AIM： To investigate the functions of promoter hypermethylation of secreted frizzled-related proteins （sFRPs） genes in colorectal tumorigenesis and progression. METHODS： The promoter hypermethylation and expression...AIM： To investigate the functions of promoter hypermethylation of secreted frizzled-related proteins （sFRPs） genes in colorectal tumorigenesis and progression. METHODS： The promoter hypermethylation and expression of sFRP genes in 72 sporadic colorectal carcinomas, 33 adenomas, 18 aberrant crypt foci （ACF） and colorectal cancer cell lines RKO, HCT116 and SW480 were detected by methylation-specific PCR and reverse transcription PCR, respectively. RESULTS： None of the normal colorectal mucosa tissues showed methylated bands of any of four sFRP genes, sFRP1, 2, 4 and 5 were frequently methylated in colorectal carcinoma, adenoma and ACF （sFRP1 〉 85%, sFRP2 〉75%, sFRP5 〉 50%）, and the differences between three colorectal tissues were not significant （P 〉 0.05）. IVlethylation in colorectal tumors was more frequent than in normal mucosa and adjacent normal mucosa. The mRNA of sFRP1-5 genes was expressed in all normal colorectal mucosa samples. Expression of sFRP1, 2, 4 and 5 and sFRP1, 2 and 5 was downregulated in carcinoma and adenoma, respectively. The downregulation of sFRP2, 4 and 5 was more frequent in carcinoma than in adenoma. Expression of sFRP3 which promoter has no CpG island was downregulated in only a few of colorectal tumor samples （7/105）. The downregulation ofsFRP1, 2, 4 and 5 expression was significantly associated with promoter hypermethylation in colorectal tumor. After cells were treated by DAC/TSA combination, the silenced sFRP mRNA expression could be effectively re-expressed in colorectal cancer cell lines. CONCLUSION： Hypermethylation of sFRP genes is a common early event in the evolution of colorectal tumor, occurring frequently in ACF, which is regarded as the earliest lesion of multistage colorectal carcinogenesis. It appears to functionally silence sFRP genes expression. Methylation of sFRP1, 2 and 5 genes might serve as indicators for colorectal tumor.展开更多
AIM： To investigate the feasibility of detecting methylated fecal DNA as a screening tool for colorectal carcinoma （CRC） and precancerous lesions. METHODS： Methylated secreted frizzled-related protein gene 2 （SF...AIM： To investigate the feasibility of detecting methylated fecal DNA as a screening tool for colorectal carcinoma （CRC） and precancerous lesions. METHODS： Methylated secreted frizzled-related protein gene 2 （SFRP2）, hyperplastic polyposis protein gene （HPP1） and O6-methylguanine-DNA methyltransferase gene （MGMT） in stools from 52 patients with CRC, 35 patients with benign colorectal diseases and 24 normal individuals were analyzed using methylation-specific PCR. RESULTS： Methylated SFRP2, HPP1 and MGMT were detected in 94.2%, 71.2%, 48.1% of CRC patients and 52.4%, 57.1%, 28.6% of adenoma patients, respectively. The overall prevalence of fecal DNA with at least one methylated gene was 96.2% and 81.8% in patients with CRC and precancerous lesions, respectively. In contrast, only one of the 24 normal individuals revealed methylated DNA. These results indicated a 93.7% sensitivity and a 77.1% specificity of the assay for detecting CRC and precancerous lesions. CONCLUSION： IVlethylation testing of fecal DNA using a panel of epigenetic markers may be a simple and promising non-invasive screening method for CRC and precancerous lesions.展开更多
Wnts are a large family of growth factors that mediate essential biological processes like embryogenesis, morpho- genesis and organogenesis. These proteins also play a role in oncogenesis, and they regulate apoptosis ...Wnts are a large family of growth factors that mediate essential biological processes like embryogenesis, morpho- genesis and organogenesis. These proteins also play a role in oncogenesis, and they regulate apoptosis in many tissues. Wnts bind to a membrane receptor complex comprised of a frizzled （FZD） G-protein-coupled receptor and a low-density lipoprotein （LDL） receptor-related protein （LRP）. The formation of this ligand-receptor complex initiates a number of signaling cascades that include the canonical/beta-catenin pathway as well as several noncanonical pathways. In recent years, canonical Wnt signaling has been reported to play a significant role in the control of bone formation. Clinical studies have found that mutations in LRP-5 are associated with reduced bone mineral density （BMD） and fractures. Investigations of knockout and transgenic mouse models of Wnt pathway components have shown that canonical Wnt signaling modulates most aspects ofosteoblast physiology including proliferation, differentiation, function and apoptosis. Transgenic mice expressing a gain of function mutant of LRP-5 in bone, or mice lacking the Wnt antagonist secreted frizzled-related protein-l, exhibit elevated BMD and suppressed osteoblast apoptosis. In addition, preclinical studies with pharmacologic compounds such as those that inhibit glycogen synthase kinase-3β support the importance of the canonical Wnt pathway in modulation of bone formation and osteoblast apoptosis.展开更多
AIM: To investigate the feasibility of detecting aberrantly hypermethylated Wnt-antagonist gene promoters (SFRP2 and WIF-1) in fecal DNA as non-invasive biomarkers for early colorectal cancer (CRC).
