RESUMO
Gastric cancer is the fourth most common malignancy world-wide that bears a high mortality by invasiveness and metastases. To this end, we examined the role of miR-1 in mobility and migration of gastric cancer cells. miR-1 was down-regulated and Sorcin, which supports invasion, was highly expressed in gastric cancer cell lines as compared to the control. The overexpression of miR-1 significantly inhibited the mobility and migration of gastric cancer cells, while, its knockdown exerted an oppoiste effect. In addition, while overexpression of miR-1 suppressed the expression of Sorcin, the siRNA knockdown of Sorcin significantly counteracted the effect of miR-1 inhibitor on cell invasion and migration of gastric cancer cells. A miR-1 mimic decreased while its inhibitor increased the MMP-7 and VEGF required for invasion. Taken together, the findings support the view that miR-1 controls the mobility and migration of gastric cancer cells and might be a therapeutic target for blocking gastric cancer invasion.
Assuntos
Proteínas de Ligação ao Cálcio/genética , Movimento Celular/genética , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , Neoplasias Gástricas/genética , Regiões 3' não Traduzidas/genética , Sequência de Bases , Proteínas de Ligação ao Cálcio/metabolismo , Linhagem Celular , Linhagem Celular Tumoral , Humanos , Metaloproteinase 7 da Matriz/genética , Metaloproteinase 7 da Matriz/metabolismo , Invasividade Neoplásica , Interferência de RNA , Homologia de Sequência do Ácido Nucleico , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
PURPOSE: The influence of X-inactive specific transcript (XIST) and X-chromosome inactivation associated long non-coding RNAs (lncRNAs) just proximal to XIST (JPX) on hepatocellular carcinoma (HCC) remains controversial in light of previous reports, which the present study aimed to verify. MATERIALS AND METHODS: The DIANA lncRNA-microRNA (miRNA) interaction database was used to explore miRNA interactions with JPX or XIST. JPX, XIST, and miR-155-5p expression levels in paired HCC specimens and adjacent normal tissue were analyzed by RT-qPCR. Interaction between XIST and miR-155-5p was verified by dual luciferase reporter assay. Expression levels of miR-155-5p and its known target genes, SOX6 and PTEN, were verified by RT-qPCR and Western blot in HepG2 cells with or without XIST knock-in. The potential suppressive role of XIST and JPX on HCC was verified by cell functional assays and tumor formation assay using a xenograft model. RESULTS: JPX and XIST expression was significantly decreased in HCC pathologic specimens, compared to adjacent tissue, which correlated with HCC progression and increased miR-155-5p expression. Dual luciferase reporter assay revealed XIST as a direct target of miR-155-5p. XIST knock-in significantly reduced miR-155-5p expression level and increased that of SOX6 and PTEN, while significantly inhibiting HepG2 cell growth in vitro, which was partially reversed by miR-155-5p mimic transfection. JPX knock-in significantly increased XIST expression and inhibited HepG2 cell growth in vitro or tumor formation in vivo in a XIST dependent manner. CONCLUSION: JPX and XIST play a suppressive role in HCC. JPX increases expression levels of XIST in HCC cells, which suppresses HCC development by sponging the cancer promoting miR-155-5p.
Assuntos
Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , MicroRNAs/genética , PTEN Fosfo-Hidrolase/genética , RNA Longo não Codificante/metabolismo , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica/genética , Células Hep G2 , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , MicroRNAs/metabolismo , PTEN Fosfo-Hidrolase/metabolismoRESUMO
The mechanism underlying the metastasis of gastric cancer (GC) cells remains elusive. REG3A is considered an oncogene in various cancers, but in GC its role is unclear. Here, we report that the expression of REG3A was significantly increased in the tumor tissues of patients with GC compared with the matched normal tissues. Knockdown of REG3A induced by specific small interfering RNA (siRNA) significantly repressed the proliferation of GC cells for 24 h or 48 h. Moreover, knockdown of REG3A significantly suppressed the migration, invasion, and adhesion of GC cells in vitro. Furthermore, knockdown of REG3A reduced the phosphorylation of JAK2 and STAT3, and altered the messenger RNA (mRNA) and protein expression levels of E-cadherin, Snail, RhoC, MTA1, MMP-2, and MMP-9. Taken together, REG3A is overexpressed in GC and promotes the proliferation, migration, invasion, and adhesion of GC cells by regulating the JAK2/STAT3 signal pathway. REG3A may be a potential therapeutic target for GC.
