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Objective:To explore the effects of microRNA 562 (miR-562) regulating fibroblast growth factor receptor 1 (FGFR1) on the migration and invasion of colorectal cancer cells.Methods:From October 2019 to October 2020, 25 colorectal cancer patients undergoing surgical resection in our hospital were selected to obtain their colorectal cancer tissue and normal adjacent tissue samples at the tumor edge>5 cm; Real-time fluorescent quantitative PCR (qRT-PCR) method was used to detect the expression of miR-562 in adjacent tissues, colon cancer tissues, human normal colorectal cells (FHC cells) and human colorectal cancer cell lines (SW480, SW620, HT29 and HCT116 cells) ; SW480 cells were divided into control group, miR-NC group, miR-562 mimics group, miR-562 mimics+pcDNA3.1 group, and miR-562 mimics+pcDNA3.1-FGFR1 group; The proliferation of SW480 cells was detected by CCK-8 method; Transwell method was used to detect the invasion and migration of SW480 cells; Double luciferase reporter gene was used to detect the targeting relationship between miR-562 and FGFR1; Western blot was used to detect the expression of FGFR1, Cyclin D1 (CyclinD1) and matrix metalloproteinase 2 (MMP2) in SW480 cells.Results:Compared with adjacent tissues, the expression of miR-562 in colon cancer tissues was significantly reduced [ (0.59±0.08) vs (1.01±0.10) ] ( P<0.05) ; compared with FHC cells (1.00±0.08) , the expression level of miR-562 in SW480, SW620, HT29 and HCT116 cells was significantly reduced (0.48±0.06, 0.76±0.14, 0.70±0.11, 0.56±0.10) ( P<0.05) , and its expression level was the lowest in SW480 cells; compared with the control group, the expression level of miR-562 and proliferation inhibition rate in the miR-562 mimics group were significantly increased, the expression levels of FGFR1, CyclinD1, the numbers of migration and invasion cells, and the expression level of MMP2 were significantly reduced ( P<0.05) . FGFR1 was a potential target gene of miR-562. High expression of FGFR1 could reverse the inhibitory effect of miR-562 overexpression on migration and invasion of SW480 cells. Conclusion:The overexpression of miR-562 may inhibit the migration and invasion of SW480 cells by inhibiting the expression of FGFR1.
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The background of this study is FGFR1 belongs to a family of four, high-affinity receptor tyrosine kinase and is a legitimate oncogene associated with uterine, cervical, prostate, bladder, colorectal and lung cancers. It is rarely concomitant in myeloid and lymphoid neoplasms but has an aggressive clinical course with a high mortality rate when present. Cytogenetic abnormalities involving the FGFR1 gene is most frequently observed in AML, MPN with eosinophilia, T-ALL and T-LBL with ZMYM2 gene being the most common fusion partner. Methods of this study was to authors report a series of 4 cases with FGFR1 rearrangements. Results is three patients presented as T-cell Lymphoblastic lymphoma (T-LBL) and one as mixed phenotype acute leukemia (MPAL). The T-LBL cases harboured the FGFR1/ ZMYM2 fusion and the MPAL case harbored the CNTRL/FGFR1 fusion as identified by conventional cytogenetics and confirmed by molecular studies. Conclusion is authors herewith describe the clinical, biochemical, molecular and cytogenetic features observed in these cases.
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Objective@#To investigate the role of fibroblast growth factor receptor(FGFR) 1 in endothelial to-mesenchymal transition(EndMT) and epithelial-to-mesenchymal transition(EMT), and to find out a new strategy to study the vascular endothelial function of diabetic renal fibrosis.@*Methods@#Culture media from FRS2 knockdown HMVECs was transferred to HK-2 cells. Western blot and immunofluorescence staining were used to measure EMT markers and key moleculars of transforming growth factor(TGFβ).@*Results@#It was found that the medium from FRS2 siRNA-transfected HMVECs reduced E-cadherin protein levels, increased EMT markers levels, and activated TGFβ signal pathway in HK-2 cells.@*Conclusion@#Endothelial FGFR1 deficiency-induced EndMT leads to EMT in neighboring cells in a manner dependent on TGFβ1 signaling. Endothelial cell FGFR1 is an important molecule for maintaining endothelial homeostasis and epithelial homeostasis, and seems to be a key target for anti-diabetic renal fibrosis.
