Background： Increased level of serum macrophage inhibitory cytokine- 1 （MIC- 1 ）, a member oftransfonning growth thctor-β superfamily, was found in patients with epithelial tumors. This study aimed to evaluate whe...Background： Increased level of serum macrophage inhibitory cytokine- 1 （MIC- 1 ）, a member oftransfonning growth thctor-β superfamily, was found in patients with epithelial tumors. This study aimed to evaluate whether serum level of MIC-I can be a candidate diagnostic and prognostic indicator for early-stage nonsmall cell lung cancer （NSCLC）. Methods： A prospective study enrolled 152 patients with Stage I-II NSCLC, who were followed up after surgical resection. Forty-eight patients with benign pulmonary disease （BPD） and 105 healthy controls were also included in the study. Serum M IC- 1 levels were measured using an enzyme-linked immunosorbent assay, and the association with clinical and prognostic features was analyzed. Results： In patients with NSCLC, serum protein levels of M IC-I were significantly increased compared with healthy controls and BPD patients （all P 〈 0.001 ）. A threshold of 1000 pg/ml ofM IC-1 was found in patients with early-stage （Stage 1 and II） NSCLC, with sensitivity and specificity of 70.4% and 99.0%, respectively. The serum levels ofMIC- ] were associated with age （P = 0.001 ）, gender （P = 0.030）, and T stage （P = 0.022）. Serum MIC-1 threshold of 1465 pg/ml was found in patients with poor early outcome, with sensitivity and specificity of 72.2% and 66.1%, respectively. The overall 3-year survival rate of NSCLC patients with high serum levels of MIC-1 （〉I 465 pg/ml） was lower than that of NSCLC patients with low serum MIC-1 levels （77.6% vs. 94.8%）. Multivariate Cox regression survival analysis showed that a high serum level ofMIC- 1 was an independent risk factor lbr reduced overall survival （hazard ratio - 3.37, 95% confidential interval： 1.09-10.42, P = 0.035）. Conclusion： The present study suggested that serum M1C-I may be a potential diagnostic and prognostic biomarker ~cbr patients with early-stage NSCLC.展开更多
Background:Recent studies have indicated that a high-fat diet(HFD)and/or HFD-induced obesity may influence prostate cancer(PCa)progression,but the role of HFD in PCa microenvironment is unclear.This study aimed to del...Background:Recent studies have indicated that a high-fat diet(HFD)and/or HFD-induced obesity may influence prostate cancer(PCa)progression,but the role of HFD in PCa microenvironment is unclear.This study aimed to delineate the molecular mechanisms of PCa progression underHFDmilieus and define the stromal microenvironment focusing on macrophage inhibitory cytokine-1(MIC-1)activation.Methods:We investigated the effects of HFD on PCa stromal microenvironment and MIC-1 signaling activation using PC-3M-luc-C6 PCa model mice fed with HFD or control diet.Further,we explored the effect of periprostatic adipocytes derived from primary PCa patients on activation and cytokine secretion of prostate stromal fibroblasts.Expression patterns and roles of MIC-1 signaling on human PCa stroma activation and progression were also investigated.Results:HFD stimulated PCa cell growth and invasion as a result of upregulated MIC-1 signaling and subsequently increased the secretion of interleukin(IL)-8 and IL-6 from prostate stromal fibroblasts in PC-3M-luc-C6 PCa mousemodel.In addition,periprostatic adipocytes directly stimulatedMIC-1 production from PC-3 cells and IL-8 secretion in prostate stromal fibroblasts through the upregulation of adipose lipolysis and free fatty acid release.The increased serum MIC-1 was significantly correlated with human PCa stroma activation,high serum IL-8,IL-6,and lipase activity,advanced PCa progression,and high body mass index of the patients.Glial-derived neurotrophic factor receptor α-like(GFRAL),a specific receptor of MIC-1,was highly expressed in both cytoplasm and membrane of PCa cells and surrounding stromal fibroblasts,and the expression levelwas decreased by androgen deprivation therapy and chemotherapy.Conclusion:HFD-mediated activation of the PCa stromal microenvironment through metabolically upregulated MIC-1 signaling by increased available free fatty acids may be a critical mechanism of HFD and/or obesity-induced PCa progression.展开更多
