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BIRC3 induces the phosphoinositide 3-kinase-Akt pathway activation to promote trastuzumab resistance in human epidermal growth factor receptor 2-positive gastric cancer
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作者 Shu-Liang Li Pei-Yao Wang +7 位作者 Yang-Pu Jia Zhao-Xiong Zhang Hao-Yu He Peng-Yu Chen Xin Liu Bang Liu Li Lu Wei-Hua Fu 《World Journal of Gastrointestinal Oncology》 SCIE 2024年第11期4436-4455,共20页
BACKGROUND Trastuzumab-targeted therapy is currently the standard of care for advanced human epidermal growth factor receptor 2(HER2)-positive gastric cancer.However,the emergence of resistance to trastuzumab poses si... BACKGROUND Trastuzumab-targeted therapy is currently the standard of care for advanced human epidermal growth factor receptor 2(HER2)-positive gastric cancer.However,the emergence of resistance to trastuzumab poses significant challenges.AIM To identify the key genes associated with trastuzumab resistance.These results provide a basis for the development of interventions to address drug resistance and improve patient outcomes.METHODS High-throughput sequencing and bioinformatics were used to identify the differentially expressed pivotal gene BIRC3 and delineate its potential function and pathway regulation.Tumor samples were collected from patients with HER2-positive gastric cancer to evaluate the correlation between BIRC3 expression and trastuzumab resistance.We established gastric cancer cell lines with both highly expressed and suppressed levels of BIRC3,followed by comprehensive in vitro and in vivo experiments to confirm the involvement of BIRC3 in trastuzumab resistance and to elucidate its underlying mechanisms.RESULTS In patients with HER2-positive gastric cancer,there is a significant correlation between elevated BIRC3 expression in tumor tissues and higher T stage,tumor node metastasis stage,as well as poor overall survival and progressionfree survival.BIRC3 is highly expressed in trastuzumab-resistant gastric cancer cell lines,where it inhibits tumor cell apoptosis and enhances trastuzumab resistance by promoting the phosphorylation and activation of the phosphoinositide 3-kinase-Akt(PI3K-AKT)pathway in HER2-positive gastric cancer cells,both in vivo and in vitro.CONCLUSION This study revealed a robust association between high BIRC3 expression and an unfavorable prognosis in patients with HER2-positive gastric cancer.Thus,the high expression of BIRC3 stimulated PI3K-AKT phosphorylation and activation,stimulating the proliferation of HER2-positive tumor cells and suppressing apoptosis,ultimately leading to trastuzumab resistance. 展开更多
关键词 Gastric cancer Human epidermal growth factor receptor 2 TRASTUZUMAB DRUG-RESISTANCE BIRC3
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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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Stage-specific localization of transforming growth factor β1 and β3 and their receptors during spermatogenesis in men 被引量:19
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作者 Yuan-QiangZhang Xiao-ZhouHe +3 位作者 Jin-ShanZhang Rui-AnWang JieZhou Ruo-JunXu 《Asian Journal of Andrology》 SCIE CAS CSCD 2004年第2期105-109,共5页
Aim: To investigate the stage-specific localization of transforming growth factor (TGF) β1 and β3 during spermatogenesis in adult human testis. Methods: The localization of TGFβ1 and β3 was investigated by immunoh... Aim: To investigate the stage-specific localization of transforming growth factor (TGF) β1 and β3 during spermatogenesis in adult human testis. Methods: The localization of TGFβ1 and β3 was investigated by immunohis tochemical staining method employing specific polyclonal antibodies. Results: Both TGFβ1 and β3 and their recep tors were preponderant in the Leydig celis. TGFβ1 could not be detected in the seminiferous tubules. TGFβ3 and TGFβ-Receptor (R) I were mainly seen in the elongated spermatids, while TGFβ-RⅡ in the pachytene spermatocytes and weak in the spermatogonia, spermatids and Sertoli celis. Only TGFβ-RⅡ was detected in the Sertoli celis. TGFβ3, TGFβ-RⅠ and TGFβ-RⅡ showed a staining pattern dependent upon the stages of the seminiferous epithelium cycle. Conclusion: TGFβ isoforms and their receptors are present in the somatic and germ celis of the adult human testis, suggesting their involvement in the regulation of spermatogenesis. 展开更多
关键词 transforming growth factor transforming growth factor receptors human testis
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Epigallocatechin-3-gallate suppresses transforming growth factor-beta signaling by interacting with the transforming growth factor-beta typeⅡreceptor 被引量:1
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作者 Masaki Tabuchi Sumio Hayakawa +7 位作者 Eiko Honda Kana Ooshima Tatsuki Itoh Koji Yoshida Ah-Mee Park Hideaki Higashino Mamoru Isemura Hiroshi Munakata 《World Journal of Experimental Medicine》 2013年第4期100-107,共8页
