carcinoma cell lines was analyzed using TUNEL assay.For identifying the mechanism of apoptosis induced by TGF-β1, cell lines were transfected with a TGF-β1-inducible luciferase reportor plasmid containing Smad4 binding elements.After transfection, cells were treated with TGF-β1, then assayed for luciferase activity.Results The apoptosis rate of HepG2 cell lines (48.51%± 8.21%) was significantly higher than control ( 12.72%±2.18%, P<0.05).But TGF-β1 was not able to induce apoptosis of Huh-7 and Hep3B cell lines.The relative luciferase activity of TGF-β1-treated HepG2 cell lines (4.38) was significantly higher than control (1.00, P< 0.05).But the relative luciferase activity of TGF-β1-treated Huh-7 and Hep3B cell lines less increased compared with control.Conclusions HepG2 cells seem to be highly susceptible to TGF-β1-induced apoptosis compared with Hep3B and Huh-7 cell lines.Smad4 is a central mediator of TGF-β1 signaling transdution pathway.TGF-β1/Smad signaling pathway might mediate p53-dependent apoptosis in hepatoma cell lines. 展开更多
关键词 transforming growth factor-β1 APOPTOSIS hepatoma cell line signal transduction pathway
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Nerve Growth Factor Enhances Tau Isoform Expression and Transcription in IMR32 Cells 被引量:2
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作者 Cheryl L. Cragg Bettina E. Kalisch 《Neuroscience & Medicine》 2014年第2期119-130,共12页
The present study characterized the nerve growth factor (NGF)-mediated regulation of tau protein expression and transcription in IMR32 human neuroblastoma cells. Treatment of IMR32 cells with 50 ng/mL NGF resulted in ... The present study characterized the nerve growth factor (NGF)-mediated regulation of tau protein expression and transcription in IMR32 human neuroblastoma cells. Treatment of IMR32 cells with 50 ng/mL NGF resulted in increased levels of specific tau protein isoforms. A 550 bp fragment of the tau promoter was cloned and treatment of transfected IMR32 and PC12 cells with NGF also resulted in increased promoter activation, suggesting that the NGF-mediated increase in tau isoforms is regulated, at least in part, at the level of transcription. Pretreatment with the MAP kinase inhibitor U0126 or the PKC inhibitor bisindolylmaleimide 1 (BIS-1) attenuated the NGF-mediated increase in tau transcription, indicating that the NGF-mediated activation of the MAP kinase and PKC signaling pathways modulate tau transcription. Pre-treatment of cells with the Akt inhibitor, LY294002 or with NOS inhibitors Nω-nitro-L-arginine methylester (L-NAME) or s-methylisothiourea (S-MIU) had no effect on the NGF-mediated increase in tau promoter activation, suggesting that NO and the NGF-Akt signaling pathway do not modulate tau transcription. Taken together, these data demonstrate that NGF increases the levels of multiple human tau isoforms in IMR32 cells which may result, at least in part, from NGF-mediated PKC and MAP kinase-induced tau transcription. 展开更多
关键词 Nerve growth factor (NGF) TAU signal transduction Transcription NITRIC Oxide (NO) IMR32 CELLS PC12 CELLS
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Dihydroergotamine ameliorates liver fibrosis by targeting transforming growth factor β type Ⅱ receptor 被引量:1
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作者 Ke-Xin Zheng Shou-Li Yuan +12 位作者 Meng Dong Han-Lin Zhang Xiao-Xiao Jiang Chun-Long Yan Rong-Cai Ye Hui-Qiao Zhou Li Chen Rui Jiang Zi-Yu Cheng Zhi Zhang Qi Wang Wan-Zhu Jin Wen Xie 《World Journal of Gastroenterology》 SCIE CAS 2023年第20期3103-3118,共16页
BACKGROUND The transforming growth factor β(TGFβ) signaling pathway plays a crucial role in the development of liver fibrosis by activating TGFβ type Ⅱ receptor(TGFβR2), followed by the recruitment of TGFβR1 fin... BACKGROUND The transforming growth factor β(TGFβ) signaling pathway plays a crucial role in the development of liver fibrosis by activating TGFβ type Ⅱ receptor(TGFβR2), followed by the recruitment of TGFβR1 finally triggering downstream signaling pathway.AIM To find drugs targeting TGFβR2 that inhibit TGFβR1/TGFβR2 complex formation, theoretically inhibit TGFβ signaling pathway, and thereby ameliorate liver fibrosis.METHODS Food and Drug Administration-approved drugs were screened for binding affinity with TGFβR2 by virtual molecular docking. We identified 6 candidates and further explored their potential by Cell Counting Kit-8(CCK-8) cell cytotoxic experiment to validate toxicity and titrated the best cellular working concentrations. Next, we further demonstrated the detailed molecular working mechanisms using mutagenesis analysis. Finally, we used a mouse model to investigate its potential anti-liver fibrosis effect.RESULTS We identified 6 drug candidates. Among these 6 drugs, dihydroergotamine(DHE) shows great ability in reducing fibrotic gene expressions such as collagen, p-SMAD3, and α-SMA in TGFβ induced cellular model of liver fibrosis in LX-2 cells. Furthermore, we demonstrated that DHE binds to TGFβR2. Moreover, mutation of Leu27, Phe30, Thr51, Ser52, Ile53, and Glu55 of TGFβR2 disrupted the binding of TGFβR2 with DHE. In addition, DHE significantly improved liver fibrosis, as evidenced by Masson’s trichrome staining of liver sections. This is further supported by the width and the velocity of the portal vein, and serum markers of liver function. In line with those observations, DHE also decreased macrophages infiltration and extracellular matrix deposition in the liver.CONCLUSION DHE alleviates liver fibrosis by binding to TGFβR2 thereby suppressing TGFβ signaling pathway. We show here that as far as drug repurposing, DHE has great potential to treat liver fibrosis. 展开更多