BACKGROUND The expression of macrophage inhibitory factor-1(MIC-1) is increased in peripheral blood of patients with chronic hepatitis and liver cirrhosis. However, whether MIC-1 gene polymorphism is correlated with r...BACKGROUND The expression of macrophage inhibitory factor-1(MIC-1) is increased in peripheral blood of patients with chronic hepatitis and liver cirrhosis. However, whether MIC-1 gene polymorphism is correlated with relevant diseases is not yet reported.AIM To explore the correlation between gene polymorphism in MIC-1 exon region and chronic hepatitis C virus(HCV) infection.METHODS This case-control study enrolled 178 patients with chronic hepatitis C(CHC) in the case group, and 82 healthy subjects from the same region who had passed the screening examination comprised the control group. The genotypes of rs1059369 and rs1059519 loci in the MIC-1 gene exon were detected by DNA sequencing. Also, the MIC-1 level, liver function metrics, liver fibrosis metrics, and HCV RNA load were determined. Univariate analysis was used to compare the differences and correlations between the two groups with respect to these parameters. Multivariate logistic regression was used to analyze the independent relevant factors of CHC.RESULTS The plasma MIC-1 level in the CHC group was higher than that in the control group(P < 0.05), and it was significantly positively correlated with alanine aminotransferase, aspartate aminotransferase(AST), type III procollagen N-terminal peptide(known as PIIINP), type IV collagen, and HCV RNA(P < 0.05), whereas negatively correlated with total protein and albumin(P < 0.05). The genotype and allele frequency distribution at the rs1059519 locus differed between the two groups(P < 0.05). The allele frequency maintained significant difference after Bonferroni correction(Pc < 0.05). Logistic multiple regression showed that AST, PIIINP, MIC-1, and genotype GG at the rs1059519 locus were independent relevant factors of CHC(P < 0.05). Linkage disequilibrium(LD) was found between rs1059369 and rs1059519 loci, and significant difference was detected in the distribution of haplotype A-C between the CHC and control groups(P < 0.05). Meanwhile, we found the MIC-1 level trend to increase among rs1059519 genotypes(P = 0.006) and the level of MIC-1 in GG genotype to be significantly higher than CC genotype(P = 0.009, after Bonferroni correction).CONCLUSION Plasma MIC-1 level was increased in CHC patients and correlated with liver cell damage, liver fibrosis metrics, and viral load. The polymorphism at the MIC-1 gene rs1059519 locus was correlated with HCV infection, and associated with the plasma MIC-1 level. G allele and GG genotype may be an important susceptible factor for CHC.展开更多
AIM:To investigate the effects of macrophage migration inhibitory factor (MIF) on proliferation of human gastric cancer MGC-803 cells and expression of cyclin D1 and p27Kip1 in them,and further determine whether the e...AIM:To investigate the effects of macrophage migration inhibitory factor (MIF) on proliferation of human gastric cancer MGC-803 cells and expression of cyclin D1 and p27Kip1 in them,and further determine whether the effects are related to the PI3K/Akt signal transduction pathway. METHODS:Gastric cancer MGC-803 cells were cultured and then treated with 50 μg/L recombinant human MIF (rhMIF) with and without a PI3K inhibitor,LY294002 (25 μmol/L). MTT assay was used to detect the prolifer-ation of MGC-803 cells. Cell cycle was detected by flow cytometry. Expression of cyclin D1 and p27Kip1 mRNA was by reverse transcription-polymerase chain reaction. Protein expression of phosphorylated Akt (p-Akt),Akt,cyclin D1 and p27Kip1 was examined by immunocyto-chemistry and Western blotting. RESULTS:rhMIF signifi cantly stimulated the prolifera-tion of MGC-803 cells and cell cycle progression from G1 phase to S phase in a concentration-and time-de-pendent manner. After the MGC-803 cells were treated with rhMIF for 24 h,the expression of cyclin D1 was signifi cantly up-regulated compared with the cells not treated with rhMIF at both mRNA and protein levels(0.97 ± 0.02 vs 0.74 ± 0.01,P = 0.002; 0.98 ± 0.05 vs 0.69 ± 0.04,P = 0.003). The p27Kip1 was down-regulated but only statistically significant at the protein level. rhMIF significantly increased the expression of p-Akt,which reached the peak at 30 min,but did not affect the expression of Akt. However,LY294002 inhibited all the effects of rhMIF.CONCLUSION:Macrophage MIF increases the proliferation of gastric cancer cells,induces the expression of cyclin D1 at the transcriptional level and inhibits the expression of p27Kip1 at the post-transcriptional level via the PI3K/Akt pathway.展开更多
