Tumor-induced osteomalacia （TIO） is a rare paraneoplastic syndrome in which ectopic production of fibroblast growth factor 23 （FGF23） by non-malignant mesenchymal tumors causes phosphate wasting and bone fractures...Tumor-induced osteomalacia （TIO） is a rare paraneoplastic syndrome in which ectopic production of fibroblast growth factor 23 （FGF23） by non-malignant mesenchymal tumors causes phosphate wasting and bone fractures. Recent studies have implicated the hypoxia-inducible factor-la （HIF-la） in other phosphate wasting disorders caused by elevated FGF23, including X-linked hypophosphatemic rickets and autosomal dominant hypophosphatemia. Here we provide evidence that HIF-la mediates aberrant FGF23 in TIO by transcriptionally activating its promoter. Immunohistochemical studies in phosphaturic mesenchymal tumors resected from patients with documented TIO showed that HIF-la and FGF23 were co-localized in spindle- shaped cells adjacent to blood vessels. Cultured tumor tissue produced high levels of intact FGF23 and demonstrated increased expression of HIF-la protein. Transfection of MC3T3-E1 and Saos-2 cells with a HIF-la expression construct induced the activity of a FGF23 reporter construct. Prior treatment of tumor organ cultures with HIF-la inhibitors decreased HIF-la and FGF23 protein accumulation and inhibited HIF-la-induced luciferase reporter activity in transfected cells. Chromatin immunoprecipitation assays confirmed binding to a HIF-la consensus sequence within the proximal FGF23 promoter, which was eliminated by treatment with a HIF-la inhibitor. These results show for the first time that HIF-la is a direct transcriptional activator of FGF23 and suggest that upregulation of HIF-la activity in TIO contributes to the aberrant FGF23 production in these patients.展开更多
BACKGROUND The incidence and prevalence of atrial fibrillation are increasing each year,and this condition is one of the most common clinical arrhythmias.AIM To investigate the levels and significance of serum fibrobl...BACKGROUND The incidence and prevalence of atrial fibrillation are increasing each year,and this condition is one of the most common clinical arrhythmias.AIM To investigate the levels and significance of serum fibroblast growth factor 23(FGF-23)and miR-208 b in patients with atrial fibrillation and their relationship with prognosis.METHODS From May 2018 to October 2019,240 patients with atrial fibrillation were selected as an observation group,including 134 with paroxysmal atrial fibrillation and 106 with persistent atrial fibrillation;150 patients with healthy sinus rhythm were selected as a control group.The serum levels of FGF-23 and miR-208 b in the two groups were measured.In the observation group,cardiac parameters were determined by echocardiography.RESULTS The serum levels of FGF-23 and miR-208 b in the observation group were 210.20±89.60 ng/mL and 5.30±1.22 ng/mL,which were significantly higher than the corresponding values in the control group(P<0.05).In the observation group,the serum levels of FGF-23 and miR-208 b in patients with persistent atrial fibrillation were 234.22±70.05 ng/mL and 5.83±1.00 ng/mL,which were significantly higher than the corresponding values in patients with paroxysmal atrial fibrillation(P<0.05).The left atrial dimension(LAD)of patients with persistent atrial fibrillation was 38.81±5.11 mm,which was significantly higher than that of patients with paroxysmal atrial fibrillation(P>0.05).The serum levels of FGF-23and miR-208 b were positively correlated with the LAD(r=0.411 and 0.382,P<0.05).In the observation group,the serum levels of FGF-23 and miR-208 b in patients with a major cardiovascular event(MACE)were 243.30±72.29 ng/mL and 6.12±1.12 ng/mL,which were significantly higher than the corresponding values in patients without a MACE(P<0.05).CONCLUSION The serum levels of FGF-23 and miR-208 b are increased in patients with atrial fibrillation and are related to the type of disease,cardiac parameters,and prognosis.展开更多
基金supported by NIH grants AR049510 (TLC) and AR045955 (LDQ)
文摘Tumor-induced osteomalacia （TIO） is a rare paraneoplastic syndrome in which ectopic production of fibroblast growth factor 23 （FGF23） by non-malignant mesenchymal tumors causes phosphate wasting and bone fractures. Recent studies have implicated the hypoxia-inducible factor-la （HIF-la） in other phosphate wasting disorders caused by elevated FGF23, including X-linked hypophosphatemic rickets and autosomal dominant hypophosphatemia. Here we provide evidence that HIF-la mediates aberrant FGF23 in TIO by transcriptionally activating its promoter. Immunohistochemical studies in phosphaturic mesenchymal tumors resected from patients with documented TIO showed that HIF-la and FGF23 were co-localized in spindle- shaped cells adjacent to blood vessels. Cultured tumor tissue produced high levels of intact FGF23 and demonstrated increased expression of HIF-la protein. Transfection of MC3T3-E1 and Saos-2 cells with a HIF-la expression construct induced the activity of a FGF23 reporter construct. Prior treatment of tumor organ cultures with HIF-la inhibitors decreased HIF-la and FGF23 protein accumulation and inhibited HIF-la-induced luciferase reporter activity in transfected cells. Chromatin immunoprecipitation assays confirmed binding to a HIF-la consensus sequence within the proximal FGF23 promoter, which was eliminated by treatment with a HIF-la inhibitor. These results show for the first time that HIF-la is a direct transcriptional activator of FGF23 and suggest that upregulation of HIF-la activity in TIO contributes to the aberrant FGF23 production in these patients.