AIM： To identify the methylation of secreted frizzled-related protein 1 （SFRP1） in gastric cancer and to investigate the aberrant expression of SFRP1 and its correlation with the clinical pathological features of p...AIM： To identify the methylation of secreted frizzled-related protein 1 （SFRP1） in gastric cancer and to investigate the aberrant expression of SFRP1 and its correlation with the clinical pathological features of patients. METHODS： We determined SFRP1 methylation and SFRP1 mRNA expression in 3 gastric cancer cell lines SGC-7901, BGC-823, HGC-27, from 52 primary gastric cancer specimens and matched tumor adjacent tissue specimens by methylation-specific （MSP） PCR and RT-PCR respectively. Fisher＇s exact test was used to analyze the statistical association between clinical pathological data and aberrant expression of SFRP1. RESULTS： In 3 cancer cell lines, BGC-823 and HGC-27 had methylated SFRP1 and lost SFRP1 mRNA expression. After treatment of BGC-823 and HGC-27 with the demethylating agent, 5-aza-2′-deoxycytidine, SFRP1 was re-expressed. In 52 primary gastric cancer specimens and matched tumor adjacent tissue specimens, hypermethylation of SFRP1 was detected in 23 （44%） and 8 （15%） specimens respectively （x^2= 10.34, P 〈 0.01）. Loss of SFRP1 expression was detected in 17（33%） and 6 （12%） specimens respectively （x^2= 6.75, P 〈 0.01）. There was a significant correlation between SFRP1 hypermethylation and SFRP1 expression loss. SFRP1 expression was also correlated significantly with tumor stage and lymph node status, but not with patient sex, age and histological type. CONCLUSION： SFRP1 inactivation is a common and early event caused mainly by hypermethylation in gastric cancer. SFRP1 expression loss may be correlated with tumor metastasis in primary gastric cancer.展开更多
Many researches have focused on the wnt-frizzled cascade in the recent years, while much work has been done in neoplastic diseases and embryology, the role of the wnt-frizzled signal transduction pathway in cardiovasc...Many researches have focused on the wnt-frizzled cascade in the recent years, while much work has been done in neoplastic diseases and embryology, the role of the wnt-frizzled signal transduction pathway in cardiovascular diseases has only recently begun to be explored. It plays a very important role in many physiological and pathophysiological processes, such as its transduction pathway, the healing after myocardial infarction, the proliferation, differentiation and orientation of cardiomyocytes, angiogenesis/neovascularization, cardiac hypertrophy and heart failure, the deposition of the extracellular matrix and so on. This article is aimed at its relation with myocardial infarction and the role of this pathway in cardiovascular diseases.[展开更多
AIM To analyze colorectal carcinogenesis and age-related DNA methylation alterations of gene sequences associated with epigenetic clock CpG sites. METHODS In silico DNA methylation analysis of 353 epigenetic clock Cp ...AIM To analyze colorectal carcinogenesis and age-related DNA methylation alterations of gene sequences associated with epigenetic clock CpG sites. METHODS In silico DNA methylation analysis of 353 epigenetic clock Cp G sites published by Steve Horvath was performed using methylation array data for a set of 123 colonic tissue samples [64 colorectal cancer(CRC), 42 adenoma, 17 normal; GEO accession number: GSE48684]. Among the differentially methylated agerelated genes, secreted frizzled related protein 1(SFRP1) promoter methylation was further investigated in colonic tissue from 8 healthy adults, 19 normal children, 20 adenoma and 8 CRC patients using bisulfite-specific PCR followed by methylation-specific high resolution melting(MS-HRM) analysis. m RNA expression of age-related "epigenetic clock" genes was studied using Affymetrix HGU133 Plus2.0 whole transcriptome data of 153 colonic biopsy samples(49 healthy adult, 49 adenoma, 49 CRC, 6 healthy children)(GEO accession numbers: GSE37364, GSE10714, GSE4183, GSE37267). Whole promoter methylation analysis of genes showing inverse DNA methylationgene expression data was performed on 30 colonic samples using methyl capture sequencing.RESULTS Fifty-seven age-related Cp G sites including hypermethylated PPP1R16 B, SFRP1, SYNE1 and hypomethylated MGP, PIPOX were differentially methylated between CRC and normal tissues(P < 0.05, ?β≥ 10%). In the adenoma vs normal comparison, 70 CpG sites differed significantly, including hypermethylated DKK3, SDC2, SFRP1, SYNE1 and hypomethylated CEMIP, SPATA18(P < 0.05, ?β≥ 10%). In MS-HRM analysis, the SFRP1 promoter region was significantly hypermethylated in CRC(55.0% ± 8.4 %) and adenoma tissue samples(49.9% ± 18.1%) compared to normal adult(5.2% ± 2.7%) and young(2.2% ± 0.7%) colonic tissue(P < 0.0001). DNA methylation of SFRP1 promoter was slightly, but significantly increased in healthy adults compared to normal young samples(P < 0.02). This correlated with significantly increased SFRP1 m RNA levels in children compared展开更多
