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Fibulin protein family is a class of extracellular matrix (ECM) proteins that are widely expressed in various tissues and plays an important role in the formation and stabilization of ECM. More and more studies have found that Fibulin protein family can play a role in tumor suppression or tumor promotion in different tumor tissues, which affects tumor proliferation, invasion and metastasis and is closely related to tumor chemotherapy resistance. Furthermore, Fibulin protein family is expected to be the target of inhibiting and reversing tumor chemotherapy resistance. This article reviews the role, target and molecular mechanism of Fibulin protein family in tumor development, progression and chemotherapy resistance, aiming to find a new research direction for tumor chemotherapy resistance.
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Objective:To investigate the role and mechanisms of fibulin-1 in senescence-related calcification of rat vascular smooth muscle cells induced by high-concentrationphosphate treatment.Methods:From September 2020 to September 2021, rat primary vascular smooth muscle cells were extracted from the thoracic aorta and abdominal aorta of 10 male SD rats aged 6 to 8 weeks.Phosphate(2.5 mmol/L Pi)was used to stimulate the calcification of vascular smooth muscle cells(VSMCs)in a model of stress-induced senescence-related calcification.Cellular senescence was assessed by SA-β-gal staining.Cellular calcification was determined by alizarin red staining and quantification of calcium deposition.Phenotypic transformation indexes and the expression of fibulin-1 during the process of calcification were detected by Western blot.The expression of fibulin-1 in primary rat vascular smooth muscle cells was knocked down by siRNA, the expression of pSmad3 was detected by immunofluorescence, and the effects of fibulin-1 on phenotypic transformation indexes of smooth muscle cells were detected by Western blot.The cells were cultured with recombinant fibulin-1 while transforming growth factor beta(TGF-β)inhibitor A83-01 and pSmad3 inhibitor SIS3 were also added.The senescence and calcification indexes of smooth muscle cells were detected by Western blot.Results:In the stress-induced aging model with phosphate stimulation of calcification in rat VSMCs, the expression of fibulin-1 was up-regulated( t=11.20, P<0.01), the expressions of MHC and SM22α was down-regulated( t=7.97, P<0.01; t=10.27, P<0.01), and the expression of osteoblastic phenotype markers OPN and Bmp2 and senescence marker P53 was up-regulated( t=4.79, P<0.01; t=9.56, P<0.01; t=14.07, P<0.01). Knockdown of fibulin-1 attenuated the degree of senescence and calcium deposition in VSMCs( t=12.90, P<0.05)and decreased the expression of OPN, Bmp2 and P53( t=5.92, P<0.05; t=10.15, P<0.01; t=8.28, P<0.01), at the same time, and TGF-β and pSmad3 expression was inhibited( t=12.90, P<0.01; t=7.46, P<0.01). After the addition of TGF-β/ smad3 pathway inhibitors, the stimulatory effect of recombinant fibulin-1 on phenotypic transformation and senescence protein expression inVSMCs was significantly reduced( t=4.52, P<0.01; t=9.82, P<0.01; t=3.85, P<0.05). Conclusions:Fibulin-1 can promote aging-related calcification of vascular smooth muscle cells through the TGF-β/smad3 signaling pathway.