基金grants from the National Natural Science Foundation of China，National High-tech R&D Program (863Program)，Capital Characteristic clinic projects
文摘Background： Increased level of serum macrophage inhibitory cytokine- 1 （MIC- 1 ）, a member oftransfonning growth thctor-β superfamily, was found in patients with epithelial tumors. This study aimed to evaluate whether serum level of MIC-I can be a candidate diagnostic and prognostic indicator for early-stage nonsmall cell lung cancer （NSCLC）. Methods： A prospective study enrolled 152 patients with Stage I-II NSCLC, who were followed up after surgical resection. Forty-eight patients with benign pulmonary disease （BPD） and 105 healthy controls were also included in the study. Serum M IC- 1 levels were measured using an enzyme-linked immunosorbent assay, and the association with clinical and prognostic features was analyzed. Results： In patients with NSCLC, serum protein levels of M IC-I were significantly increased compared with healthy controls and BPD patients （all P 〈 0.001 ）. A threshold of 1000 pg/ml ofM IC-1 was found in patients with early-stage （Stage 1 and II） NSCLC, with sensitivity and specificity of 70.4% and 99.0%, respectively. The serum levels ofMIC- ] were associated with age （P = 0.001 ）, gender （P = 0.030）, and T stage （P = 0.022）. Serum MIC-1 threshold of 1465 pg/ml was found in patients with poor early outcome, with sensitivity and specificity of 72.2% and 66.1%, respectively. The overall 3-year survival rate of NSCLC patients with high serum levels of MIC-1 （〉I 465 pg/ml） was lower than that of NSCLC patients with low serum MIC-1 levels （77.6% vs. 94.8%）. Multivariate Cox regression survival analysis showed that a high serum level ofMIC- 1 was an independent risk factor lbr reduced overall survival （hazard ratio - 3.37, 95% confidential interval： 1.09-10.42, P = 0.035）. Conclusion： The present study suggested that serum M1C-I may be a potential diagnostic and prognostic biomarker ~cbr patients with early-stage NSCLC.
基金This work was supported by the Japan Society for the Pro-motion of Science(JSPS,Grant No.:16H02679,16K10992,19K09663)AMED-CREST,Japan Agency for Medical Research and Development(AMED).
文摘Background:Recent studies have indicated that a high-fat diet(HFD)and/or HFD-induced obesity may influence prostate cancer(PCa)progression,but the role of HFD in PCa microenvironment is unclear.This study aimed to delineate the molecular mechanisms of PCa progression underHFDmilieus and define the stromal microenvironment focusing on macrophage inhibitory cytokine-1(MIC-1)activation.Methods:We investigated the effects of HFD on PCa stromal microenvironment and MIC-1 signaling activation using PC-3M-luc-C6 PCa model mice fed with HFD or control diet.Further,we explored the effect of periprostatic adipocytes derived from primary PCa patients on activation and cytokine secretion of prostate stromal fibroblasts.Expression patterns and roles of MIC-1 signaling on human PCa stroma activation and progression were also investigated.Results:HFD stimulated PCa cell growth and invasion as a result of upregulated MIC-1 signaling and subsequently increased the secretion of interleukin(IL)-8 and IL-6 from prostate stromal fibroblasts in PC-3M-luc-C6 PCa mousemodel.In addition,periprostatic adipocytes directly stimulatedMIC-1 production from PC-3 cells and IL-8 secretion in prostate stromal fibroblasts through the upregulation of adipose lipolysis and free fatty acid release.The increased serum MIC-1 was significantly correlated with human PCa stroma activation,high serum IL-8,IL-6,and lipase activity,advanced PCa progression,and high body mass index of the patients.Glial-derived neurotrophic factor receptor α-like(GFRAL),a specific receptor of MIC-1,was highly expressed in both cytoplasm and membrane of PCa cells and surrounding stromal fibroblasts,and the expression levelwas decreased by androgen deprivation therapy and chemotherapy.Conclusion:HFD-mediated activation of the PCa stromal microenvironment through metabolically upregulated MIC-1 signaling by increased available free fatty acids may be a critical mechanism of HFD and/or obesity-induced PCa progression.