Background:Bone marrow-derived mesenchymal stem cells(BM-MSCs)play an important role in cancer development and progression.However,the mechanism by which they enhance the chemoresistance of ovarian cancer is unknown.M...Background:Bone marrow-derived mesenchymal stem cells(BM-MSCs)play an important role in cancer development and progression.However,the mechanism by which they enhance the chemoresistance of ovarian cancer is unknown.Methods:Conditioned media of BM-MSCs(BM-MSC-CM)were analyzed using a technique based on microRNA arrays.The most highly expressed microRNAs were selected for testing their effects on glycolysis and chemoresistance in SKOV3 and COC1 ovarian cancer cells.The targeted gene and related signaling pathway were investigated using in silico analysis and in vitro cancer cell models.Kaplan-Merier survival analysis was performed on a population of 59 patients enrolled to analyze the clinical significance of microRNA findings in the prognosis of ovarian cancer.Results:MiR-1180 was the most abundant microRNA detected in BM-MSC-CM,which simultaneously induces glycolysis and chemoresistance(against cisplatin)in ovarian cancer cells.The secreted frizzled-related protein 1(SFRP1)gene was identified as a major target of miR-1180.The overexpression of miR-1180 led to the activation of Wnt signaling and its downstream components,namely Wnt5 a,β-catenin,c-Myc,and CyclinD1,which are responsible for glycolysis-induced chemoresistance.The miR-1180 level was inversely correlated with SFRP1 mRNA expression in ovarian cancer tissue.The overexpressed mi R-1180 was associated with a poor prognosis for the long-term(96-month)survival of ovarian cancer patients.Conclusions:BM-MSCs enhance the chemoresistance of ovarian cancer by releasing miR-1180.The released miR-1180 activates the Wnt signaling pathway in cancer cells by targeting SFRP1.The enhanced Wnt signaling upregulates the glycolytic level(i.e.Warburg effect),which reinforces the chemoresistance property of ovarian cancer cells.展开更多
Objective Microcystin-leucine-arginine(MC-LR)exposure induces lipid metabolism disorders in the liver.Secreted frizzled-related protein 5(SFRP5)is a natural antagonist of winglesstype MMTV integration site family,memb...Objective Microcystin-leucine-arginine(MC-LR)exposure induces lipid metabolism disorders in the liver.Secreted frizzled-related protein 5(SFRP5)is a natural antagonist of winglesstype MMTV integration site family,member 5A(Wnt5a)and an anti-inflammatory adipocytokine.In this study,we aimed to investigate whether MC-LR can induce lipid metabolism disorders in hepatocytes and whether SFRP5,which has anti-inflammatory effects,can alleviate the effects of hepatic lipid metabolism by inhibiting the Wnt5a/Jun N-terminal kinase(JNK)pathway.Methods We exposed mice to MC-LR in vivo to induce liver lipid metabolism disorders.Subsequently,mouse hepatocytes that overexpressed SFRP5 or did not express SFRP5 were exposed to MC-LR,and the effects of SFRP5 overexpression on inflammation and Wnt5a/JNK activation by MC-LR were observed.Results MC-LR exposure induced liver lipid metabolism disorders in mice and significantly decreased SFRP5 mRNA and protein levels in a concentration-dependent manner.SFRP5 overexpression in AML12cells suppressed MC-LR-induced inflammation.Overexpression of SFRP5 also inhibited Wnt5a and phosphorylation of JNK.Conclusion MC-LR can induce lipid metabolism disorders in mice,and SFRP5 can attenuate lipid metabolism disorders in the mouse liver by inhibiting Wnt5a/JNK signaling.展开更多
Objective:To investigate the correlation between serum secretory frizzled-related protein 5(SFRP-5)expression levels and insulin resistance and glucolipid metabolism in patients with gestational diabetes mellitus(GDM)...Objective:To investigate the correlation between serum secretory frizzled-related protein 5(SFRP-5)expression levels and insulin resistance and glucolipid metabolism in patients with gestational diabetes mellitus(GDM).Methods:Baseline data were collected from 58 patients with GDM and 51 healthy controls who were admitted Affiliated Hospital of Hebei University from May 2020 to June 2022.sSTRA5 concentrations in peripheral blood of pregnant women were measured,and SFRP-5 levels in patients with different GDM types and normal controls were analyzed by logistic regression models.Results:The levels of triglyceride(TG),total cholesterol(TC),low-density lipoprotein cholesterol(LDL-C),fasting blood glucose(FBG),fasting insulin(FINS),hemoglobin A1c(HbA1c),and homeostasis model assessment-estimated insulin resistance(HOMA-IR)were higher in the observation group than in the control group,with statistically significant differences(P<0.05),while the expression levels of high-density lipoprotein cholesterol(HDL-C)and serum SFRP-5 were lower than in the control group,with statistically significant differences(P<0.05);serum SFRP-5,TG,TC,FBG,and HOMA-IR were all risk factors for GDM(P<0.05).Conclusion:Elevated serum sSTRA5 may be involved in the regulation of insulin resistance in the body and the regulation of blood glucose in the body by affecting lipid metabolism and inflammatory response.展开更多