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Objective@#To investigate the clinic-pathological features, diagnosis and treatment of 8p11 myeloproliferative syndrome (EMS) .@*Methods@#Five patients diagnosed as EMS from Jan 2014 to May 2018 at Blood Disease Hospital, Chinese Academy of Medical Sciences were enrolled. The clinical manifestations, laboratory characteristics, treatment and outcome of these patients were summarized.@*Results@#The peripheral blood leukocyte count of 5 patients with EMS increased significantly, accompanied with an elevated absolute eosinophils value (the average as 18.89×109/L) . The hypercellularity of myeloid cells was common in bone marrow, always with the elevated proportion of eosinophils (the average as 17.24%) , but less than 5% of blast cells. The chromosome karyotype of the 5 cases differed from each other, but presenting with the same rearrangement of FGFR1 gene by fluorescence in situ hybridization technology. The average interval between onset and diagnosis was 4.8 months with a median survival of only 14 months.@*Conclusion@#EMS was a rare hematologic malignancy with poor prognosis and short survival. It was commonly to be misdiagnosed. Analysis of cytogenetics and molecular biology were helpful for early diagnosis.
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BACKGROUND@#The methods of detection for recurrence and metastasis in patients with non-small cell lung cancer (NSCLC) have hysteresis and one-sidedness. This study summarizes the relationship between the circulating tumor cell (CTC) in peripheral blood, expression of fibroblast growth factor receptor 1 (FGFR1) and clinic pathological features in 30 patients with NSCLC so as to provide new ideas for the detection of tumor recurrence and metastasis.@*METHODS@#To analyze the clinical data and CTC detection data of 30 cases of NSCLC in Department of Thoracic Surgery, Peking Union Medical College Hospital from November 2016 to June 2017.@*RESULTS@#Data analysis showed that the positive rate of CTC in peripheral blood was remarkably correlated with the smoking history (P=0.016). There was no significant correlation among the pathological type and CTC positive rate and the expression of FGFR1 (P=0.202, P=0.806). There was no significant difference in the expression of FGFR1 in different type CTC cells (P=0.094).@*CONCLUSIONS@#The positive rate of CTC was significantly correlated with the smoking history of patients with NSCLC. There was no significant difference in CTC classification and FGFR1 expression in different pathological types of NSCLC. There was no significant difference in the expression of FGFR1 between different types of CTCs. We look forward to a larger sample size and inclusion of follow-up data to arrive at more clinically relevant conclusions about CTC and FGFR1 gene expression.
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Adult , Female , Humans , Male , Middle Aged , Young Adult , Carcinoma, Non-Small-Cell Lung , Genetics , Metabolism , Lung Neoplasms , Genetics , Metabolism , Neoplastic Cells, Circulating , Metabolism , Receptor, Fibroblast Growth Factor, Type 1 , Genetics , MetabolismABSTRACT
Objective: To investigate the role and mechanism of S100 calcium binding protein B (S100B) in osteoarthritis (OA) cartilage damage repair. Methods: Twenty New Zealand rabbits were randomly divided into control group and model group, with 10 rabbits in each group. Rabbits in the model group were injured by the right knee joint immobilization method to make the artilage injury model, while the control group did not deal with any injury. After 4 weeks, the levels of interleukin-1β (IL-1β) and tumor necrosis factor α (TNF-α) in synovial fluid were detected by ELISA method; the mRNA and protein expressions of S100B, fibroblast growth factor 2 (FGF-2), and FGF receptor 1 (FGFR1) in cartilage tissue were examined by real-time fluorescence quantitative PCR (qRT-PCR) and Western blot assay. Human synovial fibroblasts (SF) were isolated and cultured in vitro. The effects of S100B overexpression and knockdown on the levels of IL-1β and TNF-α (ELISA method) and the expressions of FGF-2 and FGFR1 gene (qRT-PCR) and protein (Western blot) were observed. Moreover, the effects of FGFR1 knockdown in above S100 overexpression system on the levels of IL-1β and TNF-α (ELISA method) and the expressions of FGF-2 and FGFR1 gene (qRT-PCR) and protein (Western blot) were observed. Results: ELISA detection showed that the expressions of IL-1β and TNF-α in the synovial fluid of the model group were significantly higher than those of the control group ( P<0.05); qRT-PCR and Western blot detection showed that the mRNA and protein expressions of S100B, FGF-2, and FGFR1 in cartilage tissue were significantly higher than those of the control group ( P<0.05). Overexpression and knockdown S100 could respectively significantly increase and decrease lipopolysaccharides (LPS) induced IL-1β and TNF-α levels elevation and the mRNA and protein expressions of FGF-2 and FGFR1 ( P<0.05); whereas FGFR1 knockdown could significantly decrease LPS induced IL-1β and TNF-α levels elevation and the mRNA and protein expressions of FGF-2 and FGFR1 ( P<0.05). Conclusion: S100B protein can regulate the inflammatory response of SF and may affect the repair of cartilage damage in OA, and the mechanism may be related to the activation of FGF-2/FGFR1 signaling pathway.