AIM: To investigate the(-)-epigallocatechin-3-gallate(EGCG) binding to transforming growth factor-β(TGF-β) type Ⅱ receptor(TGFRⅡ).METHODS: The expression of α-smooth muscle actin(α-SMA) was used as a marker for ... AIM: To investigate the(-)-epigallocatechin-3-gallate(EGCG) binding to transforming growth factor-β(TGF-β) type Ⅱ receptor(TGFRⅡ).METHODS: The expression of α-smooth muscle actin(α-SMA) was used as a marker for fibrotic change inhuman lung fibroblast MRC-5 cells. The α-SMA expression level was determined by western blotting and immunohistological analysis. We examined whether the anti-fibrotic effects of EGCG on MRC-5 cells was dependent on antioxidant mechanism by using edaravone and N-acetylcysteine(NAC). The suppression effects of EGCG on Smad2/3 activation were studied by confocal fluorescence microscopy. The binding of EGCG to recombinant TGFRⅡ protein was analyzed by immunoprecipitation and affinity chromatography.RESULTS: When MRC-5 cells were treated with TGF-β, EGCG decreased the expression of α-SMA in a dose dependent manner, whereas catechin did not influence the α-SMA expression in the cells. Except for EGCG, antioxidant compounds(e.g., edaravone and NAC) had no effects on the TGF-β-induced α-SMA expression. Nuclear localization of phosphorylated Smad2/3 was observed after TGF-β treatment; however, EGCG treatment attenuated the nuclear transportation of Smad2/3 in the presence or absence of TGF-β. After a TGFRⅡ expression vector was introduced into COS-7 cells, cell lysates were untreated or treated with EGCG or catechin. The immunoprecipitation experiments using the lysates showed that EGCG dose-dependently bound to TGFRⅡ and that catechin did not at all. Affinity chromatography study indicated that EGCG would bind to TGFRⅡ.CONCLUSION: Our results demonstrate that EGCG interacts with TGFRⅡ and inhibits the expression of α-SMA via the TGF-β-Smad2/3 pathway in human lung fibroblast MRC-5 cells. 展开更多
关键词 Epigallocatechin-3-gallate transforming growth factor MYOFIBROBLAST α-smooth muscle ACTIN Fibrosis
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Roles of Smad3 and Smad7 in rat pancreatic stellate cells activated by transforming growth factor-beta 1 被引量:13
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作者 Qian, Zhu-Yin Peng, Quan +2 位作者 Zhang, Zheng-Wei Thou, Long-An Miao, Yi 《Hepatobiliary & Pancreatic Diseases International》 SCIE CAS 2010年第5期531-536,共6页
BACKGROUND: Pancreatic stellate cells (PSCs) play a major role in promoting pancreatic fibrosis. Transforming growth factor beta 1 (TGF-beta 1) is a critical mediator of this process. This study aimed to determine the... BACKGROUND: Pancreatic stellate cells (PSCs) play a major role in promoting pancreatic fibrosis. Transforming growth factor beta 1 (TGF-beta 1) is a critical mediator of this process. This study aimed to determine the expression of the Smad3 and Smad7 genes in the process of PSC activation, and explore the mechanisms of chronic pancreatitis. METHODS: The expressions of Smad3 and Smad7 in PSCs before and after TGF-beta 1 treatment were detected by reverse transcription-polymerase chain reaction and Western blotting analysis. Smad3 expression was detected in PSCs after treatment with 5 ng/ml of TGF-beta 1 for 24 hours. RESULTS: Smad7 expression was decreased in TGF-beta 1 -activated PSCs (P<0.05) in a dose-dependent manner. When TGF-beta 1 concentration reached 10 ng/ml, the expression of p-Smad3, Smad3, and Smad7 was inhibited (P<0.05). CONCLUSIONS: TGF-beta 1 promotes the expression of Smad3 and inhibits the expression of Smad7 during the activation of PSCs. In contrast, high-dose TGF-beta 1 downregulates the expression of Smad3 in completely activated PSCs. 展开更多
关键词 pancreatic stellate cell transforming growth factor beta 1 chronic pancreatitis SMAD3 SMAD7
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Chondrogenesis of periodontal ligament stem cells by transforming growth factor-β3 and bone morphogenetic protein-6 in a normal healthy impacted third molar 被引量:5
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作者 Sunyoung Choi Tae-Jun Cho +2 位作者 Soon-Keun Kwon Gene Lee Jaejin Cho 《International Journal of Oral Science》 SCIE CAS CSCD 2013年第1期7-13,共7页
The periodontal ligament-derived mesenchymal stem cell is regarded as a source of adult stem cells due to its multipotency.However, the proof of chondrogenic potential of the cells is scarce.Therefore,we investigated ... The periodontal ligament-derived mesenchymal stem cell is regarded as a source of adult stem cells due to its multipotency.However, the proof of chondrogenic potential of the cells is scarce.Therefore,we investigated the chondrogenic differentiation capacity of periodontal ligament derived mesenchymal stem cells induced by transforming growth factor(TGF)-p3 and bone morphogenetic protein(BMP)-6.After isolation of periodontal ligament stem cells(PDLSCs) from human periodontal ligament,the cells were cultured in Dulbecco’s modified Eagle’s medium(DMEM) with 20%fetal bovine serum(FBS).A mechanical force initiated chondrogenic differentiation of the cells.For chondrogenic differentiation,10μg·LTGF-β3 or 100μg·LBMP-6 and the combination treating group for synergistic effect of the growth factors.We analyzed the PDLSCs by fluorescence-activated cell sorting and chondrogenesis were evaluated by glycosaminoglycans assay,histology,immunohistochemistry and genetic analysis.PDLSCs showed mesenchymal stem cell properties proved by FACS analysis.Glycosaminoglycans contents were increased 217%by TGF-β3 and 220%by BMP-6. The synergetic effect of TGF-β3 and BMP-6 were shown up to 281%compared to control.The combination treatment increased Sox9, aggrecan and collagen II expression compared with not only controls,but also TGF-P3 or BMP-6 single treatment dramatically.The histological analysis also indicated the chondrogenic differentiation of PDLSCs in our conditions.The results of the present study demonstrate the potential of the dental stem cell as a valuable cell source for chondrogenesis,which may be applicable for regeneration of cartilage and bone fracture in the field of cell therapy. 展开更多