RESUMO
There is now growing evidence suggesting that Vitamin D is playing a critical role in modulating the innate and adaptive immune responses. Several polymorphisms have been identified in the vitamin D receptor (VDR) gene but their association with ulcerative colitis (UC) susceptibility remained controversy. In the current study, we examined the association between VDR polymorphisms and serum level of 25-hydroxyvitamin D [25(OH)D] with UC in Chinese Han population. Polymorphisms of FokI (rs2228570)/BsmI (rs1544410)/ApaI (rs7975232)/TaqI (rs731236) in the VDR gene were assessed in a case-control study comprising 404 UC patients and 612 controls. Moreover, 25(OH)D levels were measured by electro-chemiluminescence immunoassay in 75 UC patients and 120 controls. Our results suggested that BsmI polymorphism frequency was significantly lower in UC patients (P=0.028), and the frequency of AAC haplotype formed by BsmI, ApaI and TaqI was also significantly lower in UC patients (P=0.012). Moreover, FokI polymorphism was more frequently observed in patients with mild and moderate UC as compared to those with severe UC (P=0.001, P<0.001, respectively). Average 25(OH)D level was lower in UC patients than in controls (19.3±6.8 vs. 21.8±7.3ng/mL, P=0.017), and was significantly correlated with hemoglobin (ß=0.49, P<0.001), C-reactive protein (ß=-0.36, P<0.001), severity of UC (ß=-0.21, P=0.025) and FokI polymorphism (ß=-0.20, P=0.031) in UC patients. Interestingly, there was a significant correlation between FokI polymorphism and vitamin D deficiency (<20ng/mL) in UC patients (P=0.006). Together, these results supported that VDR polymorphisms and 25(OH)D level were significantly correlated with UC risk and severity in Chinese Han population.
Assuntos
Colite Ulcerativa/genética , Polimorfismo de Nucleotídeo Único/genética , Receptores de Calcitriol/genética , Vitamina D/análogos & derivados , Adulto , Alelos , Povo Asiático/estatística & dados numéricos , Estudos de Casos e Controles , China/epidemiologia , Colite Ulcerativa/etnologia , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Vitamina D/sangue , Vitamina D/genéticaRESUMO
BACKGROUND AND AIM: The vitamin D receptor (VDR) regulates immune responses and inflammation through binding with 1,25-dihydroxyvitamin D, the active form of vitamin D. The serum 25-hydroxyvitamin D (25(OH)D) level clinically reflects vitamin D status in the human body. We investigated the association of VDR polymorphisms and 25(OH)D levels in Chinese patients with Crohn's disease (CD). METHODS: Vitamin D receptor polymorphisms (FokI, BsmI, ApaI, and TaqI) were genotyped by SNaPshot. Serum 25(OH)D levels were measured by electro-chemiluminescence immunoassay. RESULTS: A total of 297 patients with CD and 446 controls were recruited. Compared with controls, mutant alleles and genotypes of BsmI and TaqI were less prevalent in patients with CD (all P < 0.05/4 = 0.0125). The AAC haplotype formed by BsmI, ApaI, and TaqI was also less prevalent in patients with CD (P = 0.004). Furthermore, 124 patients and 188 controls were randomly selected for measurements of 25(OH)D levels. Average 25(OH)D level was lower in patients with CD than in controls (15.46 ± 8.11 vs 21.64 ± 9.45 ng/mL, P < 0.001) and negatively linked to CD activity index (ß = -0.829, P < 0.001), platelet count (ß = -0.253, P < 0.001) and neutrophil percentage (ß = -0.136, P = 0.005) in patients with CD. The ApaI mutant genotype and vitamin D deficiency (<20 ng/mL) were independently associated with CD (P = 0.009, P < 0.001, respectively). In patients with CD, vitamin D deficiency interacted with FokI, ApaI, and TaqI mutant genotypes (P = 0.027, P = 0.024, and P = 0.040, respectively). CONCLUSIONS: Vitamin D receptor (BsmI, ApaI, and TaqI) mutations and lower 25(OH)D levels are associated with CD in Chinese patients. Moreover, VDR (FokI, ApaI, and TaqI) mutations and vitamin D deficiency may have a combined impact on CD.