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Objective To investigate the mineralization impact of fibroblast growth factor receptors 1 dominant negative (FGFR1DN) on osteogenic induction culture of bone marrow stromal cells (BMSCs).Methods The 3rd generation BMSCs were divided into 4 equal groups (n =24).FGFR1-DN group was transfected by pcDNA3.1 (+)-FGFR1DN,FGFRI group by pcDNA3.1 (+)-FRFR1,blank load group by pcDNA3.1 (+)-blank vehicle and non-transtection group by nothing.After successful transfection was confirmed when the cells were in the logarithmic phase,osteogenic induction culture was conducted continuously for 21 days.Mineralized nodule formation was observed by alizarin red staining.The amount of mineralized material was calculated according to the standard curve of alizarin red concentration.Results Continuous osteogenic induction for 21 days showed on the bottom of the hole visible round opaque calcified nodules after alizarin red staining.The BMSCs in the FGFR1-DN group induced in the logarithmic growth phase by osteoblasts exhibited significantly increased osteogenic capacity while those in the FGFR1 group displayed diminished osteogenic capacity.The concentration of alizarin red was the highest in the FGFRI-DN group (1.33 ±0.19),the lowest in the FGFRI group (1.00 ± 1.17),and moderate in the blank load group (1.20 ± 0.16) and non-transfection group (1.17 ± 0.17),showing significant between-group differences (P ＜ O.05).Conclusions FGFR1-DN can promote cell proliferation in the early differentiation of BMSCs and also mineralization of osteoblasts in bone induction culture after the logarithmic growth phase.This may provide a hint for local gene treatment of bone defects.
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Objective To investigate the mineralization impact of fibroblast growth factor receptors 1 dominant negative (FGFR1DN) on osteogenic induction culture of bone marrow stromal cells (BMSCs).Methods The 3rd generation BMSCs were divided into 4 equal groups (n =24).FGFR1-DN group was transfected by pcDNA3.1 (+)-FGFR1DN,FGFRI group by pcDNA3.1 (+)-FRFR1,blank load group by pcDNA3.1 (+)-blank vehicle and non-transtection group by nothing.After successful transfection was confirmed when the cells were in the logarithmic phase,osteogenic induction culture was conducted continuously for 21 days.Mineralized nodule formation was observed by alizarin red staining.The amount of mineralized material was calculated according to the standard curve of alizarin red concentration.Results Continuous osteogenic induction for 21 days showed on the bottom of the hole visible round opaque calcified nodules after alizarin red staining.The BMSCs in the FGFR1-DN group induced in the logarithmic growth phase by osteoblasts exhibited significantly increased osteogenic capacity while those in the FGFR1 group displayed diminished osteogenic capacity.The concentration of alizarin red was the highest in the FGFRI-DN group (1.33 ±0.19),the lowest in the FGFRI group (1.00 ± 1.17),and moderate in the blank load group (1.20 ± 0.16) and non-transfection group (1.17 ± 0.17),showing significant between-group differences (P ＜ O.05).Conclusions FGFR1-DN can promote cell proliferation in the early differentiation of BMSCs and also mineralization of osteoblasts in bone induction culture after the logarithmic growth phase.This may provide a hint for local gene treatment of bone defects.
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Objective To explore the effect of fibroblast growth factor receptors 1-dominant negative strategy (FGFR1-DN) on alkaline phosphatase (ALP) activity of bone marrow stromal stem cells (BMSCs) after osteogenic induction.Methods BMSCs were transfected with eukaryotic expression plasmid pcDNA 3.1 (+)-DN FGFR1 and pcDNA3.1 (+)-FGFR1.The experiment was conducted in 4 groups:FGFR1-DN transfection group,FGFR1 transfection group,pcDNA3.1(+) empty vector transfection group and non-transfection group.The ALP activity of BMSCs was detected in logarithmic growth phase after osteogenic culture.The qualitative detection of ALP activity was carried out immunohistochemically while the quantitative detection by cALP kit.The ALP activity was compared between the 4 groups at 7 and 14 days after osteogenic induction.Results Compared with 7 days,the ALP activity at 14 days was significantly increased in the 4 groups,and the increase in FGFR1-DN transfection group was significantly higher than in the other 3 groups (P ＜ 0.05).At both 7 and 14 days,the ALP activity in FGFR1-DN transfection group was the highest while that in FGFR1 transfection group was the lowest (P ＜ 0.05).Conclusions FGFR1-DN can promote the ALP activity of BMSCs during osteogenesis.This may provide an experimental basis for the joint application of local gene therapy and tissue engineering and for construction of tissue engineered bone with better biocompatibility.
