ABSTRACT
FOXC2,a transcription factor of the forkhead/winged-helix family,possesses a classical forkhead domain,which is required for embryonic and prenatal development.FOXC2 acts as a crucial modulator during tumor cell proliferation,metastasis,angiogenesis,lymphangiogenesis,renal disease and metabolism,but very little is known about the precise underlying mechanisms.Therefore,an in-depth study of FOXC2 is helpful to further understand the pathogenesis and developmental mechanism of FOXC2-related diseases.The purpose of this review is to summarize the current understanding of FOXC2 and its function.
ABSTRACT
OBJECTIVES: In varicose veins, vascular smooth muscle cells (VSMCs) often shows phenotypic transition and abnormal proliferation and migration. Evidence suggests the FOXC2-Notch pathway may be involved in the pathogenesis of varicose veins. Here, this study aimed to explore the role of long non-coding RNA FOXC2-AS1 (FOXC2 antisense RNA 1) in phenotypic transition, proliferation, and migration of varicose vein-derived VSMCs and to explore whether the FOXC2-Notch pathway was involved in this process. METHODS: The effect of FOXC2-AS1 on the proliferation and migration of human great saphenous vein smooth muscle cells (SV-SMCs) was analyzed using MTT assay and Transwell migration assay, respectively. The levels of contractile marker SM22α and synthetic marker osteopontin were measured by immunohistochemistry and Western blot to assess the phenotypic transition. RESULTS: The human varicose veins showed thickened intima, media and adventitia layers, increased synthetic VSMCs, as well as upregulated FOXC2-AS1 and FOXC2 expression. In vitro assays showed that FOXC2-AS1 overexpression promoted phenotypic transition, proliferation, and migration of SV-SMCs. However, the effect of FOXC2-AS1 overexpression could be abrogated by both FOXC2 silencing and the Notch signaling inhibitor FLI-06. Furthermore, FOXC2-AS1 overexpression activated the Notch pathway by upregulating FOXC2. CONCLUSION: FOXC2-AS1 overexpression promotes phenotypic transition, proliferation, and migration of SV-SMCs, at least partially, by activating the FOXC2-Notch pathway.
Subject(s)
Humans , Saphenous Vein/metabolism , Cell Movement/physiology , Myocytes, Smooth Muscle/metabolism , Cell Proliferation/physiology , Forkhead Transcription Factors/metabolism , Phenotype , Saphenous Vein/pathology , Signal Transduction , Up-Regulation , Cells, Cultured , Myocytes, Smooth Muscle/pathologyABSTRACT
Objective To identify the role of FOXC2 in the invasion and migration of colorectal cancer cells .Methods Stable cell lines expressing FOXC2(SW480/FOXC2) or vector (SW480/pBabe) were established using retroviral infection method .The morphology alterations of SW480 cells were observed using a microscope .Western blot analysis and immunofluorescence staining assays were performed to detect the expression of E‐cadherin ,Vimentin and N‐cadherin .The invasive and migratory abilities of colorectal cancer cells evaluated using Transwell invasion chamber experiment detection .Results The morphology of SW480 cells was significantly changed after overexpression .From the original shape typical of epithelial cells became spindle shaped growth , similar to the morphology of fibroblasts .Western blot analysis and immunofluorescence staining displayed that overexpression of FOXC2 led to significant downregulation of the epithelial marker E‐cadherin ,but upregulation of the mesenchymal markers Vimen‐tin and N‐cadherin .Transwell assay reveals that overexpression of FOXC2 strongly enhanced the migratory and invasive ability of SW480 cells .Conclusion FOXC2 induces epithelial‐mesenchymal transition and promotes the invasive ability of colorectal cancer cells .
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Objective To investigate the expression and effect of FOXC2 (forkhead box C2) and Vimentin in gastric carcinoma tissues .Methods To detect the protein expression of FOXC2 and Vimentin in 20 normal gastric tissues and 65 gastric carcinoma tissues with immunochemistry .Results FOXC2 and Vimentin were highly expressed in all gastric carcinoma tissues .In all gastric carcinoma cases ,the FOXC2 expression rate was 41 .53% ,the rate of Vimentin was 35 .38% .The average expression rates of FOXC2 and Vimentin in TNM ( Ⅲ + Ⅳ ) group were significantly higher than those in TNM (Ⅰ + Ⅱ ) group ,respectively (58 .60% vs .27 .78% ,P=0 .012 ;55 .88% vs .29 .03% ,P=0 .018) .The expression rates of FOXC2 and Vimentin in lymph node transfer group were statistically higher than those in no lymph node transfer group (51 .72% vs .22 .22% ,P=0 .013;41 .20% vs . 14 .80% ,P=0 .010) .The correlation between FOXC2 and Vimentin was positive (P= 0 .037) .Conclusion It is possible that FOXC2 and Vimentin are involved in the transformation of epithelial cells into the mesenchymal cells .And they may play an impor-tant role in the metastasis of gastric carcinoma .