关键词 bone morphogenetic protein-6 chondrogenesis growth factor periodental ligament cell stem cell transforming growth factor3
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Transforming growth factor-β and toll-like receptor-4 polymorphisms are not associated with fibrosis in haemochromatosis 被引量:1
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作者 Marnie J Wood Lawrie W Powell +2 位作者 Jeannette L Dixon V Nathan Subramaniam Grant A Ramm 《World Journal of Gastroenterology》 SCIE CAS 2013年第48期9366-9376,共11页
AIM:To investigate the role of genetic polymorphisms in the progression of hepatic fibrosis in hereditary haemochromatosis.METHODS:A cohort of 245 well-characterised C282Y homozygous patients with haemochromatosis was... AIM:To investigate the role of genetic polymorphisms in the progression of hepatic fibrosis in hereditary haemochromatosis.METHODS:A cohort of 245 well-characterised C282Y homozygous patients with haemochromatosis was studied,with all subjects having liver biopsy data and DNA available for testing.This study assessed the association of eight single nucleotide polymorphisms(SNPs)in a total of six genes including toll-like receptor 4(TLR4),transforming growth factor-beta(TGF-β),oxoguanine DNA glycosylase,monocyte chemoattractant protein 1,chemokine C-C motif receptor 2 and interleukin-10 with liver disease severity.Genotyping was performed using high resolution melt analysis and sequencing.The results were analysed in relation to the stage of hepatic fibrosis in multivariate analysis incorporating other cofactors including alcohol consumption and hepatic iron concentration.RESULTS:There were significant associations between the cofactors of male gender(P=0.0001),increasing age(P=0.006),alcohol consumption(P=0.0001),steatosis(P=0.03),hepatic iron concentration(P<0.0001)and the presence of hepatic fibrosis.Of the candidate gene polymorphisms studied,none showed a significant association with hepatic fibrosis in univariate or multivariate analysis incorporating cofactors.We also specifically studied patients with hepatic iron loading above threshold levels for cirrhosis and compared the genetic polymorphisms between those with no fibrosis vs cirrhosis however there was no significant effect from any of the candidate genes studied.Importantly,in this large,well characterised cohort of patients there was no association between SNPs for TGF-βor TLR4and the presence of fibrosis,cirrhosis or increasing fibrosis stage in multivariate analysis.CONCLUSION:In our large,well characterised group of haemochromatosis subjects we did not demonstrate any relationship between candidate gene polymorphisms and hepatic fibrosis or cirrhosis. 展开更多
关键词 HAEMOCHROMATOSIS Genetic polymorphism Liver FIBROSIS TOLL-LIKE receptor 4 Interleukin 10 Monocyte CHEMOATTRACTANT protein 1 Chemokine(C-C motif) ligand 2 transforming growth factor beta 8-oxoguanine DNA GLYCOSYLASE
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EDIL3 depletion suppress epithelial-mesenchymal transition of lens epithelial cells via transforming growth factor β pathway 被引量:3
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作者 Rui Zhang You-Heng Wei +7 位作者 Chun-Yan Zhao Hong-Yuan Song Ni Shen Xiao Cui Xin Gao Zhong-Tian Qi Ming Zhong Wei Shen 《International Journal of Ophthalmology(English edition)》 SCIE CAS 2018年第1期18-24,共7页
AIM: To study the effect of discoidin I-like domaincontaining protein 3(EDIL3) depletion on the proliferation and epithelial-mesenchymal transition(EMT) in human lens epithelial cells(LECs). METHODS: RNA inter... AIM: To study the effect of discoidin I-like domaincontaining protein 3(EDIL3) depletion on the proliferation and epithelial-mesenchymal transition(EMT) in human lens epithelial cells(LECs). METHODS: RNA interference was used to inhibit the expression of EDIL3 in human LECs in vitro. The morphology of cells was observed using an inverted microscope. Cell proliferation was assessed using Ed U kit. Cell migration was investigated using Transwell chamber and EMT of LECs was assessed using confocal microscope and Western blotting. The transforming growth factor β(TGFβ) pathway was investigated using Western blotting. RESULTS: The data showed that silencing EDIL3 expression changed LECs morphology and suppressed LECs proliferation(P〈0.05) and migration(P〈0.01). Furthermore, the result of Western blotting showed that EDIL3 depletion reduced the expression of α-smooth muscle actin(α-SMA)(P〈0.001) and vimentin(P〈0.01), while increased the expression of E-cadherin(P〈0.001). EDIL3 depletion could suppress the phosphorylation of Smad2(P〈0.01) and Smad3(P〈0.01) and the activation of exracellular signal regulated kinase(ERK)(P〈0.05). CONCLUSION: The findings indicate that EDIL3 might participate in the proliferation and EMT in LECs via TGFβ pathway and may be a potential therapeutic target for the treatment of posterior capsule opacification. 展开更多