Background:Hirschsprung's disease (HSCR) is a congenital gut motility disorder of infants,and if left untreated,it is fatal to the affected infants.This study aimed to identify key microRNAs (miRNAs),signaling pat...Background:Hirschsprung's disease (HSCR) is a congenital gut motility disorder of infants,and if left untreated,it is fatal to the affected infants.This study aimed to identify key microRNAs (miRNAs),signaling pathways and genes involved in the pathogenesis of HSCR.Methods:The miRNA microarray dataset GSE77296 was downloaded.Nine colon tissue samples were available:six from HSCR patients and three matched control samples.Differentially expressed miRNAs (DEMs) were identified after data preprocessing.Target genes of the selected upregulated and downregulated DEMs were predicted.In addition,functional enrichment analyses for the selected DEMs and target genes were conducted.Finally,interaction networks between the DEMs and target genes were constructed.Results:A total of 162 DEMs (73 upregulated and 89 downregulated) were obtained.A total of 2511 DEM-target gene pairs for the 40 selected DEMs were identified,including 1645 pairs for the upregulated DEMs and 866 pairs for the downregulated DEMs.The upregulated DEM miR-141-3p and down-regulated DEM miR-30a-3p were identified as key miRNAs by Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment and network analyses.Besides,KEGG pathway enrichment analysis revealed that pathways in cancer and the mitogen-activated protein kinase (MAPK) signaling pathway were key pathways.The key genes frizzled class receptor 3 (FZD3) and docking protein 6 (DOK6) were obtained through the DEM-target gene interaction networks.Conclusion:Two key miRNAs (miR-141-3p and miR-30a-3p),the MAPK signaling pathway and two key genes (FZD3 and DOK6) were implicated in the pathogenesis of HSCR.展开更多
AIM： To investigate the expression and methylation status of the secreted frizzled-related protein 2 （SFRP2） in esophageal squamous cell carcinoma （ESCC） and ex- plore its role in ESCC carcinogenesis.METHODS： Se...AIM： To investigate the expression and methylation status of the secreted frizzled-related protein 2 （SFRP2） in esophageal squamous cell carcinoma （ESCC） and ex- plore its role in ESCC carcinogenesis.METHODS： Seven ESCC cell lines （KYSE 30, KYSE150, KYSE410, KYSE510, EC109, EC9706 and TE-1） and one immortalized human esophageal epithelial cell line （Het- 1A）, 20 ESCC tissue samples and 20 paired adjacent non-tumor esophageal epithelial tissues were analyzed in this study. Reverse-transcription polymerase chain reaction （RT-PCR） was employed to investigate the expression of SFRP2 in cell lines, primary ESCC tumor tissue, and paired adjacent normal tissue. Methylation status was evaluated by methylation-specific PCR and bisulfite sequencing. The correlation between expres- sion and promoter methylation of the SFRP2 gene was confirmed with treatment of 5-aza-2＇-deoxycytidine. To assess the potential role of SFRP2 in ESCC, we es-tablished stable SFRP2-transfected cells and examined them with regard to cell proliferation, colony formation, apoptosis and cell cycle in vivo and in vitro.RESULTS： SFRP2 mRNA was expressed in the im- mortalized normal esophageal epithelial cell line but not in seven ESCC cell lines. By methylation-specific PCR, complete methylation was detected in three cell lines with silenced SFRP2 expression, and extensive methylation was observed in the other four ESCC cell lines. 5-aza-2＇-deoxycytidine could restore the expres- sion of SFRP2 mRNA in the three ESCC cell lines lack- ing SFRP2 expression. SFRP2 mRNA expression was obviously lower in primary ESCC tissue than in adjacent normal tissue （0.939 ± 0.398 vs 1.51 ± 0.399, P 〈 0.01）. SFRP2 methylation was higher in tumor tissue than in paired normal tissue （95% vs 65%, P 〈 0.05）. The DNA methylation status of the SFRP2 correlated inversely with the SFRP2 expression. To assess the potential role of SFRP2 in ESCC, we established stable SFRP2 transfectants and control counterparts by in- troducing pcDNA3.1展开更多
Objective: To study the correlation of SFRP2 and TPX2 expression with cancer cell apoptosis and EMT process in cervical cancer. Methods: Patients with cervical cancer who received surgical resection in No.174 Hospital...Objective: To study the correlation of SFRP2 and TPX2 expression with cancer cell apoptosis and EMT process in cervical cancer. Methods: Patients with cervical cancer who received surgical resection in No.174 Hospital of PLA between June 2015 and December 2016 were selected as the research subjects, moderate amount of cervical cancer lesion and adjacent lesion were collected after surgical resection to extract RNA, and then fluorescent quantitative PCR kit was used to determine the expression of SFRP2, TPX2, apoptosis genes and EMT genes in lesion tissue. Results: SFRP2, SARI, AIF, FHIT, NDRG4, MCPH1 and E-cadherin mRNA expression in cervical cancer lesion were greatly lower than those in adjacent lesions whereas TPX2, SP2, CyclinD1, Piwil2, HERC4, EFEMP1, EZH2, TGF-β1, N-cadherin and Vimentin1 mRNA expression were greatly higher than those in adjacent lesions;SFRP2 mRNA expression in cervical cancer lesion was positively correlated with SARI, AIF, FHIT, NDRG4, MCPH1 and E-cadherin mRNA expression, and negatively correlated with SP2, CyclinD1, Piwil2, HERC4, EFEMP1, EZH2, TGF-β1, N-cadherin and Vimentin1 mRNA expression whereas TPX2 mRNA expression was negatively correlated with SARI, AIF, FHIT, NDRG4, MCPH1 and E-cadherin mRNA expression, and positively correlated with SP2, CyclinD1, Piwil2, HERC4, EFEMP1, EZH2, TGF-β1, N-cadherin and Vimentin1 mRNA expression. Conclusion: The lowly expressed SFRP2 and highly expressed TPX2 in cervical cancer lesions can inhibit the apoptosis of cancer cells and promote the EMT process of cancer cells.展开更多
