AIM: To investigate the contribution of the fibroblast growth factor receptor 4 (FGFR4) Gly388Arg polymorphism as a genetic risk factor for gastric cancer (GC) and to investigate any associations between this polymorp...AIM: To investigate the contribution of the fibroblast growth factor receptor 4 (FGFR4) Gly388Arg polymorphism as a genetic risk factor for gastric cancer (GC) and to investigate any associations between this polymorphism and clinicopathological parameters and survival. METHODS: Tumors and matched adjacent non-cancer tissues were collected from 304 GC patients, and 5 mL of venous blood was collected from 62 GC patients and 392 ageand sex-matched healthy controls without cancer history from the same ethnic population. DNA was extracted, and direct sequencing analyses were performed to genotype the FGFR4 Gly388Arg polymorphism in all the samples. Differences in the genotype frequencies of the FGFR4 Gly388Arg polymorphism between GC patients and healthy controls were estimated using the χ 2 test. Binary logistic regression was used for all analysis variables to estimate risk as the ORs with 95%CIs. The relationships between the FGFR4 genotype and clinicopathological parameters were tested with the χ 2 test. The Kaplan-Meier product-limit method, the log-rank test, and the Cox regression model were applied to evaluate the effect of the FGFR4 genotype on the overall survival of patients with GC. RESULTS: In the present GC cohort, 118 patients (38.8%) were homozygous for the Gly388 allele, 124 patients (40.8%) were heterozygous, and 62 patients (20.4%) were homozygous for the Arg388 allele. The frequencies of the Gly/Gly, Gly/Arg, and Arg/Arg genotypes in the healthy controls were 33.6%, 48.0%, and 18.4%, respectively. The distributions of genotypes (χ 2 = 3.589, P = 0.166) and alleles (χ 2 = 0.342, P = 0.559) of the FGFR4 Gly388Arg polymorphism were not different between the GC patients and the healthy controls. Although we observed no correlation between the FGFR4 Gly388Arg polymorphism and clinicopathological parameters or survival in the total cohort of GC patients, the presence of the Arg388 allele was associated with shorter survival time in patients with GC if the tumor was small (log rank χ 2 = 5.449, P = 0.020), well differentiated (log rank χ 2 = 12.798, P = 0.000), T1 or T2 stage (log rank χ 2 = 4.745, P = 0.029), without lymph node involvement (log rank χ 2 = 6.647, P = 0.010), and at an early clinical stage (log rank χ 2 = 4.615, P = 0.032). CONCLUSION: Our results suggest that the FGFR4 Gly388Arg polymorphism is not a risk factor for GC cancer initiation but that it is a useful prognostic marker for GC patients when the tumor is relatively small, well differentiated, or at an early clinical stage.展开更多
AIM:To investigate fibroblast growth factor receptor4(FGFR4)protein expression in Chinese patients with resectable gastric cancer(GC)and the association with clinicopathological characteristics and survival.who underw...AIM:To investigate fibroblast growth factor receptor4(FGFR4)protein expression in Chinese patients with resectable gastric cancer(GC)and the association with clinicopathological characteristics and survival.who underwent curative surgical procedures were enrolled in this study.The protein expression of FGFR4 in formalin-fixed,paraffin-embedded(FFPE)GC tissues was determined by immunohistochemical(IHC)analysis.Patient clinicopathological data and survival information were also collected andχ2 statistical analysis was performed to analyze FGFR4 protein expression in the subgroups with differing clinicopathological characteristics including;gender,age,tumor location,differentiation,tumor-node-metastasis stage,macroscopic type,depth of invasion,lymph node metastases,distant metastasis,neural invasion and vascular invasion.Furthermore,some common molecular markers of GC in our cancer center,including p53,p27,topoisomeraseⅡα(TopoⅡα)were also determined by IHC and their association with FGFR4 protein expression evaluated.The probability of survival for different subgroups with different clinicopathological characteristics was calculated using