关键词 discoidin I-like domain-containing protein 3 transforming growth factor β epithelial-mesenchymal transition human lens epithelial cells
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Detection of Frameshift Mutations of the Transforming Growth Factor p ReceptorⅡin Gastric Cancers with Microsatellite Instability 被引量:1
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作者 Dong Wang Xin Geng Yanyun Li Yuchuan Wang Yanni Li Linsheng Zhao Weiming Zhang 《Chinese Journal of Clinical Oncology》 CSCD 2006年第4期267-272,共6页
OBJECTIVE To study the relationship among microsatellite instability (MSI), frameshift mutations (FM) of the transforming growth factor β receptor Ⅱ (TGF β R Ⅱ), methylation state of the hMLH1 promoter and h... OBJECTIVE To study the relationship among microsatellite instability (MSI), frameshift mutations (FM) of the transforming growth factor β receptor Ⅱ (TGF β R Ⅱ), methylation state of the hMLH1 promoter and hMLH1 protein expression level in gastric cancers, and to explore their relationship to gastric carcinogenesis. METHODS DNA was isolated from 101 gastric specimens and 5 microsatellite loci were detected. PCR, electrophoresis on denatured polyacrylamide gels and silver staining were performed to detect the MSI. The FMs of TGFβR Ⅱ were also screened with the same method. HMLH1 methylation was analyzed by methylation specific PCR (MSP) and sequencing. HMLH1 protein expression was detected using immunohistochemistry. RESULTS The incidence of MSIs was 53.7% and 0% in the cancers and normal tissues, respectively, with the frequency of MSIs being significantly higher in the gastric cancers compared to the normal gastric tissues (P〈0.05). The frequency of hMLH1 methylation was 41.5%(17/41) in the gastric cancers and 0%(0/60) in the normal group. Decreased hMLH1 expression was observed in 94.1%(16/17) of cases exhibiting methylation. FMs of TGFβR Ⅱ were identified in 5 (62.5%) of the 8 samples with MSIH. In contrast, FMs were not found in MSI-L or microsatellite stable (MSS) cases. CONCLUSION MSIs and FMs of TGFβR Ⅱ may play an important role in gastric carcinogenesis. HMLH1 methylation is an important modification of the DNA which results in inactivation of hMLH1 and mismatch repair defects which lead to MSls and FMs of TGFβR Ⅱ. 展开更多
关键词 gastric cancer microsateUite instabilily methylolion specific PCR HMLH1 transforming growth factor β receptor Ⅱ.
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Transforming growth factor β receptor Ⅱ expression inexperimental cryptorchidism and apoptosisin spermatogenic cells in rats
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作者 Yuan-QiangZhang Jin-ShanZhang +1 位作者 LanSun Xiao-ZhouHe 《Asian Journal of Andrology》 SCIE CAS CSCD 2004年第1期66-66,共1页
Objective: To study the transforming growth factor β receptor Ⅱ (TGFβ-R Ⅱ) expression in experimental cryptorchidism and apoptosis in spermatogenic cells in rats. Methods: The apoptosis of spermatogenic cells was ... Objective: To study the transforming growth factor β receptor Ⅱ (TGFβ-R Ⅱ) expression in experimental cryptorchidism and apoptosis in spermatogenic cells in rats. Methods: The apoptosis of spermatogenic cells was detected by means of the terminal deoxynucleotldyl transferase mediated dUTP nick end lableling method (TUNEL) and the TGFβ-R Ⅱ expression was observed with the immunohistochemistry SABC methods. Results: There was a significant increase in the TGFβ-R Ⅱ expression in unilateral undescended testes (UUTs) compared with that in contralateral descended testes (CDTs, P<0.01). However, there was a significant and time-dependent increase in the mean apoptotic index in UUTs than in CDTs. Conclusion: TGFβ-R Ⅱ may play an important role in spermatogenic cell apoptosis. 展开更多
关键词 transforming growth factor receptor CRYPTORCHIDISM RAT spermmatogenic cell APOPTOSIS
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Expression of transforming growth factor β receptors in CCI_4, -induced cirrhotic liver in rats
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作者 梁志清 何振平 《Journal of Medical Colleges of PLA(China)》 CAS 1999年第2期124-126,共3页
Objective: To investigate the expression and the role of transforming growth factor 6 (TGF-β) receptors in CCI4 --Induced cirrhotic liver. Methods: In situ hybridization was used. Results: The TGF--β type I receptor... Objective: To investigate the expression and the role of transforming growth factor 6 (TGF-β) receptors in CCI4 --Induced cirrhotic liver. Methods: In situ hybridization was used. Results: The TGF--β type I receptors mRNA was mainly expressed in Ito cells, endothelial cells and myofibroblasts. Only a few hepatocytes expressed it. However. the TGF-β type Ⅱ receptors was mostly localized in endothelial cells and Ito cells but few hepatocytes. The expression of mRNA of both the 2 types of receptors were significantly increased in the cirrhotic liver than in the control. Conclusion: The autocrine and paracrine effects of TGF-β on matrix production and activation of Ito cells might be an important factor of fibrogenesis in CCI4 cirrhotic ever. 展开更多