基金Supported by the Special-purpose Scientific Research Foundation for University Doctorate Project of the Ministry of Education of China, No. 301090255
文摘AIM： To investigate the functions of promoter hypermethylation of secreted frizzled-related proteins （sFRPs） genes in colorectal tumorigenesis and progression. METHODS： The promoter hypermethylation and expression of sFRP genes in 72 sporadic colorectal carcinomas, 33 adenomas, 18 aberrant crypt foci （ACF） and colorectal cancer cell lines RKO, HCT116 and SW480 were detected by methylation-specific PCR and reverse transcription PCR, respectively. RESULTS： None of the normal colorectal mucosa tissues showed methylated bands of any of four sFRP genes, sFRP1, 2, 4 and 5 were frequently methylated in colorectal carcinoma, adenoma and ACF （sFRP1 〉 85%, sFRP2 〉75%, sFRP5 〉 50%）, and the differences between three colorectal tissues were not significant （P 〉 0.05）. IVlethylation in colorectal tumors was more frequent than in normal mucosa and adjacent normal mucosa. The mRNA of sFRP1-5 genes was expressed in all normal colorectal mucosa samples. Expression of sFRP1, 2, 4 and 5 and sFRP1, 2 and 5 was downregulated in carcinoma and adenoma, respectively. The downregulation of sFRP2, 4 and 5 was more frequent in carcinoma than in adenoma. Expression of sFRP3 which promoter has no CpG island was downregulated in only a few of colorectal tumor samples （7/105）. The downregulation ofsFRP1, 2, 4 and 5 expression was significantly associated with promoter hypermethylation in colorectal tumor. After cells were treated by DAC/TSA combination, the silenced sFRP mRNA expression could be effectively re-expressed in colorectal cancer cell lines. CONCLUSION： Hypermethylation of sFRP genes is a common early event in the evolution of colorectal tumor, occurring frequently in ACF, which is regarded as the earliest lesion of multistage colorectal carcinogenesis. It appears to functionally silence sFRP genes expression. Methylation of sFRP1, 2 and 5 genes might serve as indicators for colorectal tumor.
基金grant from Scientific and Technologic Bureau of Wuxi, No. CS055010
文摘AIM： To investigate the feasibility of detecting methylated fecal DNA as a screening tool for colorectal carcinoma （CRC） and precancerous lesions. METHODS： Methylated secreted frizzled-related protein gene 2 （SFRP2）, hyperplastic polyposis protein gene （HPP1） and O6-methylguanine-DNA methyltransferase gene （MGMT） in stools from 52 patients with CRC, 35 patients with benign colorectal diseases and 24 normal individuals were analyzed using methylation-specific PCR. RESULTS： Methylated SFRP2, HPP1 and MGMT were detected in 94.2%, 71.2%, 48.1% of CRC patients and 52.4%, 57.1%, 28.6% of adenoma patients, respectively. The overall prevalence of fecal DNA with at least one methylated gene was 96.2% and 81.8% in patients with CRC and precancerous lesions, respectively. In contrast, only one of the 24 normal individuals revealed methylated DNA. These results indicated a 93.7% sensitivity and a 77.1% specificity of the assay for detecting CRC and precancerous lesions. CONCLUSION： IVlethylation testing of fecal DNA using a panel of epigenetic markers may be a simple and promising non-invasive screening method for CRC and precancerous lesions.
文摘Wnts are a large family of growth factors that mediate essential biological processes like embryogenesis, morpho- genesis and organogenesis. These proteins also play a role in oncogenesis, and they regulate apoptosis in many tissues. Wnts bind to a membrane receptor complex comprised of a frizzled （FZD） G-protein-coupled receptor and a low-density lipoprotein （LDL） receptor-related protein （LRP）. The formation of this ligand-receptor complex initiates a number of signaling cascades that include the canonical/beta-catenin pathway as well as several noncanonical pathways. In recent years, canonical Wnt signaling has been reported to play a significant role in the control of bone formation. Clinical studies have found that mutations in LRP-5 are associated with reduced bone mineral density （BMD） and fractures. Investigations of knockout and transgenic mouse models of Wnt pathway components have shown that canonical Wnt signaling modulates most aspects ofosteoblast physiology including proliferation, differentiation, function and apoptosis. Transgenic mice expressing a gain of function mutant of LRP-5 in bone, or mice lacking the Wnt antagonist secreted frizzled-related protein-l, exhibit elevated BMD and suppressed osteoblast apoptosis. In addition, preclinical studies with pharmacologic compounds such as those that inhibit glycogen synthase kinase-3β support the importance of the canonical Wnt pathway in modulation of bone formation and osteoblast apoptosis.