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Objective:To investigate the effect of modified Si Junzitang on the expression of fibrous protein-5（Fibulin-5）， phosphorylated protein kinase B（p-Akt ）in hippocampus of rats after cerebral ischemia-reperfusion （I/R） injury and the anoikis of nerve cells. Method:The 60 male SD rats of SPF grade were randomly divided into sham operation group， model group， Edaravone group （3.2 mg·kg-1）and modified Si Junzitang high， medium and low-dose groups（19.08，9.54，4.77 g·kg-1）.The middle cerebral artery occlusion （MCAO） model was established by suture method，the rats were killed 7 days later，neurological deficit score was evaluated before the death，histopathological observation was performed by hematoxylin eosin staining， apoptosis index of nerve cells was detected by TdT-mediated dUTP nick end labeling（TUNEL）staining， the expression of Fibulin-5， p-Akt and protein in ischemic hippocampus were detected by immunohistochemistry and Western blot. Result:The neurological deficit score showed that，compared with the sham operation group， the neurological deficit score of the model group was significantly increased （P<0.01）， compared with model group， the neurological deficit score of Edaravone group，the high， medium， low dose groups of modified Si Junzitang were decreased （P<0.05，P<0.01）. Immunohistochemical results showed that，compared with the sham operation group， the expression of Fibulin-5， p-Akt protein and the apoptosis index of nerve cells in the model group were significantly increased （P<0.05，P<0.01）， compared with model group， the protein expressions of Fibulin-5 and p-Akt in Edaravone group， high， medium and low-dose groups of modified Si Junzitang were significantly increased （P<0.05，P<0.01）， and the apoptosis index of nerve cells was obvious，there was a significant decrease （P<0.05，P<0.01）. Western blot results showed that，compared with the sham operation group， the relative expression of Fibulin-5 and p-Akt protein in the model group was significantly down-regulated （P<0.01）， compared with model group， the protein expressions of Fibulin-5 and p-Akt in the Edaravone group， the high， medium and low-dose groups of modified Si Junzitang were significantly up-regulated （P<0.05，P<0.01）. Conclusion:The modified Si Junzitang may stabilize the extracellular matrix （ECM） Fibulin-5， increase the adhesion of ECM to cells and promote the expression of p-Akt protein， thus inhibiting neuronal apoptosis and protecting cerebral ischemia injury.
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Background: Colorectal cancer (CRC) is one of the most common cancers in China and even in the world, and metastasis is the main cause of death. However, there is lack of sufficient molecular biomarkers for predicting effectively the occurrence of metastasis. Aims: To explore the expression of fibulin-2 (FBLN2) in CRC and the underlying mechanism of its effect on tumor invasion and metastasis. Methods: Bioinformatics data of PRJNA218851 data set from the SRA database were extracted to screen CRC metastasis-associated genes. Then these differentially expressed genes were applied for gene enrichment analysis to identify the most significant pathways. Data from TCGA and clinical CRC samples were used to analyze the expression of FBLN2 in CRC tissues and normal tissues, and the relationship between FBLN2 and clinicopathological features and prognosis of CRC patients. Expression of FBLN2 in normal colorectal mucosal cell line, CRC cell lines, and clinical CRC samples was detected by real-time PCR. After FBLN2 was knockdown or over expressed in CRC cells, CCK-8 assay, clone formation assay, Transwell cell invasion and migration assay, and wound healing assay were performed to observe the effect of FBLN2 on the proliferation, invasion and migration abilities of CRC cells. Gene set enrichment analysis was conducted to screen the potential downstream pathway of FBLN2, and then the pathway screened was verified. Results: The expression of FBLN2 was low in eight CRC cell lines and CRC tissues, yet the expression in metastatic CRC was significantly higher than that in non-metastatic ones. Compared with CRC patients with low FBLN2 expression, CRC patients with high FBLN2 expression were prone to have lymph node metastasis and distant metastasis, and with higher clinical stage and poorer prognosis. Knockdown of FBLN2 could decrease the invasion and migration abilities of CRC cells, but had no impact on cell proliferation. FBLN2 was positively correlated with CDH2, Snai1 and vimentin, indicating that the epithelial-mesenchymal transition (EMT) pathway might be the downstream pathway of FBLN2. Conclusions: FBLN2 is low expressed in CRC but the expression is increased in metastatic CRC. Therefore, it might be used as a molecular biomarker for screening early metastasis. FBLN2 might enhance CRC invasion and metastasis through activating EMT pathway and is associated with poor prognosis.
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The Fibulin family is a kind of secreted glycoprotein,belonging to the extracellular matrix protein.A total of 7 family members are widely distributed in basement membrane,elastic fiber and loose connective tissue.The Fibulin family is widely involved in the regulation of cell morphology,growth and adhesion.When Fibulin is disturbed,it can cause a range of diseases,such as skin laxity,tooth hypoplasia and various tumors.The researches show that Fibulin-1 is expressed abnormally in fibrosarcoma,gastric cancer and liver cancer,and the expression of Fibulin-2 is down-regulated in breast cancer and up-regulated in lung cancer.The other members of the family also show abnormal expression in various tumor tissues,which indicates the members of the Fibulin family play important roles in the genesis and development of tumors.