the Kaplan-Meier method and survival curves plotted using the log rank test.RESULTS:Seventy seven cases(44%)were found to have high expression of FGFR4 protein.Significantly different FGFR4 expression was observed between gastric cancers with differing expression of TopoⅡα(log rankχ2=9.4760,P=0.0236).No significant differences were observed between subgroups defined by any of the other clinicopathological characteristics.The median survival time of the FGFR4 high expression(77 cases)and low expression groups(98 cases)was27 mo and 39 mo,respectively.The five-year survival rates and median survival times of gastric cancers with high FGFR4 expression were worse than those with low expression(30.8%vs 39.2%,27 mo vs 39 mo),respectively,however,no significant difference was observed in survival time(log rankχ2=1.0477,P=0.3060).Survival analysis revealed that high expression of FGFR4 was a predictor of poor outcome in GC patients if the tumor was small(less than or equal to 3cm in size)(log rankχ2=5.5033,P=0.0190),well dif-ferentiated(log rankχ2=7.9757,P=0.0047),and of T1 or T2 stage invasion depth(log rankχ2=4.8827,P=0.0271).CONCLUSION:Our results suggest that high tumor expression of FGFR4 protein is not an independent risk factor for GC cancer initiation,but is a useful prognostic marker for GC patients when the tumor is relatively small,well differentiated,or in the early stages of invasion.展开更多
The expression of basic fibroblast growth factor (bFGF) and fibroblast growth factor receptor-1 (FGFR-1) in human meningiomas and the relationships between their expression and the tumors' histological features an...The expression of basic fibroblast growth factor (bFGF) and fibroblast growth factor receptor-1 (FGFR-1) in human meningiomas and the relationships between their expression and the tumors' histological features and angiogenesis were investigated by means of immunohistochemical technique. The expression of bFGF and FGFR-1 was detected by antibody of bFGF or FGFR-1. The tumors' angiogenesis was evaluated by microvascular density (MVD) and, which was observed by use of CD34-antibody immunohistochemically. The results showed that there were varied degrees of the expression of bFGF and FGFR-1 proteins in meningiomas. The expression was correlated with the tumors' histological characters and angiogenesis. It was concluded that bFGF and FGFR-1 might play important roles in meningiomas' angiogenesis and proliferation. The expression positive rate of bFGF and FGFR-1 may provide an indication of evaluating the histological and malignant degree of the tumor.展开更多
Fibroblast growth factors(FGFs)play pivotal roles in cell migration and proliferation.However,the identity of the FGF that plays a dominant role in kidney cell proliferation remains unclear.Therefore,in this study,we ...Fibroblast growth factors(FGFs)play pivotal roles in cell migration and proliferation.However,the identity of the FGF that plays a dominant role in kidney cell proliferation remains unclear.Therefore,in this study,we investigated the dominant FGF among all FGFs.To this end,RNA-sequencing,qRT-PCR,western blotting,and ChIP assays were performed.FGF9 showed the highest expression among all FGFs,and its overexpression significantly promoted proliferation in the mouse kidney cell line C57BL/6 and increased JNK and AKT phosphorylation levels.Further,RNA-seq analysis identified 365 upregulated and 276 downregulated genes in FGF9-overexpressed cells.These differentially expressed genes were classified primarily into 20 biological pathways and were enriched in 31 gene ontology terms.qRT-PCR revealed that the expression of WNT and NF-κB signaling genes,as well as ANXA4 expression patterns,correlated with the RNA-seq data,while FGF9-overexpressed cells accumulated moreβ-catenin,a key WNT signaling protein,compared to control cells.Moreover,downregulation of the gene that encodesβ-catenin or ANXA4 inhibited C57BL/6 cell proliferation.Additionally,the expression of ANXA4 was lower in CTNNB1-knockdown cells than in the control group.Additionally,the ChIP assay revealed that a transcription factor complex containing TCF4 andβ-catenin directly binds to the ANXA4 promoter.Taken together,these results suggest a role of FGF9 in the regulation of kidney cell migration.These findings may prove useful in the development of future therapies.展开更多