基金Supported by The National Natural Science Foundation of China,No.81101868The Natural Science Foundation of Hubei Province of China,No.2011CDB505
文摘AIM: To investigate the feasibility of detecting aberrantly hypermethylated Wnt-antagonist gene promoters (SFRP2 and WIF-1) in fecal DNA as non-invasive biomarkers for early colorectal cancer (CRC).
基金Supported by Liaoning Education Divison Foundation, No.05L557
文摘AIM： To identify the methylation of secreted frizzled-related protein 1 （SFRP1） in gastric cancer and to investigate the aberrant expression of SFRP1 and its correlation with the clinical pathological features of patients. METHODS： We determined SFRP1 methylation and SFRP1 mRNA expression in 3 gastric cancer cell lines SGC-7901, BGC-823, HGC-27, from 52 primary gastric cancer specimens and matched tumor adjacent tissue specimens by methylation-specific （MSP） PCR and RT-PCR respectively. Fisher＇s exact test was used to analyze the statistical association between clinical pathological data and aberrant expression of SFRP1. RESULTS： In 3 cancer cell lines, BGC-823 and HGC-27 had methylated SFRP1 and lost SFRP1 mRNA expression. After treatment of BGC-823 and HGC-27 with the demethylating agent, 5-aza-2′-deoxycytidine, SFRP1 was re-expressed. In 52 primary gastric cancer specimens and matched tumor adjacent tissue specimens, hypermethylation of SFRP1 was detected in 23 （44%） and 8 （15%） specimens respectively （x^2= 10.34, P 〈 0.01）. Loss of SFRP1 expression was detected in 17（33%） and 6 （12%） specimens respectively （x^2= 6.75, P 〈 0.01）. There was a significant correlation between SFRP1 hypermethylation and SFRP1 expression loss. SFRP1 expression was also correlated significantly with tumor stage and lymph node status, but not with patient sex, age and histological type. CONCLUSION： SFRP1 inactivation is a common and early event caused mainly by hypermethylation in gastric cancer. SFRP1 expression loss may be correlated with tumor metastasis in primary gastric cancer.
文摘Many researches have focused on the wnt-frizzled cascade in the recent years, while much work has been done in neoplastic diseases and embryology, the role of the wnt-frizzled signal transduction pathway in cardiovascular diseases has only recently begun to be explored. It plays a very important role in many physiological and pathophysiological processes, such as its transduction pathway, the healing after myocardial infarction, the proliferation, differentiation and orientation of cardiomyocytes, angiogenesis/neovascularization, cardiac hypertrophy and heart failure, the deposition of the extracellular matrix and so on. This article is aimed at its relation with myocardial infarction and the role of this pathway in cardiovascular diseases.[
基金Supported by the National Research,Development and Innovation Office,No.KMR-12-1-2012-0216the Hungarian Scientific Research Fund,No.OTKA-K111743
文摘AIM To analyze colorectal carcinogenesis and age-related DNA methylation alterations of gene sequences associated with epigenetic clock CpG sites. METHODS In silico DNA methylation analysis of 353 epigenetic clock Cp G sites published by Steve Horvath was performed using methylation array data for a set of 123 colonic tissue samples [64 colorectal cancer(CRC), 42 adenoma, 17 normal; GEO accession number: GSE48684]. Among the differentially methylated agerelated genes, secreted frizzled related protein 1(SFRP1) promoter methylation was further investigated in colonic tissue from 8 healthy adults, 19 normal children, 20 adenoma and 8 CRC patients using bisulfite-specific PCR followed by methylation-specific high resolution melting(MS-HRM) analysis. m RNA expression of age-related "epigenetic clock" genes was studied using Affymetrix HGU133 Plus2.0 whole transcriptome data of 153 colonic biopsy samples(49 healthy adult, 49 adenoma, 49 CRC, 6 healthy children)(GEO accession numbers: GSE37364, GSE10714, GSE4183, GSE37267). Whole promoter methylation analysis of genes showing inverse DNA methylationgene expression data was performed on 30 colonic samples using methyl capture sequencing.RESULTS Fifty-seven age-related Cp G sites including hypermethylated PPP1R16 B, SFRP1, SYNE1 and hypomethylated MGP, PIPOX were differentially methylated between CRC and normal tissues(P < 0.05, ?β≥ 10%). In the adenoma vs normal comparison, 70 CpG sites differed significantly, including hypermethylated DKK3, SDC2, SFRP1, SYNE1 and hypomethylated CEMIP, SPATA18(P < 0.05, ?β≥ 10%). In MS-HRM analysis, the SFRP1 promoter region was significantly hypermethylated in CRC(55.0% ± 8.4 %) and adenoma tissue samples(49.9% ± 18.1%) compared to normal adult(5.2% ± 2.7%) and young(2.2% ± 0.7%) colonic tissue(P < 0.0001). DNA methylation of SFRP1 promoter was slightly, but significantly increased in healthy adults compared to normal young samples(P < 0.02). This correlated with significantly increased SFRP1 m RNA levels in children compared
基金Project supported by the National Key Research and Development Program of China(No.2016YFC1303100)the Science and Technology Commission of Shanghai Municipality(Nos.15441905700,15DZ1940502,and 12411950200)+1 种基金the Shanghai Municipal Commission of Health and Family Planning(No.2013ZYJB0202)the National Natural Science Foundation of China(Nos.81572548,81772770,81272882,and 81072137)