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The human Fibulin protein family includes seven extracellular matrix proteins with similar structures.These proteins play important roles in the formation and stability of the extracellular matrix;the major components of this matrix are composed of elastic fibers and the basement membrane.In addition to their significant roles in formation of the extracellular matrix,the Fibulin family pro-teins regulate cell adhesion,growth,migration,and proliferation.Recent research confirmed that Fibulin family proteins play a signifi-cant role in tumor suppression and oncogenic activities as well as tumor invasion,proliferation,and prognosis.In this review,we sum-marize the functions and mechanisms of the Fibulin protein family in various tumors,with the goal to identify a novel biomarker for tu-mor therapy.
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Objective To study the expression of Fibulin-5 in gastric cancer and its correlation with the prognosis of gastric cancer.Methods Tissue chips from 90 gastric cancer cases were used to study the expression of Fibulin-5 protein in cancer tissue and para-carcinoma tissue by immunohistochemistry,and analyze the correlation of Fibulin-5 expression and clinical pathological characteristics.Results The expression of Fibulin-5 in gastric cancer tissue was higher than that of para-carcinoma tissue [cytoplasm:(6.2±4.2) vs.(5.1 ±3.7);nucleus:(7.2 ±3.8) vs.(4.9 ±2.5),all P＜0.05],which was positively related with patient's age (r =0.213,P =0.044) in the cytoplasm of cancerous tissue.The expression of Fibulin-5 in the cytoplasm of cancerous tissue was negatively related with patient's overall survival (25％ vs.56％,P =0.027),which was an independent predictor (P =0.037).Conclusion Fibulin-5 is an independent prognostic factor of gastric cancer,its expression might be related with shortend patient's survival time.
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Objective To investigate effects of mouse nerve growth factor on serum brain-derived neurotrophic factor, Fibulin-5 and intracranial blood flow in patients with acute cerebral infarction.Methods 98 patients with acute cerebral infarction in our hospital from September 2015 to September 2016 were selected as the research object, divided into observation group and control group, 49 cases in each group.The control group was treated with conventional treatment of acute cerebral infarction, patients in the observation group on the basis of conventional treatment combined with mouse nerve growth factor, Enzyme-linked immunosorbent assay was used to detect serum brain-derived neurotrophic factor, Fibulin-5, Intracranial ultrasonography was used to detect intracranial blood flow, the brain-derived neurotrophic factor, Fibulin-5, cerebral blood flow were compared between the two groups before and after treatment.Results Before treatment, two groups of patients with brain-derived neurotrophic factor (BDNF), Fibulin-5 and hemodynamics, the difference was not statistically significant.After treatment, the levels of BDNF and Fibulin-5 in the observation group were (5.63 ±1.34), (156.63 ±12.79), significantly higher than the control group (4.26 ±1.54), (115.52 ±15.66), the difference was statistically significant ( P<0.05 ) , the observation group of patients with cerebral hemodynamics index , average blood flow ( Qmean ) , the average blood flow velocity (Vmean), dynamic impedance (DR), cerebral vascular characteristic impedance (ZCV), cerebral vascular peripheral resistance (R) were significantly better than the control group, the difference was statistically significant (P<0.05), the prognosis of the observation group was better than that of the control group, the difference was statistically significant ( P<0.05 ) .Conclusion Clinical effect of mouse nerve growth factor on acute cerebral infarction is helpful to promote the growth of nerve function inhibition, improve cerebral blood flow, better prognosis.