There is evidence that the expression of members of the fibroblast growth factor （FGF） protein family is altered in post-mortem brains of humans suffering from major depressive disorder. The present study examined w...There is evidence that the expression of members of the fibroblast growth factor （FGF） protein family is altered in post-mortem brains of humans suffering from major depressive disorder. The present study examined whether the expression of fibroblast growth factor-2 （FGF2） and fibroblast growth factor receptor-1 （FGFR1） protein is altered following chronic stress in an animal model. Rats were exposed to 35 days of chronic unpredictable mild stress, and then tested using open-field and sucrose consumption tests. Compared with the control group, rats in the chronic stress group exhibited obvious depressive-like behaviors, including anhedonia, anxiety and decreased mobility. The results of western blot analysis and immunohistochemical analysis revealed a downregulation of the expression of FGF2 and FGFR1 in the hippocampus of rats, particularly in the CA1, CA3 and dentate gyrus. This decreased expression is in accord with the results of post-mortem studies in humans with major depressive disorder. These findings suggest that FGF2 and FGFR1 proteins participate in the pathophysiology of depressive-like behavior, and may play an important role in the mechanism of chronic stress-induced depression.展开更多
BACKGROUND Head and neck squamous cell carcinoma(HNSCC) is considered to be a progressive disease resulting from alterations in multiple genes regulating cell proliferation and differentiation like receptor tyrosine k...BACKGROUND Head and neck squamous cell carcinoma(HNSCC) is considered to be a progressive disease resulting from alterations in multiple genes regulating cell proliferation and differentiation like receptor tyrosine kinases(RTKs) and members of the fibroblast growth factor receptors(FGFR)-family. Singlenucleotide polymorphism(SNP) Arg388 of the FGFR4 is associated with a reduced overall survival in patients with cancers of various types. We speculate that FGFR4 expression and SNP is associated with worse survival in patients with HSNCC.AIM To investigate the potential clinical significance of FGFR4 Arg388 in the context of tumors arising in HNSCC, a comprehensive analysis of FGFR4 receptor expression and genotype in tumor tissues and correlated results with patients' clinical data in a large cohort of patients with HNSCC was conducted.METHODS Surgical specimens from 284 patients with HNSCC were retrieved from the Institute of Pathology at the Ludwig-Maximilian-University in Germany.Specimens were analyzed using immunohistochemistry and polymerase chain reaction-restriction fragment length polymorphism(PCR-RFLP). The expression of FGFR4 was analyzed in 284 surgical specimens of HNSCC using immunohistochemstry. FGFR4 polymorphism was detected by PCR-RFLP.Patients' clinical data with a minimum follow-up of 5 years were statistically evaluated with a special emphasis on survival analysis employing Kaplan-Meier estimator and Cox regression analysis.RESULTS Concerning the invasive tumor areas the intensity of the FGFR4 expression was evaluated in a four-grade system: no expression, low expression, intermediate and high expression. FGFR4 expression was scored as "high"(+++) in 74(26%),"intermediate"(++) in 103(36.3%), and "low"(+) in 107(36.7%) cases. Analyzing the FGFR4 mutation it was found in 96 tumors(33.8%), 84 of them(29.6%) having a heterozygous and 12(4.2%) homozygous mutated Arg388 allele. The overall frequency concerning the mutant alleles demonstrated 65% vs 34% mutated alleles in general. FGFR4 Arg388 was significantly associated with advanced tumor stage(P < 0.004), local metastasis(P < 0.0001) and reduced disease-free survival(P < 0.01). Furthermore, increased expression of FGFR4 correlated significantly with worse overall survival(P < 0.003).CONCLUSION In conclusion, the FGFR4 Arg388 genotype and protein expression of FGFR4 impacts tumor progression in patients with HNSCC and may present a useful target within a multimodal therapeutic intervention.展开更多