关键词 Liver fibrosis Transforming growth factorβ(TGFβ)signaling pathway TGFβtype II receptor(TGFβR2) Virtual screening Drug-repurposing Dihydroergotamine
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Protein tyrosine phosphatase 1B regulates migration of ARPE-19 cells through EGFR/ERK signaling pathway 被引量:3
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作者 Zhao-Dong Du Li-Ting Hu +4 位作者 Gui-Qiu Zhao Qian Wang Qiang Xu Nan Jiang Jing Lin 《International Journal of Ophthalmology(English edition)》 SCIE CAS 2015年第5期891-897,共7页
AIMTo evaluate whether protein tyrosine phosphatase 1B (PTP1B) contributed to initiate human retinal pigment epithelium cells (A)-19 migration and investigate the signaling pathways involved in this process.METHODSARP... AIMTo evaluate whether protein tyrosine phosphatase 1B (PTP1B) contributed to initiate human retinal pigment epithelium cells (A)-19 migration and investigate the signaling pathways involved in this process.METHODSARPE-19 cells were cultured and treated with the siRNA-PTP1B. Expression of PTP1B was confirmed by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR). AG1478 [a selective inhibitor of epidermal growth factor receptor (EGFR)] and PD98059 (a specific inhibitor of the activation of mitogen-activated protein kinase) were used to help to determine the PTP1B signaling mechanism. Western blot analysis verified expression of EGFR and extracellular signal-regulated kinase (ERK) in ARPE-19 cells. The effect of siRNA-PTP1B on cell differentiation was confirmed by immunostaining for &#x003b1;-smooth muscle actin (&#x003b1;-SMA) and qRT-PCR. Cell migration ability was analyzed by transwell chamber assay.RESULTSThe mRNA levels of PTP1B were reduced by siRNA-PTP1B as determined by qRT-PCR assay. SiRNA-PTP1B activated EGFR and ERK phosphorylation. &#x003b1;-SMA staining and qRT-PCR assay demonstrated that siRNA-PTP1B induced retinal pigment epithelium (RPE) cells to differentiate toward better contractility and motility. Transwell chamber assay proved that PTP1B inhibition improved migration activity of RPE cells. Treatment with AG1478 and PD98059 abolished siRNA-PTP1B-induced activation of EGFR and ERK, &#x003b1;-SMA expression and cell migration.CONCLUSIONPTP1B inhibition promoted myofibroblast differentiation and migration of ARPE-19 cells, and EGFR/ERK signaling pathway played important role in migration process. 展开更多
关键词 protein tyrosine phosphatase 1B retinal pigment epithelium cell migration epidermal growth factor receptor extracellular signal-regulated kinase
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FGF2 promotes the chemotherapy resistance in colon cancer cells through activating PI3K/Akt signaling pathway 被引量:1
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作者 Xiao-Lan Jian Pu-Hua Zeng +1 位作者 Ke-Xiong Li Wei Peng 《Oncology and Translational Medicine》 2023年第6期281-286,共6页
Background:To investigate the role of fibroblast growth factor 2(FGF2)in chemotherapy resistance of colon cancer.Methods:An HCT116/5-fluorouracil(5-FU)-resistant cell line was established,and FGF2 levels were detected... Background:To investigate the role of fibroblast growth factor 2(FGF2)in chemotherapy resistance of colon cancer.Methods:An HCT116/5-fluorouracil(5-FU)-resistant cell line was established,and FGF2 levels were detected in a sensitive cell group(HCT116)and a resistant cell group(HCT1116-R)using different methods.Fibroblast growth factor 2 levels in the medium were determined by enzyme-linked immunoassay.The protein expressions of FGF2,fibroblast growth factor receptor 1(FGFR1),and phospho-FGFR1 were assessed by Western blotting,and FGF2 mRNA levels were detected by quantitative real-time polymerase chain reaction.Fibroblast growth factor 2 recombinant protein was added to sensitive cells,and FGFR inhibitor AZD4547 was added to resistant cells,and the cell survival rate was determined using the cell counting kit-8 method and the protein expressions of PI3K(phosphatidylinositol 3 kinase),p-PI3K(phospho-PI3K),Akt(protein kinase B),p-Akt(phospho-Akt),mammalian target of rapamycin(mTOR),p-mTOR(phospho-mTOR),Bad(Bcl-xL/Bcl-2-associated death promoter),NF-κB(nuclear factorκB),GSK-3(glycogen synthase kinase-3),FKHR(forkhead box protein O1),and PTEN(phosphatase and tensin homolog deleted on chromosome ten)were detected by Western blotting.Results:Fibroblast growth factor 2 protein and mRNA expression levels in the HCT116-R group were significantly higher than those in the HCT116 group.Fibroblast growth factor 2 increased the survival rate of HCT116 cells;improved tolerance to 5-FU;upregulated p-PI3K,p-Akt,and p-mTOR;and downregulated Bad.The FGFR inhibitor AZD4547 decreased cell survival rate and tolerance to 5-FU;downregulated p-PI3K,p-Akt,and p-mTOR expression;and upregulated Bad.Conclusions:Fibroblast growth factor 2 promotes chemotherapy tolerance in colon cancer cells by activating the Akt/mTOR and Akt/Bad signaling pathways downstream of PI3K. 展开更多
关键词 Chemotherapy drug resistance Colorectal cancer Fibroblast growth factor PI3K/Akt signaling pathway
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