基金Supported by the Medical and Health Research Science and Technology Plan Project of Zhejiang Province,No. 2016KYB191。
文摘BACKGROUND The expression of macrophage inhibitory factor-1(MIC-1) is increased in peripheral blood of patients with chronic hepatitis and liver cirrhosis. However, whether MIC-1 gene polymorphism is correlated with relevant diseases is not yet reported.AIM To explore the correlation between gene polymorphism in MIC-1 exon region and chronic hepatitis C virus(HCV) infection.METHODS This case-control study enrolled 178 patients with chronic hepatitis C(CHC) in the case group, and 82 healthy subjects from the same region who had passed the screening examination comprised the control group. The genotypes of rs1059369 and rs1059519 loci in the MIC-1 gene exon were detected by DNA sequencing. Also, the MIC-1 level, liver function metrics, liver fibrosis metrics, and HCV RNA load were determined. Univariate analysis was used to compare the differences and correlations between the two groups with respect to these parameters. Multivariate logistic regression was used to analyze the independent relevant factors of CHC.RESULTS The plasma MIC-1 level in the CHC group was higher than that in the control group(P < 0.05), and it was significantly positively correlated with alanine aminotransferase, aspartate aminotransferase(AST), type III procollagen N-terminal peptide(known as PIIINP), type IV collagen, and HCV RNA(P < 0.05), whereas negatively correlated with total protein and albumin(P < 0.05). The genotype and allele frequency distribution at the rs1059519 locus differed between the two groups(P < 0.05). The allele frequency maintained significant difference after Bonferroni correction(Pc < 0.05). Logistic multiple regression showed that AST, PIIINP, MIC-1, and genotype GG at the rs1059519 locus were independent relevant factors of CHC(P < 0.05). Linkage disequilibrium(LD) was found between rs1059369 and rs1059519 loci, and significant difference was detected in the distribution of haplotype A-C between the CHC and control groups(P < 0.05). Meanwhile, we found the MIC-1 level trend to increase among rs1059519 genotypes(P = 0.006) and the level of MIC-1 in GG genotype to be significantly higher than CC genotype(P = 0.009, after Bonferroni correction).CONCLUSION Plasma MIC-1 level was increased in CHC patients and correlated with liver cell damage, liver fibrosis metrics, and viral load. The polymorphism at the MIC-1 gene rs1059519 locus was correlated with HCV infection, and associated with the plasma MIC-1 level. G allele and GG genotype may be an important susceptible factor for CHC.
基金Supported by Grant from Hunan Provincial Science and Technology Department (2008 FJ 3088), China
文摘AIM:To investigate the effects of macrophage migration inhibitory factor (MIF) on proliferation of human gastric cancer MGC-803 cells and expression of cyclin D1 and p27Kip1 in them,and further determine whether the effects are related to the PI3K/Akt signal transduction pathway. METHODS:Gastric cancer MGC-803 cells were cultured and then treated with 50 μg/L recombinant human MIF (rhMIF) with and without a PI3K inhibitor,LY294002 (25 μmol/L). MTT assay was used to detect the prolifer-ation of MGC-803 cells. Cell cycle was detected by flow cytometry. Expression of cyclin D1 and p27Kip1 mRNA was by reverse transcription-polymerase chain reaction. Protein expression of phosphorylated Akt (p-Akt),Akt,cyclin D1 and p27Kip1 was examined by immunocyto-chemistry and Western blotting. RESULTS:rhMIF signifi cantly stimulated the prolifera-tion of MGC-803 cells and cell cycle progression from G1 phase to S phase in a concentration-and time-de-pendent manner. After the MGC-803 cells were treated with rhMIF for 24 h,the expression of cyclin D1 was signifi cantly up-regulated compared with the cells not treated with rhMIF at both mRNA and protein levels(0.97 ± 0.02 vs 0.74 ± 0.01,P = 0.002; 0.98 ± 0.05 vs 0.69 ± 0.04,P = 0.003). The p27Kip1 was down-regulated but only statistically significant at the protein level. rhMIF significantly increased the expression of p-Akt,which reached the peak at 30 min,but did not affect the expression of Akt. However,LY294002 inhibited all the effects of rhMIF.CONCLUSION:Macrophage MIF increases the proliferation of gastric cancer cells,induces the expression of cyclin D1 at the transcriptional level and inhibits the expression of p27Kip1 at the post-transcriptional level via the PI3K/Akt pathway.