The present study explored the distribution and localization of fibroblast growth factor-8 and its potential receptor, fibroblast growth factor receptor-3, in adult rat brain in vivo and in nerve cells during differen...The present study explored the distribution and localization of fibroblast growth factor-8 and its potential receptor, fibroblast growth factor receptor-3, in adult rat brain in vivo and in nerve cells during differentiation of neural stem/progenitor cells in vitro. Immunohistochemistry was used to examine the distribution of fibroblast growth factor-8 in adult rat brain in vivo. Localization of fibroblast growth factor-8 and fibroblast growth factor receptor-3 in cells during neural stem/progenitor cell differentiation in vitro was detected by immunofluorescence. Flow cytometry and immunofluorescence were used to evaluate the effect of an anti-fibroblast growth factor-8 antibody on neural stem/progenitor cell differentiation and expansion in vitro. Results from this study confirmed that fibroblast growth factor-8 was mainly distributed in adult midbrain, namely the substantia nigra, compact part, dorsal tier, substantia nigra and reticular part, but was not detected in the forebrain comprising the caudate putamen and striatum. Unusual results were obtained in retrosplenial locations of adult rat brain. We found that fibroblast growth factor-8 and fibroblast growth factor receptor-3 were distributed on the cell membrane and in the cytoplasm of nerve cells using immunohistochemistry and immunofluorescence analyses. We considered that the distribution of fibroblast growth factor-8 and fibroblast growth factor receptor-3 in neural cells corresponded to the characteristics of fibroblast growth factor-8, a secretory factor. Addition of an anti-fibroblast growth factor-8 antibody to cultures significantly affected the rate of expansion and differentiation of neural stem/progenitor cells. In contrast, addition of recombinant fibroblast growth factor-8 to differentiation medium promoted neural stem/progenitor cell differentiation and increased the final yields of dopaminergic neurons and total neurons. Our study may help delineate the important roles of fibroblast growth factor-8 in brain activities and neural stem/progenitor cell differentiation.展开更多
Genome-wide studies have reported that Parkinson’s disease is associated with abnormal expression of various growth factors. In this study, male C57 BL/6 mice aged 10 weeks were used to establish Parkinson’s disease...Genome-wide studies have reported that Parkinson’s disease is associated with abnormal expression of various growth factors. In this study, male C57 BL/6 mice aged 10 weeks were used to establish Parkinson’s disease models using an intraperitoneal injection of 60 mg/kg 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. 28 days later, 10 or 100 ng fibroblast growth factor 20 was injected intracerebroventricularly. The electrophysiological changes in the mouse hippocampus were recorded using a full-cell patch clamp. Expression of Kv4.2 in the substantia nigra was analyzed using a western blot assay. Serum malondialdehyde levels were analyzed by enzyme-linked immunosorbent assay. The motor coordination of mice was evaluated using the rotarod test. The results showed that fibroblast growth factor 20 decreased A-type potassium current in neurons of the substantia nigra, increased long-term potentiation amplitude in the hippocampus, and downregulated Kv4.2 expression. A high dose of fibroblast growth factor 20 reduced serum malondialdehyde levels and enhanced the motor coordination of mice. These findings confirm that fibroblast growth factor 20 has a therapeutic effect on the toxicity induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, and its mechanism of action is associated with the inhibition of A-type K+ currents and Kv4.2 expression. All animal procedures were approved by the Animal Care and Use Committee of Qilu Hospital of Shandong University, China in 2017(approval No. KYLL-2017-0012).展开更多