文摘Background:Bone marrow-derived mesenchymal stem cells(BM-MSCs)play an important role in cancer development and progression.However,the mechanism by which they enhance the chemoresistance of ovarian cancer is unknown.Methods:Conditioned media of BM-MSCs(BM-MSC-CM)were analyzed using a technique based on microRNA arrays.The most highly expressed microRNAs were selected for testing their effects on glycolysis and chemoresistance in SKOV3 and COC1 ovarian cancer cells.The targeted gene and related signaling pathway were investigated using in silico analysis and in vitro cancer cell models.Kaplan-Merier survival analysis was performed on a population of 59 patients enrolled to analyze the clinical significance of microRNA findings in the prognosis of ovarian cancer.Results:MiR-1180 was the most abundant microRNA detected in BM-MSC-CM,which simultaneously induces glycolysis and chemoresistance(against cisplatin)in ovarian cancer cells.The secreted frizzled-related protein 1(SFRP1)gene was identified as a major target of miR-1180.The overexpression of miR-1180 led to the activation of Wnt signaling and its downstream components,namely Wnt5 a,β-catenin,c-Myc,and CyclinD1,which are responsible for glycolysis-induced chemoresistance.The miR-1180 level was inversely correlated with SFRP1 mRNA expression in ovarian cancer tissue.The overexpressed mi R-1180 was associated with a poor prognosis for the long-term(96-month)survival of ovarian cancer patients.Conclusions:BM-MSCs enhance the chemoresistance of ovarian cancer by releasing miR-1180.The released miR-1180 activates the Wnt signaling pathway in cancer cells by targeting SFRP1.The enhanced Wnt signaling upregulates the glycolytic level(i.e.Warburg effect),which reinforces the chemoresistance property of ovarian cancer cells.
基金supported by the Natural Science Research Project of colleges and Universities in Anhui Province[2022AH052336]High Level Talent Research Initiation Fund Of Anhui Medical College[2023RC004]。
文摘Objective Microcystin-leucine-arginine(MC-LR)exposure induces lipid metabolism disorders in the liver.Secreted frizzled-related protein 5(SFRP5)is a natural antagonist of winglesstype MMTV integration site family,member 5A(Wnt5a)and an anti-inflammatory adipocytokine.In this study,we aimed to investigate whether MC-LR can induce lipid metabolism disorders in hepatocytes and whether SFRP5,which has anti-inflammatory effects,can alleviate the effects of hepatic lipid metabolism by inhibiting the Wnt5a/Jun N-terminal kinase(JNK)pathway.Methods We exposed mice to MC-LR in vivo to induce liver lipid metabolism disorders.Subsequently,mouse hepatocytes that overexpressed SFRP5 or did not express SFRP5 were exposed to MC-LR,and the effects of SFRP5 overexpression on inflammation and Wnt5a/JNK activation by MC-LR were observed.Results MC-LR exposure induced liver lipid metabolism disorders in mice and significantly decreased SFRP5 mRNA and protein levels in a concentration-dependent manner.SFRP5 overexpression in AML12cells suppressed MC-LR-induced inflammation.Overexpression of SFRP5 also inhibited Wnt5a and phosphorylation of JNK.Conclusion MC-LR can induce lipid metabolism disorders in mice,and SFRP5 can attenuate lipid metabolism disorders in the mouse liver by inhibiting Wnt5a/JNK signaling.
基金Youth Science and Technology Fund of Affiliated Hospital of Hebei University(Project number:2017Q024)Baoding City Science and Technology Plan Projects(Project number:2041ZF295)Hebei University Medical Subject Cultivation Project(Project number:2022B03)。
文摘Objective:To investigate the correlation between serum secretory frizzled-related protein 5(SFRP-5)expression levels and insulin resistance and glucolipid metabolism in patients with gestational diabetes mellitus(GDM).Methods:Baseline data were collected from 58 patients with GDM and 51 healthy controls who were admitted Affiliated Hospital of Hebei University from May 2020 to June 2022.sSTRA5 concentrations in peripheral blood of pregnant women were measured,and SFRP-5 levels in patients with different GDM types and normal controls were analyzed by logistic regression models.Results:The levels of triglyceride(TG),total cholesterol(TC),low-density lipoprotein cholesterol(LDL-C),fasting blood glucose(FBG),fasting insulin(FINS),hemoglobin A1c(HbA1c),and homeostasis model assessment-estimated insulin resistance(HOMA-IR)were higher in the observation group than in the control group,with statistically significant differences(P<0.05),while the expression levels of high-density lipoprotein cholesterol(HDL-C)and serum SFRP-5 were lower than in the control group,with statistically significant differences(P<0.05);serum SFRP-5,TG,TC,FBG,and HOMA-IR were all risk factors for GDM(P<0.05).Conclusion:Elevated serum sSTRA5 may be involved in the regulation of insulin resistance in the body and the regulation of blood glucose in the body by affecting lipid metabolism and inflammatory response.