关键词 transforming growth factor β receptorS FIBROSIS LIVER
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Ontogeny of expression of transforming growth factor-βand its receptors and their possible relationship with scarless or scar-forming healing in human fetal and postnatal skins 被引量:1
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作者 Chen Wei Fu Xiaobing Ge Shili~1 Sun Tongzhu Zhou Gang Jiang Duyin Sheng Zhiyong Research Department of Burn Institute,304th Hospital,Beijing 100037 Institute of Radiation Medicine,Academy of Military Medicine Sciences,Beijing 100850,People’s Republic of China 《感染.炎症.修复》 2003年第4期197-205,共9页
Fetal eutaneous wounds that oeeur in earlygestation heal without sear formation.Althoughmueh work has been done to eharaeterize the roleof transforming growth
关键词 in et for of Ontogeny of expression of transforming growth factor and its receptors and their possible relationship with scarless or scar-forming healing in human fetal and postnatal skins TGF were that TBR EGA with
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Correlation between expression of two transforming growth factor-beta 1 receptors and microvascular density in a rat model of cerebral ischemia and reperfusion injury
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作者 Li Jiang Qingzhu Yue +1 位作者 Lingzhi Yu Xudong Liu 《Neural Regeneration Research》 SCIE CAS CSCD 2011年第11期850-854,共5页
The effects of transforming growth factor-β1 (TGF-β1) are currently controversial. Whether TGF-β1 promotes or inhibits revascularization under different conditions remains poorly understood. Based on previous stu... The effects of transforming growth factor-β1 (TGF-β1) are currently controversial. Whether TGF-β1 promotes or inhibits revascularization under different conditions remains poorly understood. Based on previous studies, the current experiment established rat models of cerebral ischemia and reperfusion injury (IRI), and demonstrated that pathological and functional damage was also increased after IRI. The most serious damage was observed at 3 days after reperfusion, at which time microvascular density fell to its lowest level. Soon afterwards, microvascular density increased, new collateral circulation was gradually established at 4 to 7 days after reperfusion, and pathological damage and neurological deficits were improved. TGF-β1, activin receptor-like kinase 5 (ALK5) mRNA and protein expression levels increased gradually over time. In contrast, ALK1 mRNA and protein expression decreased over the same period. A significant negative correlation was detected between microvascular density and expression of the ALK5 gene transcript. There was no correlation between microvascular density and ALK1 gene transcriptional expression following cerebral IRI in a rat model. These findings suggest that ALK5, rather than ALK1, is the critical receptor in the TGF-β1 signal pathways after cerebral IRI. 展开更多
关键词 cerebral ischemia and reperfusion injury transforming growth factor-β1 transforming growth factor-β1 receptor/activin receptor-like kinase 1 activin receptor-like kinase 5 microvascular density neural regeneration
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Expression of transforming growth factor-β_1 and its typeⅠ receptor in different phases of post-burn hypertrophic scars
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作者 夏炜 郭树忠 鲁开化 《Journal of Medical Colleges of PLA(China)》 CAS 2000年第2期131-134,共4页
Objective: To analyze and compare the expression pattern of the transforming growth factor-β1(TGF-β1) and its type I receptor (TGF-β RI ) in nounal human skin and various phases of post-burn hypertrophic scars (HTS... Objective: To analyze and compare the expression pattern of the transforming growth factor-β1(TGF-β1) and its type I receptor (TGF-β RI ) in nounal human skin and various phases of post-burn hypertrophic scars (HTS). Method: The immunohistochemical ABC method was employed. Results: In nounal human skin, no evident immunoreactivity of TGF-β1 and TGF-β R I was observed. In activation phase of post-burn HTS, TGF-β R I and TGF-β1 were highly expressed in most dermal fibroblasts which seemed to be the same subset. However, in remission phase, no staining was seen in der mal fibroblasts. Conclusion: The formation of all may involve the increase of TGF-β responsiveness in fibroblasts The ac cumulation at the wound site and failure of apoptosis of over-resposive fibroblasts may contribute to the formation of HTS. 展开更多
关键词 HYPERTROPHIC scar transforming growth factor-β1 transforming growth factor receptor I immunohistochemistry
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Alterations in the human epidermal growth factor receptor 2-phosphatidylinositol 3-kinase-v-Akt pathway in gastric cancer 被引量:20