Bcl6,a critical pro-oncogene of human B-cell lymphomas,can promote tumor progress.Previous studies have found that Bcl6 participates in hypoxia injury in cardiomyocytes.However,the effect of Bcl6 on cardiac fibroblast...Bcl6,a critical pro-oncogene of human B-cell lymphomas,can promote tumor progress.Previous studies have found that Bcl6 participates in hypoxia injury in cardiomyocytes.However,the effect of Bcl6 on cardiac fibroblasts is still unclear.The aim of this study was to elucidate the functional role of Bcl6 in cardiac fibroblast activation and function.The neonatal rat cardiac fibroblasts were isolated and cultured.First,transforming growth factor β1 (TGFβ1) was used to stimulate fibroblast activation.A decreased expression level of Bcl6 was observed in fibroblasts after stimulation with TGFβ1.Then,cells were transfected with adenovirus Bcl6 to overexpress Bcl6.The results showed that Bcl6 overexpression induced decreased proliferation and reduced activation of fibroblasts which were stimulated with TGFβ1.It was found that activated smad2 and smad3 were not changed by overexpressing Bcl6,but smad4 was decreased.Furthermore,co-immunoprecipitation results showed that Bcl6 directly bound to smad4,and induced down-regulation of smad4.At last,smad4 activator could counteract the anti-fibroblast effects of Bcl6.In conclusion,Bcl6 may negatively regulate cardiac fibroblast activation and function by directly binding to smad4.展开更多
文摘AIM: To investigate the contribution of the fibroblast growth factor receptor 4 (FGFR4) Gly388Arg polymorphism as a genetic risk factor for gastric cancer (GC) and to investigate any associations between this polymorphism and clinicopathological parameters and survival. METHODS: Tumors and matched adjacent non-cancer tissues were collected from 304 GC patients, and 5 mL of venous blood was collected from 62 GC patients and 392 ageand sex-matched healthy controls without cancer history from the same ethnic population. DNA was extracted, and direct sequencing analyses were performed to genotype the FGFR4 Gly388Arg polymorphism in all the samples. Differences in the genotype frequencies of the FGFR4 Gly388Arg polymorphism between GC patients and healthy controls were estimated using the χ 2 test. Binary logistic regression was used for all analysis variables to estimate risk as the ORs with 95%CIs. The relationships between the FGFR4 genotype and clinicopathological parameters were tested with the χ 2 test. The Kaplan-Meier product-limit method, the log-rank test, and the Cox regression model were applied to evaluate the effect of the FGFR4 genotype on the overall survival of patients with GC. RESULTS: In the present GC cohort, 118 patients (38.8%) were homozygous for the Gly388 allele, 124 patients (40.8%) were heterozygous, and 62 patients (20.4%) were homozygous for the Arg388 allele. The frequencies of the Gly/Gly, Gly/Arg, and Arg/Arg genotypes in the healthy controls were 33.6%, 48.0%, and 18.4%, respectively. The distributions of genotypes (χ 2 = 3.589, P = 0.166) and alleles (χ 2 = 0.342, P = 0.559) of the FGFR4 Gly388Arg polymorphism were not different between the GC patients and the healthy controls. Although we observed no correlation between the FGFR4 Gly388Arg polymorphism and clinicopathological parameters or survival in the total cohort of GC patients, the presence of the Arg388 allele was associated with shorter survival time in patients with GC if the tumor was small (log rank χ 2 = 5.449, P = 0.020), well differentiated (log rank χ 2 = 12.798, P = 0.000), T1 or T2 stage (log rank χ 2 = 4.745, P = 0.029), without lymph node involvement (log rank χ 2 = 6.647, P = 0.010), and at an early clinical stage (log rank χ 2 = 4.615, P = 0.032). CONCLUSION: Our results suggest that the FGFR4 Gly388Arg polymorphism is not a risk factor for GC cancer initiation but that it is a useful prognostic marker for GC patients when the tumor is relatively small, well differentiated, or at an early clinical stage.