文摘Background:Hirschsprung's disease (HSCR) is a congenital gut motility disorder of infants,and if left untreated,it is fatal to the affected infants.This study aimed to identify key microRNAs (miRNAs),signaling pathways and genes involved in the pathogenesis of HSCR.Methods:The miRNA microarray dataset GSE77296 was downloaded.Nine colon tissue samples were available:six from HSCR patients and three matched control samples.Differentially expressed miRNAs (DEMs) were identified after data preprocessing.Target genes of the selected upregulated and downregulated DEMs were predicted.In addition,functional enrichment analyses for the selected DEMs and target genes were conducted.Finally,interaction networks between the DEMs and target genes were constructed.Results:A total of 162 DEMs (73 upregulated and 89 downregulated) were obtained.A total of 2511 DEM-target gene pairs for the 40 selected DEMs were identified,including 1645 pairs for the upregulated DEMs and 866 pairs for the downregulated DEMs.The upregulated DEM miR-141-3p and down-regulated DEM miR-30a-3p were identified as key miRNAs by Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment and network analyses.Besides,KEGG pathway enrichment analysis revealed that pathways in cancer and the mitogen-activated protein kinase (MAPK) signaling pathway were key pathways.The key genes frizzled class receptor 3 (FZD3) and docking protein 6 (DOK6) were obtained through the DEM-target gene interaction networks.Conclusion:Two key miRNAs (miR-141-3p and miR-30a-3p),the MAPK signaling pathway and two key genes (FZD3 and DOK6) were implicated in the pathogenesis of HSCR.
基金Supported by National Natural Science Foundation of China,No. 81050016Research Fund for the Doctoral Program of Higher Education of China,No. 200800250003
文摘AIM： To investigate the expression and methylation status of the secreted frizzled-related protein 2 （SFRP2） in esophageal squamous cell carcinoma （ESCC） and ex- plore its role in ESCC carcinogenesis.METHODS： Seven ESCC cell lines （KYSE 30, KYSE150, KYSE410, KYSE510, EC109, EC9706 and TE-1） and one immortalized human esophageal epithelial cell line （Het- 1A）, 20 ESCC tissue samples and 20 paired adjacent non-tumor esophageal epithelial tissues were analyzed in this study. Reverse-transcription polymerase chain reaction （RT-PCR） was employed to investigate the expression of SFRP2 in cell lines, primary ESCC tumor tissue, and paired adjacent normal tissue. Methylation status was evaluated by methylation-specific PCR and bisulfite sequencing. The correlation between expres- sion and promoter methylation of the SFRP2 gene was confirmed with treatment of 5-aza-2＇-deoxycytidine. To assess the potential role of SFRP2 in ESCC, we es-tablished stable SFRP2-transfected cells and examined them with regard to cell proliferation, colony formation, apoptosis and cell cycle in vivo and in vitro.RESULTS： SFRP2 mRNA was expressed in the im- mortalized normal esophageal epithelial cell line but not in seven ESCC cell lines. By methylation-specific PCR, complete methylation was detected in three cell lines with silenced SFRP2 expression, and extensive methylation was observed in the other four ESCC cell lines. 5-aza-2＇-deoxycytidine could restore the expres- sion of SFRP2 mRNA in the three ESCC cell lines lack- ing SFRP2 expression. SFRP2 mRNA expression was obviously lower in primary ESCC tissue than in adjacent normal tissue （0.939 ± 0.398 vs 1.51 ± 0.399, P 〈 0.01）. SFRP2 methylation was higher in tumor tissue than in paired normal tissue （95% vs 65%, P 〈 0.05）. The DNA methylation status of the SFRP2 correlated inversely with the SFRP2 expression. To assess the potential role of SFRP2 in ESCC, we established stable SFRP2 transfectants and control counterparts by in- troducing pcDNA3.1
文摘Objective: To study the correlation of SFRP2 and TPX2 expression with cancer cell apoptosis and EMT process in cervical cancer. Methods: Patients with cervical cancer who received surgical resection in No.174 Hospital of PLA between June 2015 and December 2016 were selected as the research subjects, moderate amount of cervical cancer lesion and adjacent lesion were collected after surgical resection to extract RNA, and then fluorescent quantitative PCR kit was used to determine the expression of SFRP2, TPX2, apoptosis genes and EMT genes in lesion tissue. Results: SFRP2, SARI, AIF, FHIT, NDRG4, MCPH1 and E-cadherin mRNA expression in cervical cancer lesion were greatly lower than those in adjacent lesions whereas TPX2, SP2, CyclinD1, Piwil2, HERC4, EFEMP1, EZH2, TGF-β1, N-cadherin and Vimentin1 mRNA expression were greatly higher than those in adjacent lesions;SFRP2 mRNA expression in cervical cancer lesion was positively correlated with SARI, AIF, FHIT, NDRG4, MCPH1 and E-cadherin mRNA expression, and negatively correlated with SP2, CyclinD1, Piwil2, HERC4, EFEMP1, EZH2, TGF-β1, N-cadherin and Vimentin1 mRNA expression whereas TPX2 mRNA expression was negatively correlated with SARI, AIF, FHIT, NDRG4, MCPH1 and E-cadherin mRNA expression, and positively correlated with SP2, CyclinD1, Piwil2, HERC4, EFEMP1, EZH2, TGF-β1, N-cadherin and Vimentin1 mRNA expression. Conclusion: The lowly expressed SFRP2 and highly expressed TPX2 in cervical cancer lesions can inhibit the apoptosis of cancer cells and promote the EMT process of cancer cells.