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作者 Yasutaka Sukawa Hiroyuki Yamamoto +12 位作者 Katsuhiko Nosho Hiroaki Kunimoto Hiromu Suzuki Yasushi Adachi Mayumi Nakazawa Takayuki Nobuoka Mariko Kawayama Masashi Mikami Takashi Matsuno Tadashi Hasegawa Koichi Hirata Kohzoh Imai Yasuhisa Shinomura 《World Journal of Gastroenterology》 SCIE CAS CSCD 2012年第45期6577-6586,共10页
AIM:To investigate human epidermal growth factor receptor 2(HER2)-phosphatidylinositol 3-kinase(PI3K)-vAkt murine thymoma viral oncogene homolog signaling pathway.METHODS:We analyzed 231 formalin-fixed,paraffinembedde... AIM:To investigate human epidermal growth factor receptor 2(HER2)-phosphatidylinositol 3-kinase(PI3K)-vAkt murine thymoma viral oncogene homolog signaling pathway.METHODS:We analyzed 231 formalin-fixed,paraffinembedded gastric cancer tissue specimens from Japanese patients who had undergone surgical treatment.The patients' age,sex,tumor location,depth of invasion,pathological type,lymph node metastasis,and pathological stage were determined by a review of the medical records.Expression of HER2 was analyzed by immunohistochemistry(IHC) using the HercepTest TM kit.Standard criteria for HER2 positivity(0,1+,2+,and 3+) were used.Tumors that scored 3+ were considered HER2-positive.Expression of phospho Akt(pAkt) was also analyzed by IHC.Tumors were considered pAkt-positive when the percentage of positive tumor cells was 10% or more.PI3K,catalytic,alpha polypeptide(PIK3CA) mutations in exons 1,9 and 20 were analyzed by pyrosequencing.Epstein-Barr virus(EBV) infection was analyzed by in situ hybridization targeting EBV-encoded small RNA(EBER) with an EBER-RNA probe.Microsatellite instability(MSI) was analyzed by polymerase chain reaction using the mononucleotide markers BAT25 and BAT26.RESULTS:HER2 expression levels of 0,1+,2+ and 3+ were found in 167(72%),32(14%),12(5%) and 20(8.7%) samples,respectively.HER2 overexpression(IHC 3+) significantly correlated with intestinal histological type(15/20 vs 98 /205,P = 0.05).PIK3CA mutations were present in 20 cases(8.7%) and significantly correlated with MSI(10/20 vs 9/211,P < 0.01).The mutation frequency was high(21%) in T4 cancers and very low(6%) in T2 cancers.Mutations in exons 1,9 and 20 were detected in 5(2%),9(4%) and 7(3%) cases,respectively.Two new types of PIK3CA mutation,R88Q and R108H,were found in exon1.All PIK3CA mutations were heterozygous missense singlebase substitutions,the most common being H1047R(6/20,30%) in exon20.Eighteen cancers(8%) were EBV-positive and this positivity significantly correlated with a diffuse histological type(13/18 vs 93/198,P = 0.04).There were 7 cases of lymphoepithelioma-like carcinomas(LELC) and 6 of those cases were EBV-positive(percent/EBV:6/18,33%;percent/all LELC:6/7,86%).pAkt expression was positive in 119(53%) cases but showed no correlation with clinicopathological characteristics.pAkt expression was significantly correlated with HER2 overexpression(16/20 vs 103/211,P < 0.01) but not with PIK3CA mutations(12/20 vs 107/211,P = 0.37) or EBV infection(8/18 vs 103/211,P = 0.69).The frequency of pAkt expression was higher in cancers with exon20 mutations(100%) than in those with exon1(40%) or exon9(56%) mutations.One case showed both HER2 overexpression and EBV infection and 3 cases showed both PIK3CA mutations and EBV infection.However,no cases showed both PIK3CA mutations and HER2 overexpression.One EBVpositive cancer with PIK3CA mutation(H1047R) was MSI-positive.Three of these 4 cases were positive for pAkt expression.In survival analysis,pAkt expression significantly correlated with a poor prognosis(hazard ratio 1.75;95%CI:1.12-2.80,P = 0.02).CONCLUSION:HER2 expression,PIK3CA mutations and EBV infection in gastric cancer were characterized.pAkt expression significantly correlates with HER2 expression and with a poor prognosis. 展开更多
关键词 Human epidermal growth factor receptor 2 Phosphatidylinositol 3-kinase CATALYTIC Alpha polypep-tide Epstein-Barr virus Aid: Gastric cancer
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Over-expression of fibroblast growth factor receptor 3 in human hepatocellular carcinoma 被引量:8
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作者 Wei-Hua Qiu Bing-Sen Zhou +7 位作者 Peiguo G. Chu Wen-Gang Chen Christopher Chung Jennifer Shih Paul Hwu Christopher Yeh Richard Lopez Yun Yen 《World Journal of Gastroenterology》 SCIE CAS CSCD 2005年第34期5266-5272,共7页
AIM: To describe the significant over-expression of fibroblast growth factor receptor 3 (FGFR3), which is a signal transduction and cell proliferation related gene in hepatocellular carcinoma (HCC).METHODS: Following ... AIM: To describe the significant over-expression of fibroblast growth factor receptor 3 (FGFR3), which is a signal transduction and cell proliferation related gene in hepatocellular carcinoma (HCC).METHODS: Following DNA microarray, Northern blot and quantitative real-time PCR were employed to confirm FGFR3 expression difference in HCC tissues and surrounding non-neoplastic liver tissue. FGFR3 expression levels were further determined by immunohistochemical study in 43 cases of HCC.RESULTS: Northern blot results showed the significant over-expression of FGFR3 in HCC tissues, which was consistent with that from DNA microarray. Quantitative real-time PCR demonstrated that the mean ratio of FGFR3 mRNA to glyceraldehyde-3-phosphate dehydrogenase (GADPH) mRNA in HCC tissue was 0.250, whereas the ratio in non-neoplastic liver tissue was 0.014. Statistical analyses of 43 cases of HCC revealed that HCC scored higher than the matched non-neoplastic liver tissues.Examination of clinicopathological features revealed a strong correlation of over-expression of FGFR3 with poor tumor differentiation and high nuclear grade.CONCLUSION: Over-expression of FGFR3 may play an important role in liver carcinogenesis. FGFR3 may be an ideal candidate as a molecular marker in the diagnosis of HCC and a potential therapeutic target. 展开更多