文摘AIM:To investigate fibroblast growth factor receptor4(FGFR4)protein expression in Chinese patients with resectable gastric cancer(GC)and the association with clinicopathological characteristics and survival.who underwent curative surgical procedures were enrolled in this study.The protein expression of FGFR4 in formalin-fixed,paraffin-embedded(FFPE)GC tissues was determined by immunohistochemical(IHC)analysis.Patient clinicopathological data and survival information were also collected andχ2 statistical analysis was performed to analyze FGFR4 protein expression in the subgroups with differing clinicopathological characteristics including;gender,age,tumor location,differentiation,tumor-node-metastasis stage,macroscopic type,depth of invasion,lymph node metastases,distant metastasis,neural invasion and vascular invasion.Furthermore,some common molecular markers of GC in our cancer center,including p53,p27,topoisomeraseⅡα(TopoⅡα)were also determined by IHC and their association with FGFR4 protein expression evaluated.The probability of survival for different subgroups with different clinicopathological characteristics was calculated using the Kaplan-Meier method and survival curves plotted using the log rank test.RESULTS:Seventy seven cases(44%)were found to have high expression of FGFR4 protein.Significantly different FGFR4 expression was observed between gastric cancers with differing expression of TopoⅡα(log rankχ2=9.4760,P=0.0236).No significant differences were observed between subgroups defined by any of the other clinicopathological characteristics.The median survival time of the FGFR4 high expression(77 cases)and low expression groups(98 cases)was27 mo and 39 mo,respectively.The five-year survival rates and median survival times of gastric cancers with high FGFR4 expression were worse than those with low expression(30.8%vs 39.2%,27 mo vs 39 mo),respectively,however,no significant difference was observed in survival time(log rankχ2=1.0477,P=0.3060).Survival analysis revealed that high expression of FGFR4 was a predictor of poor outcome in GC patients if the tumor was small(less than or equal to 3cm in size)(log rankχ2=5.5033,P=0.0190),well dif-ferentiated(log rankχ2=7.9757,P=0.0047),and of T1 or T2 stage invasion depth(log rankχ2=4.8827,P=0.0271).CONCLUSION:Our results suggest that high tumor expression of FGFR4 protein is not an independent risk factor for GC cancer initiation,but is a useful prognostic marker for GC patients when the tumor is relatively small,well differentiated,or in the early stages of invasion.
文摘The expression of basic fibroblast growth factor (bFGF) and fibroblast growth factor receptor-1 (FGFR-1) in human meningiomas and the relationships between their expression and the tumors' histological features and angiogenesis were investigated by means of immunohistochemical technique. The expression of bFGF and FGFR-1 was detected by antibody of bFGF or FGFR-1. The tumors' angiogenesis was evaluated by microvascular density (MVD) and, which was observed by use of CD34-antibody immunohistochemically. The results showed that there were varied degrees of the expression of bFGF and FGFR-1 proteins in meningiomas. The expression was correlated with the tumors' histological characters and angiogenesis. It was concluded that bFGF and FGFR-1 might play important roles in meningiomas' angiogenesis and proliferation. The expression positive rate of bFGF and FGFR-1 may provide an indication of evaluating the histological and malignant degree of the tumor.
基金funded by Wuhu Institute of Technology Talent Project[wzyrc201801]the Natural Science Foundation of Anhui Province[KJ2018A0691]+1 种基金the Project of Cultivating Outstanding Talents in Colleges[gxgwfx2019072]Science and Technology Development Plan Project of TCM.
文摘Fibroblast growth factors(FGFs)play pivotal roles in cell migration and proliferation.However,the identity of the FGF that plays a dominant role in kidney cell proliferation remains unclear.Therefore,in this study,we investigated the dominant FGF among all FGFs.To this end,RNA-sequencing,qRT-PCR,western blotting,and ChIP assays were performed.FGF9 showed the highest expression among all FGFs,and its overexpression significantly promoted proliferation in the mouse kidney cell line C57BL/6 and increased JNK and AKT phosphorylation levels.Further,RNA-seq analysis identified 365 upregulated and 276 downregulated genes in FGF9-overexpressed cells.These differentially expressed genes were classified primarily into 20 biological pathways and were enriched in 31 gene ontology terms.qRT-PCR revealed that the expression of WNT and NF-κB signaling genes,as well as ANXA4 expression patterns,correlated with the RNA-seq data,while FGF9-overexpressed cells accumulated moreβ-catenin,a key WNT signaling protein,compared to control cells.Moreover,downregulation of the gene that encodesβ-catenin or ANXA4 inhibited C57BL/6 cell proliferation.Additionally,the expression of ANXA4 was lower in CTNNB1-knockdown cells than in the control group.Additionally,the ChIP assay revealed that a transcription factor complex containing TCF4 andβ-catenin directly binds to the ANXA4 promoter.Taken together,these results suggest a role of FGF9 in the regulation of kidney cell migration.These findings may prove useful in the development of future therapies.