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Objective: To investigate the expression level of FOXC2 in adipose tissues and its correlation with obesity and insulin resistance Methods: Abdominal visceral and subcutaneous adipose tissue biopsies were obtained from 15 non-diabetic obesity patients(BMI≥35) and 8 non-diabetic controls(BMI
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Objective To study the human lymphangiogenesis in the early stage of embryo and the expression of forkhead box C2(FOXC2) in human lymphangiogenesis.Methods Lymphatic vessel endothelial haluronic acid receptor-1(LYVE-1) was used as the special marker of lymphatic vessels.Immunohistochemical and double immunofluorescence staining were used to detect the expressions of FOXC2 and LYVE-1 in lymphatic vessels of 85 human embryos of 5 to 11 weeks pregnancy and analyze the features of lymphatic vessel genesis and development.Results LYVE-1 was initially detected in lymphatic vessels in 7-week human embryos.The lymphatic vessel endothelial cells presented brown staining for LYVE-1 in jugular and thoracic region.LYVE-1 was also found to express in human embryonic mesentery lymphatic vessels on the 70th day of pregnancy.The expression of FOXC2 in human embryo was detected prior to that of LYVE-1.At the beginning of the 6th week of pregnancy,FOXC2 was obviously seen in human embryonic mesoderm mesenchyme.FOXC2 expressed not only in human embryonic lymphatic vessels,but also in the vertebral body,cardiovascular wall and other tissues.The expressions of FOXC2 and LYVE-1 were still seen in human embryonic lymphatic vessel endothelial cells after 80 days of pregnancy.Conclusion Lymphangiogenesis of human embryo begins between the 7th and 8th weeks of pregnancy.FOXC2 and LYVE-1 could have some relation with the human embryonic lymphatic vessel genesis and development.
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Objective:In order to study the effect of forkhead box c2 (Foxc2) on the development of skeleton and aorta Methods:Rat monoclonal anti mouse Foxc2 antibody was prepared by using recombinant fusion protein GST Foxc2, and used it to detect the expression of Foxc2 protein in C2C12 myoblasts and embryo of mouse Results:The titer of rat anti mouse Foxc2 antibody was 1: 5 000 This monoclonal antibody can specifically recognized Foxc2 protein producing in mouse L cells and human bladder carcinoma HTB9 cells transfected with CX Foxc2 plasmid Endogenous Foxc2 protein was detected in the mouse myoblast C2C12 cells and increased significantly in C2C12 cells after treatment with bone morphogenetic protein 2(BMP 2) Endogenous Foxc2 protein level was lowered markedly by transfecting C2C12 cells with antisense Foxc2 sequence Foxc2 protein in 11 5 dpc embryo was localized in the developing selerotome and mesenchymal tissue around the aorta Conclusion:Rat anti mouse Foxc2 monoclonal antibody was successfully prepared by using recombinant fusion protein GST Foxc2 The BMP 2 induced Foxc2 protein may play an important role in regulating the osteoblastic differentiation of C2C12 myoblasts and in the formation of axial skeleton and aortic arch
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AIM: To investigate the roles of forkhead box c2(Foxc2) in axial skeloton. METHODS: Mice lacking Foxc2 locus were produced by targeted mutation and the developmental anomalies in axial skeleton were analyzed. RESULTS: Foxc2 protein increased markedly in Myoblasts C2C12 after treating with BMP-2, and alkaline phosphatase activity and production of osteocalcin in Myoblasts C2C12 were significantly higher than that in cell lines transfecting antisense Foxc2 sequence. Expressed median cleft palatine, dysplasia of auditory ossicles and vertebral and anteroposterior facial dysplasia were found in all 15 homozygous mouse neonates with targeted mutation of Foxc2. CONCLUSION: These results suggest that Foxc2 has indispensable roles during skeletogenesis in mesoderm and cells derived from the neural crest. [
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Objective:To study the differentially expressed genes associated with lipid metabolism in adipose tissues of patients with insulin resistant(IR) type 2 diabetes mellitus(T2DM),in an effort to explore the mechanism of IR.Methods: mRNA from the omental adipose tissues of T2DM patients(n=5) and normal controls(n=5) were reversely transcribed into cDNAs with the incorporation of fluorescent dUTP(cy-5 or cy-3) to prepare hybridization probes.The mixed probes were hybridized with a cDNA microarray containing the target genes.The results were scanned and subjected to computer analysis to search for the difference between the gene spectrum of T2DM patients and normal controls.The differentially expressed gene,FOXC2,was verified by Northern blot.Results: Eighty-two differentially expressed genes were identified between these 2 groups,with 10 associated with lipid metabolism,including 5 upregulated ones and 5 downregulated ones.Northern blotting confirmed that the expression of FOXC2 mRNA was increased in IR group,which was in accordance with the result of cDNA microarray analysis.Conclusion: The pathogenesis of IR is related with lipid metabolism and the FOXC2 gene may be a candidate gene of(IR. )