文摘BACKGROUND The incidence and prevalence of atrial fibrillation are increasing each year,and this condition is one of the most common clinical arrhythmias.AIM To investigate the levels and significance of serum fibroblast growth factor 23(FGF-23)and miR-208 b in patients with atrial fibrillation and their relationship with prognosis.METHODS From May 2018 to October 2019,240 patients with atrial fibrillation were selected as an observation group,including 134 with paroxysmal atrial fibrillation and 106 with persistent atrial fibrillation;150 patients with healthy sinus rhythm were selected as a control group.The serum levels of FGF-23 and miR-208 b in the two groups were measured.In the observation group,cardiac parameters were determined by echocardiography.RESULTS The serum levels of FGF-23 and miR-208 b in the observation group were 210.20±89.60 ng/mL and 5.30±1.22 ng/mL,which were significantly higher than the corresponding values in the control group(P<0.05).In the observation group,the serum levels of FGF-23 and miR-208 b in patients with persistent atrial fibrillation were 234.22±70.05 ng/mL and 5.83±1.00 ng/mL,which were significantly higher than the corresponding values in patients with paroxysmal atrial fibrillation(P<0.05).The left atrial dimension(LAD)of patients with persistent atrial fibrillation was 38.81±5.11 mm,which was significantly higher than that of patients with paroxysmal atrial fibrillation(P>0.05).The serum levels of FGF-23and miR-208 b were positively correlated with the LAD(r=0.411 and 0.382,P<0.05).In the observation group,the serum levels of FGF-23 and miR-208 b in patients with a major cardiovascular event(MACE)were 243.30±72.29 ng/mL and 6.12±1.12 ng/mL,which were significantly higher than the corresponding values in patients without a MACE(P<0.05).CONCLUSION The serum levels of FGF-23 and miR-208 b are increased in patients with atrial fibrillation and are related to the type of disease,cardiac parameters,and prognosis.
文摘目的 探讨超声造影参数联合血清成纤维细胞生长因子-23(fibroblast growth factor-23,FGF23)和成纤维细胞生长因子受体1(fibroblast growth factor receptor 1,FGFR1)在诊断乳腺癌的临床应用价值。方法 选择2020年8月~2022年6月在新疆维吾尔自治区人民医院就诊的87例乳腺癌患者作为观察对象(恶性组),选取同期90例乳腺良性病变患者作为良性组,分析两组观察对象超声造影参数,酶联免疫吸附法(enzyme-linked immunosorbent assay,ELISA)检测血清FGF23和FGFR1表达水平,Pearson法分析乳腺癌患者血清FGF23和FGFR1水平与超声造影参数的相关性,ROC曲线分析超声造影参数、血清FGF23和FGFR1对乳腺癌的诊断价值。结果 与良性组比较,恶性组的超声造影峰值强度(peak intensity,PI)(15.36±3.47 dB vs 12.54±2.83 dB)、曲线下面积(area under curve,AUC)(382.69±90.51 dB/s vs 262.95±75.34 dB/s)及血清FGF23(119.28±26.41 pg/ml vs 86.41±20.35 pg/ml),FGFR1(11.36±3.42 ng/mL vs 7.24±2.26 ng/mL)水平升高,达峰时间(time to peak,TTP)(18.46±4.31 s vs 24.23±5.25 s)降低,差异均有统计学意义(t=5.934~9.579,均P=0.000)。相关性分析显示,乳腺癌患者血清FGF23水平与PI,AUC呈正相关(r=0.493,0.561,均P=0.000),与TTP呈负相关(r=-0.572,P=0.000);血清FGFR1水平与PI,AUC呈正相关(r=0.603,0.491,均P=0.000),与TTP呈负相关(r=-0.545,P=0.000)。超声造影参数联合血清FGF23和FGFR1诊断乳腺癌的曲线下面积为0.971,联合诊断效能明显高于单独诊断,差异均有统计学意义(Z=6.478,5.558,4.839,4.780,4.943,均P <0.05)。结论 超声造影参数联合血清FGF23和FGFR1对乳腺癌具有较高诊断价值,可为乳腺癌的临床诊治提供参考。