关键词 Fibroblast growth factor receptor 3 Human hepatocellular carcinoma MICROARRAY
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Fibroblast growth factor receptor 3 effects on proliferation and telomerase activity in sheep growth plate chondrocytes 被引量:1
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作者 Logan B Smith Janelle M Belanger Anita M Oberbauer 《Journal of Animal Science and Biotechnology》 SCIE CAS 2013年第1期41-48,共8页
Background: Fibroblast growth factor receptor 3 (FGFR3) inhibits growth-plate chondrocyte proliferation and limits bone elongation. Gain-of-function FGFR3 mutations cause dwarfism, reduced telomerase activity and s... Background: Fibroblast growth factor receptor 3 (FGFR3) inhibits growth-plate chondrocyte proliferation and limits bone elongation. Gain-of-function FGFR3 mutations cause dwarfism, reduced telomerase activity and shorter telomeres in growth plate chondroyctes suggesting that FGFR3 reduces proliferative capacity, inhibits telomerase, and enhances senescence. Thyroid hormone (1-3) plays a role in cellular maturation of growth plate chondrocytes and a known target of T3 is FGFR3. The present study addressed whether reduced FGFR3 expression enhanced telomerase activity, mRNA expression of telomerase reverse transcriptase (TERT) and RNA component of telomerase (TR), and chondrocyte proliferation, and whether the stimulation of FGFR3 by T3 evoked the opposite response. Results: Sheep growth-plate proliferative zone chondrocytes were cultured and transfected with siRNA to reduce FGFR3 expression; FGFR3 siRNA reduced chondrocyte FGFR3 mRNA and protein resulting in greater proliferation and increased TERT mRNA expression and telomerase activity (p 〈 0.0.5). Chondrocytes treated with T3 significantly enhanced FGFR3 mRNA and protein expression and reduced telomerase activity (p 〈 0.05); TERT and TR were not significantly reduced. The action of T3 at the growth plate may be partially mediated through the FGFR3 pathway. Conclusions: The results suggest that FGFR3 inhibits chondrocyte proliferation and reducing telomerase activity indicating an important role for telomerase in capacity during bone elongation. by down-regulating TERT expression sustaining chondrocyte proliferative 展开更多
关键词 CHONDROCYTES growth-plate TELOMERASE Fibroblast growth factor receptor 3 Thyroid hormone SHEEP
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Increased expressions of vascular endothelial growth factor(VEGF),VEGF-C and VEGF receptor-3 in prostate cancer tissue are associated with tumor progression 被引量:4
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作者 Jie Yang Hong-Fei Wu +7 位作者 Li-Xin Qian Wei Zhang Li-Xin Hua Mei-Lin Yu Zhen Wang Zheng-Quan Xu Yuan-Geng Sui Xin-Ru Wang 《Asian Journal of Andrology》 SCIE CAS CSCD 2006年第2期169-175,共7页
Aim: To investigate the differences in microvessel densities (MVD) and the expressions of vascular endothelial growth factor (VEGF), VEGF-C and VEGF receptor-3 (VEGFR-3) between prostate cancer (PCa) tissues ... Aim: To investigate the differences in microvessel densities (MVD) and the expressions of vascular endothelial growth factor (VEGF), VEGF-C and VEGF receptor-3 (VEGFR-3) between prostate cancer (PCa) tissues and adjacent benign tissues, and to explore the correlations among MVD, Jewett-Whitmore staging, Gleason scores and expressions of VEGF, VEGF-C and VEGFR-3 in the progression of PCa. Methods: An immunohistochemical approach was adopted to detect the expressions of CD34, VEGF, VEGF-C and VEGFR-3 in both cancer areas and peripheral benign areas of 71 primary prostatic adenocarcinoma specimens. A statistic analysis was then performed according to the experimental and clinic data. Results: Significantly upregulated expressions of VEGF, VEGF-C and VEGFR-3 were all found in malignant epithelium/cancer cells compared with adjacent benign epithelium (P 〈 0.01). Patients in stage D had a significantly higher score than patients in stage A, B or C when comparing the expression of VEGF-C or VEGFR-3 in the tumor area (P 〈 0.01). In addition, significant correlations were observed between Jewett-Whitmore staging and VEGF-C (rs = 0.738, P 〈 0.01), clinical staging and VEGFR-3 (rs = 0.410, P 〈 0.01), VEGF-C and Gleason scores (rs = 0.401, P 〈 0.01), VEGFR-3 and Gleason scores (rs = 0.581, P 〈 0.001) and MVD and VEGF (rs = 0.492, P 〈 0.001). Conclusion: Increased expressions of VEGF and VEGF-C were closely associ- ated with progression of PCa. The main contribution of increased VEGF expression for PCa progression was to upregulate MVD, which maintained the growth advantage of tumor tissue. However, the chief role of increased expressions of VEGF-C and VEGFR-3 was to enhance lymphangiogenesis and provide a main pathway for cancer cells to disseminate. (Asian J Androl 2006 Mar; 8: 169-175) 展开更多