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Objective:This study aimed to assess serum fibulin-3 levels in patients with colon cancer compared with healthy controls and its relationship to demographics and tumor pathology.Methods:A total of 97 patients (mean age,59.6 years;57.7％ males) with colon cancer and 86 controls (mean age,58.8 years;54.7％ males) were included.Serum levels of fibulin-3 were determined using a commercially available sandwich ELISA (Enzyme-Linked ImmunoSorbent Assay).Results:Preoperative serum fibulin-3 levels were significantly lower in the group of patients with colon cancer(39.86 ± 24.37) ng/mL compared with the control group (94.25 ± 31.28) ng/mL.Preoperative fibulin-3 levels and negatively correlated with the degree of tumor TNM stage (P＜0.05),fibulin-3 levels gradually decreased by tumor stage from Ⅰ to Ⅳ and the difference is statistically significant.The serum fibulin-3 levels were correlated significantly with tumor size,lymph node metastasis,distant metastasis and CEA levels(P＜0.05).Conclusion:It was concluded that fibulin-3 is expressed at a lower level in colon cancer,and it is significant correlated with tumor burden,decreased level of fibulin-3 can serve as a marker for advanced colon cancer.
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Objective To study the role of fibulin-3 in blood and pleural effusion in the early diagnosis of malignant pleural mesothelioma (MPM). Methods Chinese and English literatures about fibulin-3 in the diagnosis of MPM before February 1, 2017 were searched through the computer. After the screening according to the criteria, literature data were extracted to build the analysis model and explore the origin of the heterogeneity. Results According to the selection criteria, 9 literatures including 26 independent study were taken into Meta analysis eventually. The level of fibulin-3 in blood and pleural effusion in the experimental group was higher than that in the control group by using the random effect model. The region subgroup analysis showed that the fibulin-3 level in the experimental group was higher than that in the control group among European and American people. Conclusion Fibulin-3 in the diagnosis of MPM has a higher sensitivity and heterogeneity, which could be served as an auxiliary method in early diagnosis of MPM.
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Objective To study the role of fibulin-3 in blood and pleural effusion in the early diagnosis of malignant pleural mesothelioma (MPM). Methods Chinese and English literatures about fibulin-3 in the diagnosis of MPM before February 1, 2017 were searched through the computer. After the screening according to the criteria, literature data were extracted to build the analysis model and explore the origin of the heterogeneity. Results According to the selection criteria, 9 literatures including 26 independent study were taken into Meta analysis eventually. The level of fibulin-3 in blood and pleural effusion in the experimental group was higher than that in the control group by using the random effect model. The region subgroup analysis showed that the fibulin-3 level in the experimental group was higher than that in the control group among European and American people. Conclusion Fibulin-3 in the diagnosis of MPM has a higher sensitivity and heterogeneity, which could be served as an auxiliary method in early diagnosis of MPM.
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Fibulin-1 is a widely distributed,versatile secretory calcium-binding glycoprotein which plays an important role on the formation of the structure of the extracellular matrix,the regulation of intercellular signaling and the inhibition of cell motility.Recent studies suggested a tumor-suppressive role for Fibulin-1.Here,this review focuses on the expression,function and mechanism of Fibulin-1 genes in tumor.
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Objective To analyse the effect of dual antiplatelet drugs on fibulin-5, vWF and P-selection in serum of patients with acute cerebral infarction.Methods Diagnosed 60 patients with acute cerebral infarction in our hospital and collected. All patients were randomly divided into experimental group and control group, 30 cases in each group.The control group was treated with conventional treatment and aspirin, and the experimental group was treated with clopidogrel on the basis of control group.After treatment, the serum levels of Fibulin-5, vWF, P-selection and adverse reactions were detected in all patients.ResuIts After treatment, compared with control group, the serum Fibulin-5 level was significantly lower in experimental group ( P<0.05 );the serum vWF level in experimental group was significantly lower ( P<0.05 );the serum P-selectin level in experimental group was significantly lower (P<0.05);there was no significant difference in the incidence of adverse reactions between two groups. ConcIusion Dual antiplatelet drugs can reduce serum vWF, P-selectin and fibulin-5 in serum of patients with acute cerebral infarction, adverse reactions do not significantly increase, have guiding significance to clinical application.