文摘There is evidence that the expression of members of the fibroblast growth factor （FGF） protein family is altered in post-mortem brains of humans suffering from major depressive disorder. The present study examined whether the expression of fibroblast growth factor-2 （FGF2） and fibroblast growth factor receptor-1 （FGFR1） protein is altered following chronic stress in an animal model. Rats were exposed to 35 days of chronic unpredictable mild stress, and then tested using open-field and sucrose consumption tests. Compared with the control group, rats in the chronic stress group exhibited obvious depressive-like behaviors, including anhedonia, anxiety and decreased mobility. The results of western blot analysis and immunohistochemical analysis revealed a downregulation of the expression of FGF2 and FGFR1 in the hippocampus of rats, particularly in the CA1, CA3 and dentate gyrus. This decreased expression is in accord with the results of post-mortem studies in humans with major depressive disorder. These findings suggest that FGF2 and FGFR1 proteins participate in the pathophysiology of depressive-like behavior, and may play an important role in the mechanism of chronic stress-induced depression.
文摘BACKGROUND Head and neck squamous cell carcinoma(HNSCC) is considered to be a progressive disease resulting from alterations in multiple genes regulating cell proliferation and differentiation like receptor tyrosine kinases(RTKs) and members of the fibroblast growth factor receptors(FGFR)-family. Singlenucleotide polymorphism(SNP) Arg388 of the FGFR4 is associated with a reduced overall survival in patients with cancers of various types. We speculate that FGFR4 expression and SNP is associated with worse survival in patients with HSNCC.AIM To investigate the potential clinical significance of FGFR4 Arg388 in the context of tumors arising in HNSCC, a comprehensive analysis of FGFR4 receptor expression and genotype in tumor tissues and correlated results with patients' clinical data in a large cohort of patients with HNSCC was conducted.METHODS Surgical specimens from 284 patients with HNSCC were retrieved from the Institute of Pathology at the Ludwig-Maximilian-University in Germany.Specimens were analyzed using immunohistochemistry and polymerase chain reaction-restriction fragment length polymorphism(PCR-RFLP). The expression of FGFR4 was analyzed in 284 surgical specimens of HNSCC using immunohistochemstry. FGFR4 polymorphism was detected by PCR-RFLP.Patients' clinical data with a minimum follow-up of 5 years were statistically evaluated with a special emphasis on survival analysis employing Kaplan-Meier estimator and Cox regression analysis.RESULTS Concerning the invasive tumor areas the intensity of the FGFR4 expression was evaluated in a four-grade system: no expression, low expression, intermediate and high expression. FGFR4 expression was scored as "high"(+++) in 74(26%),"intermediate"(++) in 103(36.3%), and "low"(+) in 107(36.7%) cases. Analyzing the FGFR4 mutation it was found in 96 tumors(33.8%), 84 of them(29.6%) having a heterozygous and 12(4.2%) homozygous mutated Arg388 allele. The overall frequency concerning the mutant alleles demonstrated 65% vs 34% mutated alleles in general. FGFR4 Arg388 was significantly associated with advanced tumor stage(P < 0.004), local metastasis(P < 0.0001) and reduced disease-free survival(P < 0.01). Furthermore, increased expression of FGFR4 correlated significantly with worse overall survival(P < 0.003).CONCLUSION In conclusion, the FGFR4 Arg388 genotype and protein expression of FGFR4 impacts tumor progression in patients with HNSCC and may present a useful target within a multimodal therapeutic intervention.