关键词 prostatic neoplasms vascular endothelial growth factor vascular endothelial growth factor c vascular endothelial growth factor receptor-3 ANGIOGENESIS LYMPHANGIOGENESIS
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T-cell immunoglobulin mucin molecule-3, transformation growth factor β, and chemokine-12 and the prognostic status of diffuse large B-cell lymphoma 被引量:1
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作者 Hao Wu Hui-Cong Sun Gui-Fang Ouyang 《World Journal of Clinical Cases》 SCIE 2022年第32期11804-11811,共8页
BACKGROUND The effects of T-cell immunoglobulin mucin molecule-3(Tim-3),transforming growth factor β(TGF-β),and chemokine-12(CXCL12) expression on the prognosis of patients with diffuse large B-cell lymphoma(DLBCL) ... BACKGROUND The effects of T-cell immunoglobulin mucin molecule-3(Tim-3),transforming growth factor β(TGF-β),and chemokine-12(CXCL12) expression on the prognosis of patients with diffuse large B-cell lymphoma(DLBCL) have not been elucidated.AIM To examine the correlation between Tim-3,TGF-β and CXCL12 expression and DLBCL prognosis.METHODS Lymph node tissues of 97 patients with DLBCL and 93 normal-response hyperplastic lymph node tissues treated from January 2017 to May 2019 were selected as the DLBCL and control groups,respectively.The expression of Tim-3,TGF-β,and CXCL12 was detected immunohistochemically.Patients were followed up for 3 years,and progression-free survival was recorded.Cox mult-ifactorial analysis was performed to analyze the risk factors for poor prognosis.RESULTS The positive expression rates of Tim-3,TGF-β,and CXCL12 were higher in DLBCL tissues than in non-cancerous(control) tissues(P < 0.05).One-year postsurgery,the positive expression rates of Tim-3,TGF-β,and CXCL12 were higher in patients with effective treatment than in those with ineffective treatment(P < 0.05).The 3-year progression-free survival of 97 patients with DLBCL was 67.01%(65/97).Univariate analysis revealed that clinical stage,bone marrow infiltration,International Prognostic Index(IPI) score,Tim-3 positivity,TGF-β positivity,and CXCL12 positivity were associated with poor prognosis(P < 0.05).Multivariate Cox regression analysis demonstrated that clinical stage Ⅲ–Ⅳ,bone marrow infiltration,mediate-to-high-risk IPI scores,Tim-3 positivity,TGF-β positivity,and CXCL12 positivity were independent risk factors affecting prognosis(P < 0.05).CONCLUSION DLBCL tissues exhibit high positive expression of Tim-3,TGF-β,and CXCL12,and a high expression of all three indicates a poor prognosis. 展开更多
关键词 T-cell immunoglobulin mucin molecule-3 transforming growth factorβ Chemokine-12 Diffuse large B-cell lymphoma
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Expression of Vascular Endothelial Growth Factor-C and Vascular Endothelial Growth Factor Receptor-3 in Ovarian Epithelial Tumors 被引量:1
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作者 傅晓艳 丁明星 +2 位作者 张宁 林兴秋 李继承 《Chinese Journal of Cancer Research》 SCIE CAS CSCD 2007年第2期124-130,共7页
Objective: To explore the role of vascular endothelial growth factor-C (VEGF-C) in the process of angiogenesis, lymphangiogenesis and lymphatic metastasis in epithelial ovarian tumors. Methods: In situ hybridizati... Objective: To explore the role of vascular endothelial growth factor-C (VEGF-C) in the process of angiogenesis, lymphangiogenesis and lymphatic metastasis in epithelial ovarian tumors. Methods: In situ hybridization and immunohistochemical staining for VEGF-C were performed in 30 epithelial ovarian carcinomas, 9 borderline tumors and 26 benign tumors. Endothelial cells were immunostained with anti-VEGFR-3 pAb and anti-CD31 mAb, and VEGFR-3 positive vessels and microvessel density (MVD) were assessed by image analysis. Results: VEGF-C mRNA and protein expression were detected in cytoplasm of carcinoma cells. VEGF-C mRNA and protein expression in ovarian epithelial carcinomas were significantly higher than those in borderline tumors and benign tumors (P〈0.05 or P〈0.01). In ovarian epithelial carcinomas, VEGF-C protein expression, VEGFR-3 positive vessels and MVD were significantly higher in the cases of clinical stage Ⅲ-Ⅳ and with lymph node metastasis than those of clinical stage Ⅰ-Ⅱ and without lymph node metastasis respectively (P〈0.05 or P〈0.01). VEGFR-3 positive vessels and MVD were significantly higher in VEGF-C protein positive tumors than negative tumors (P〈0.05). VEGFR-3 positive vessels was significantly correlated with MVD(P〈0.01). Conclusion: VEGF-C might play a role in lymphatic metastasis via lymphangiogenesis and angiogenesis in epithelial ovarian tumors, and VBEGF-C could be used as a biologic marker of metastasis in ovarian epithelial tumors. 展开更多
关键词 Ovarian neoplasms Vascular endothelial growth factor-c (VEGF-C) VEGF receptor-3(VEGFR-3 CD 31 METASTASIS
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