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Objective To investigate the changes and significances of the level of serum Fibulin-3 and correlation between Fibulin-3 and branchial-ankle Pulse Wave Velocity (baPWV) in patients with hypertension. Methods A total of 50 patients with hypertension and 38 healthy people were enrolled finally, whose fasting blood were collected. The levels of Fibulin-3、MMP-9 were detected by enzyme-linked immunosorbent assay. The baPWV was detected by pulse wave velocity automatic analyzer. Results The level of serum Fibulin-3 in hypertension was lower than the control group significantly (P < 0.001). There was no significance of serum MMP-9 in the two groups. The baPWV in hypertension was higher than the control group.Correlations between the level of Fibulin-3 and baPWV were significant (r = -0.324,P = 0.006). While correlations between the level of MMP-9 and baPWV had no significance (r=0.003,P=0.968). Conclusion The level of serum Fibulin-3 and baPWV can be used as index of functional changes in the early stage of hypertensive vascular remodeling, and may be applied for forecasting the organ damage in hypertension.
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OBJECTIVES@#To explore the effect of Fibulin-5 expression on cell proliferation and invasion in human gastric cancer patients.@*METHODS@#Fibulin-5 expression was detected in 56 samples of surgically resected gastric cancer and paired noncancerous tissues using qRT-PCR and immunoblotting. Fibulin-5 was knocked down by Fibulin-5 shRNA in MGC-803 cells, then BrdU cell proliferation and transwell invasion assays were used to determine cell proliferation and invasion.@*RESULTS@#The level of Fibulin-5 mRNA in gastric cancer tissues was significantly higher as compared with that in normal tumor-adjacent tissues (P<0.05). Otherwise, the level of Fibulin-5 protein in cancer and noncancerous tissues was consistent with mRNA expression (P<0.05). Fibulin-5 protein expression in tumor tissues with poorly differentiated, lymph node metastasis and advanced TNM tumor stage was significantly higher (P<0.05, respectively). Fibulin-5 was obviously knocked down by Fibulin-5 shRNA (P<0.05), and Fibulin-5 knockdown significantly inhibited cell proliferation and invasion in MGC-803 cells (P<0.05, respectively).@*CONCLUSIONS@#The high-expression of Fibulin-5 is associated with the malignant clinicopathologic parameters in gastric cancer and Fibulin-5 knockdown inhibits cell proliferation and invasion in MGC-803 cells, suggesting Fibulin-5 may act as a key factor in the progression of gastric cancer.
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Objective To study the role of fibulin-5 in urothelial carcinoma of bladder. Methods Fibulin-5 expression was detected in bladder cancer tissues (13 cases of G_1 and G_2, 7 cases of G_3) and normal bladder mucosa samples by Western blotting assay. Fibulin-5 cDNA was amplified by PCR and cloned into pMD-19T simple vector. The pMD-19T-Fibulin-5 vector was digested by restriction endonucleases XhoI and EcoRI to generate a XhoI-Fibulin5-EcoRI fragment that was then ligated into the identical sites in p-EGFP-Nl plasmid to synthesize p-EGFP-Fibulin-5 plasmid. The p-EGFP-Fibulin-5 plasmid was finally transfected into bladder cancer cell line 5637. The migration and invasion of untransfected, vector-transfected and fibulin-5-transfected bladder cancer cells were measured by Boyden chamber assay. Results Compared to 1. 16 ±0. 28 in the normal control, the expression of fibulin-5 protein in low grade and high grade tumors were 0. 57±0. 32 and 0. 44±0. 42(P<0. 01, respectively). However, the difference between low grade and high grade tumors was not statistically significant (P>0. 05). The successfully transfected bladder cancer cells demonstrated green fluorescent light. The migrated cell number of fibulin-5-transfected cells was 127. 6 ± 3. 1 compared with 139. 3±7. 7 for vector-transfected cells and 136. 9±5. 7 for untransfected cells (P>0. 05, respectively). In contrast, the invaded cell number of fibulin-5-transfected cells was 8. 0±3. 1 compared with 31. 5±4. 8 for vector-transfected cells and 31. 7±4. 7 for untransfected cells (P<0. 01, respectively). Conclusion Fibulin-5 is down-regulated in urothelial carcinoma of bladder and acts as a tumor suppressor gene by inhibiting the invasion of bladder cancer cells.