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Objective: To search for the small molecule inhibitor with anti-tumor activity by fibroblast growth factor receptor 1 (FGFR1) as target. Methods: The analogue B6 of EF24 was obtained by reforming mono carbonyl curcumin analogues and applied to identifying the target with FGFR1 kinase activity assay. The effect of EF24 and its analogue B6 on the proliferation of HL7702 in normal human and four tumor cells, such as NCI-H460, SGC-7901, A549, and U251; With the concentration of 2.5, 5, and 10 μmol/L, B6 was used to investigate the phosphorylation inhibition of bFGF/FGFR downstream signal protein expression in NCI-H460 cells and Caspase-3 factor expression. Results: With the FGFR1 as target, B6 could inhibit the phosphorylation of FGFR1 in NCI-H460 cells, AKT, and ERK1/2; It also could inhibit the proliferation of cancer cells and promote cell apoptosis. Conclusion: The analogue B6 of EF24 is obtained from the leading compound EF24 with in vitro anti-tumor effect, which provides the basis of looking for the candidate anti-tumor drugs of FGFR1 inhibitor.
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Fibroblast growth factor receptor ( FGFR) is one of the molecules involved in tumor formation , and plays an impor-tant role in cell proliferation , angiogenesis and migration .In this article, we review the role of FGFR signal pathway in breast cancer , the correlation with the risk and prognosis , the function of FGFRs as potential therapeutic targets for breast cancer and discuss various treatment strategies of targeted FGFR 1 in clinical trials .
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The 8p11 myeloproliferative syndrome is a rare hematologic malignancy that involves the fibroblast growth factor receptor 1 (FGFR1) gene at chromosome 8p11.The clonal change of the FGFR1 rearrangement is present in BM cells,and in the T-lymphoma cells in the LN.The hematological stem cells transplantation is the only method that can cure this rare hematologic neoplasma.
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In order to investigate the anti-tumor angiogenesis activity with a recombinant Ag43/FGFR1 chimeric protein(AF)vaccine in a mouse H22 hepatoma model,tumor volume and survival rate of the mice were studied at a 3-day interval,Microvessel density(MVD)was detected by immunohistochemistry.The endothelial deposition of autoantibodies within tumor tissues was examined by immunofluorescent staining,and anti-FGFR1 antibody-producing B cells(APBCs)were tested by enzyme-linked immunospot(ELISPOT)assay.Compared with the three control groups,the tumor volume was significantly decreased and the survival time was significantly prolonged in AF-immunized group(P<0.05).The number of APBCs in AF-immunized mice(129.6±10.9)was more than in controls[6.2±1.1(FGFR1),6.0±1.2(Ag43)and 5.2±1.4(NS),P<0.01].Moreover,the endothelial deposition of autoantibodies was found in tumor tissues from AF-immunized mice,but not in control groups.MVD in AF-immunized group was significantly lower than in FGFR1-immunized group,Ag43-immunized group and NS group(10.3±3.1 vs 39.4±8.6 vs 42.3±9.8 and 43.6±10.6,P<0.01).These findings demonstrated that the AF protein vaccine effectively inhibited tumor angiogenesis and growth via production of autoantibodies against self-FGFR1.
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To explore the anti-tumor effect of immunotherapy with recombinant protein vaccine based on FGFR-1 of chicken (cFR-1) in a mouse Meth A fibrosarcoma model, tumor volume and survival rate of the mice were observed at a 3-day interval. Microvessel density (MVD) was detected by immunohistochemistry. Auto-antibodies against self-FGFR-l were detected by Western blotting and ELISA, respectively. The anti-FGFR-1 antibody-producing B cells (APBCs) were detected by enzyme-linked immunospot (ELISPOT) assay. Eighteen days after inoculation of tumor cells, the tumor volume was significantly smaller in cFR-l-immunized group than in mouse FGFR-1 (mFR-1) immunized group and normal saline (NS) control group (P＜0.05), and the survival time was significantly longer in cFR-l-immunized group than in the control groups (P＜0.01). MVD was significantly lower in cFR-l-immunized group than in mFR-l-immunized group and NS group (16.8 ±5.6 vs 64.6±1.8and 59.6±8.7, P＜0.01). Antibodies against self-FGFR-1 were found in mFR-l-immunized group, the major antibody subclasses were IgG1 and IgG2b. Compared with the two control groups, the numbers of APBCs in cFR-l-immunized group were significantly increased (P＜0.01) These results demonstrated that the cFR-1-related anti-angiogenesis protein vaccine could induce the production of auto-antibodies against self-FGFR-1, which futher inhibit angiogenesis and growth of solid tumor.