基金supported by the National Natural Science Foundation of China,No.81070614the Key Project of the Natural Science Foundation of Hubei Province of China,No. 2008CDA044the Natural Science Foundation of Hubei University of Medicine,No.2011QDZR-2
文摘The present study explored the distribution and localization of fibroblast growth factor-8 and its potential receptor, fibroblast growth factor receptor-3, in adult rat brain in vivo and in nerve cells during differentiation of neural stem/progenitor cells in vitro. Immunohistochemistry was used to examine the distribution of fibroblast growth factor-8 in adult rat brain in vivo. Localization of fibroblast growth factor-8 and fibroblast growth factor receptor-3 in cells during neural stem/progenitor cell differentiation in vitro was detected by immunofluorescence. Flow cytometry and immunofluorescence were used to evaluate the effect of an anti-fibroblast growth factor-8 antibody on neural stem/progenitor cell differentiation and expansion in vitro. Results from this study confirmed that fibroblast growth factor-8 was mainly distributed in adult midbrain, namely the substantia nigra, compact part, dorsal tier, substantia nigra and reticular part, but was not detected in the forebrain comprising the caudate putamen and striatum. Unusual results were obtained in retrosplenial locations of adult rat brain. We found that fibroblast growth factor-8 and fibroblast growth factor receptor-3 were distributed on the cell membrane and in the cytoplasm of nerve cells using immunohistochemistry and immunofluorescence analyses. We considered that the distribution of fibroblast growth factor-8 and fibroblast growth factor receptor-3 in neural cells corresponded to the characteristics of fibroblast growth factor-8, a secretory factor. Addition of an anti-fibroblast growth factor-8 antibody to cultures significantly affected the rate of expansion and differentiation of neural stem/progenitor cells. In contrast, addition of recombinant fibroblast growth factor-8 to differentiation medium promoted neural stem/progenitor cell differentiation and increased the final yields of dopaminergic neurons and total neurons. Our study may help delineate the important roles of fibroblast growth factor-8 in brain activities and neural stem/progenitor cell differentiation.
文摘Genome-wide studies have reported that Parkinson’s disease is associated with abnormal expression of various growth factors. In this study, male C57 BL/6 mice aged 10 weeks were used to establish Parkinson’s disease models using an intraperitoneal injection of 60 mg/kg 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. 28 days later, 10 or 100 ng fibroblast growth factor 20 was injected intracerebroventricularly. The electrophysiological changes in the mouse hippocampus were recorded using a full-cell patch clamp. Expression of Kv4.2 in the substantia nigra was analyzed using a western blot assay. Serum malondialdehyde levels were analyzed by enzyme-linked immunosorbent assay. The motor coordination of mice was evaluated using the rotarod test. The results showed that fibroblast growth factor 20 decreased A-type potassium current in neurons of the substantia nigra, increased long-term potentiation amplitude in the hippocampus, and downregulated Kv4.2 expression. A high dose of fibroblast growth factor 20 reduced serum malondialdehyde levels and enhanced the motor coordination of mice. These findings confirm that fibroblast growth factor 20 has a therapeutic effect on the toxicity induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, and its mechanism of action is associated with the inhibition of A-type K+ currents and Kv4.2 expression. All animal procedures were approved by the Animal Care and Use Committee of Qilu Hospital of Shandong University, China in 2017(approval No. KYLL-2017-0012).
文摘Bcl6,a critical pro-oncogene of human B-cell lymphomas,can promote tumor progress.Previous studies have found that Bcl6 participates in hypoxia injury in cardiomyocytes.However,the effect of Bcl6 on cardiac fibroblasts is still unclear.The aim of this study was to elucidate the functional role of Bcl6 in cardiac fibroblast activation and function.The neonatal rat cardiac fibroblasts were isolated and cultured.First,transforming growth factor β1 (TGFβ1) was used to stimulate fibroblast activation.A decreased expression level of Bcl6 was observed in fibroblasts after stimulation with TGFβ1.Then,cells were transfected with adenovirus Bcl6 to overexpress Bcl6.The results showed that Bcl6 overexpression induced decreased proliferation and reduced activation of fibroblasts which were stimulated with TGFβ1.It was found that activated smad2 and smad3 were not changed by overexpressing Bcl6,but smad4 was decreased.Furthermore,co-immunoprecipitation results showed that Bcl6 directly bound to smad4,and induced down-regulation of smad4.At last,smad4 activator could counteract the anti-fibroblast effects of Bcl6.In conclusion,Bcl6 may negatively regulate cardiac fibroblast activation and function by directly binding to smad4.