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The possibility that a recombinant protein vaccine based on xenogeneic homologous FGFR-1 of chicken induces production of autoantibodies against self-FGFR-1 in BALB/c mice was examined by using ELISA, Western blot analysis and ELISPOT assay respectively. Autoantibodies against mouse FGFR-1 were identified by Western blot analysis and ELISA. Compared with the two control groups, the number of APBCs, which were detected by ELISPOT assay, was significantly increased in the spleens of mice immunized with cFR1 (P＜0.05). IgG1 and IgG2b, which were detected by ELISA, were the major subclasses and were substantially increased in response to chicken FGFR-1 when compared with control group. The recombinant chicken FGFR-1 protein used as a vaccine can induce autoantibodies against self-FGFR-1 in mice and provide a basis for the active immunotherapy of tumor angiogenesis.
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Objective: To study the relevance of expression of basic fibroblast growth factor (bFGF), fibroblast growth factor receptor-1 (FGFR-1) and carcinogenesis and progression of ovarian epithelial neoplasm. Methods: Ten cases of normal ovarian tissues and 75 cases of ovarian epithelial neoplasm tissues were detected by immunohistochemical methods: S-P for bFGF, FGFR-1, double immunohistochemistry Lab-SA for Ki-67 antigen and bFGF. Results: The expression level of bFGF, FGFR-1 in ovarian epithelium and ovarian epithelial neoplasm showed a step-wise increase in the following order: normal 〈benign 〈borderline 〈malignant; The expression level and intensity of bFGF and FGFR-1 were increased with the decrease of differentiation degree and increase of clinical stage in ovarian carcinoma; There was no statistical difference between the expression of bFGF, FGFR-1 in serous cystadenocarcinoma and that of mucinous cystadenocarcinoma; The expression of bFGF was correlated with that of FGFR-1 in neoplastic tissues; There were positive expression rates of bFGF and Ki-67 antigen in ovarian epithelial neoplasm. Conclusion: As an important proliferative factor, bFGF plays an important role in carcinogenisis and progression of ovarian epithelial neoplasm.
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Objective: To express recombinant human soluble fibroblast growth factor receptor 1 ( sFGFR1) and study its antagonistic activity on FGF. Methods: Human sFGFR1 cDNA, isolated from human lung fibroblast cells with RT-PCR was confirmed by DNA sequencing and cloned into pYEX4T-1 yeast expression vector. The recombinant sFGFR1 was expressed in DY150 yeast cells and the product was identified by SDS-PAGE and Western blot. The activity of recombinant sFGFR1 was detected in N1H3T3 proliferation inhibition assay. Results: GSF-sFGFR1 fusion protein was expressed in yeast cells and was observed as a band of 60 Id) on a SDS- PAGE gel and by Western blot. The recombinant fusion protein was also found to be able to suppress FGF-induced proliferation of NIH3Th cells. Conclusion: Recombinant human GST-sFGFR1 fusion protein was expressed in yeast efficiently and showed natural biological activities.
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Objective To obtain differentiated osteoblast-specific inactivation of fgfr1 mice Methods To obtain fgfr1△/+/OC-CreTG/+ mice,fgfr1flox/flox mice obtained from NIH were crossed with OC-Cre mice To obtain fgfr1△/△/OC-CreTG/+ mutant mice,fgfr1△/+/OC-CreTG/+ further crossed with themselves or fgfr1flox/flox mice After fgfr1△/△/OC-CreTG/+ crossed with fgfr1flox/flox mice,half of their offspring were mutant mice Results Differentiated osteoblast-specific fgfr1 knockout mice were obtained Conclusion fgfr1△/△/OC-CreTG/+ mice were obtained through proper crossing strategy,which provides a suitable platform for studying fgfr1 function in bone development and fracture healing