Assuntos
Povo Asiático/genética , Doença de Crohn/sangue , Doença de Crohn/genética , Estudos de Associação Genética , Polimorfismo Genético , Receptores de Calcitriol/genética , Vitamina D/análogos & derivados , Adulto , Doença de Crohn/etiologia , Feminino , Humanos , Masculino , Mutação , Vitamina D/sangue , Deficiência de Vitamina D/complicações , Adulto JovemRESUMO
CD4+CD25+regulatory T cells (Tregs) play a key role in regulation of immnue response and maintenance of self-tolerance. Studies have found Tregs could suppress tumor-specific T cell-mediated immune response and promote cancer progression. Depletion of Tregs can enhance antitumor immunity. Dendritic cells (DCs) are professional antigen-presenting cells and capable of activating antigen-specific immune responses, which make them ideal candidate for cancer immunotherapy. Now various DC vaccines are considered as effective treatment for cancers. The aim of this study was to evaluate variation of Tregs in BALB/C mice with hepatocellular carcinoma and investigate the interaction between tumor-derived Tregs, effector T cells (Teff) and splenic DCs. We found the percentages of Tregs/CD4+ in the peripheral blood of tumor-bearing mice were higher than in normal mice. Tumor-derived Tregs diminished the up-regulation of costimulatory molecule expression on splenic DCs, even in the presence of Teff cells and simultaneously inhibited IL-12 and TNF-α secretion by DCs.
Assuntos
Apresentação de Antígeno/imunologia , Carcinoma Hepatocelular/patologia , Células Dendríticas/imunologia , Neoplasias Hepáticas/patologia , Linfócitos T Reguladores/imunologia , Animais , Antígeno B7-1/biossíntese , Antígeno B7-2/biossíntese , Antígenos CD4/metabolismo , Carcinoma Hepatocelular/sangue , Linhagem Celular Tumoral , Regulação para Baixo/imunologia , Interleucina-12/metabolismo , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Neoplasias Hepáticas/sangue , Depleção Linfocítica , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Fator de Necrose Tumoral alfa/metabolismoRESUMO
The association studies from different ethnic groups showed that vitamin D receptor (VDR) gene polymorphisms might be connected with the susceptibility to ulcerative colitis (UC); however, the conclusions were less consistent. Our study aimed to analyze the associations of UC with common mutations of VDR in Chinese patients. A total of 382 UC patients and 489 healthy controls were recruited. The genotypes of VDR FokI (rs2228570), BsmI (rs1544410), ApaI (rs7975232) and TaqI (rs731236) were examined by SNaPshot assays. Haplotype analysis was performed in all study subjects. After Bonferroni correction, the mutant alleles and genotypes of VDR FokI, BsmI, ApaI and TaqI did not statistically differ between UC patients and the controls (all p > 0.0125). However, the mutant allele C and genotype TC + CC of FokI gene were significantly increased in patients with mild and moderate UC compared to those with severe UC (C allele: 54.1% versus 39.3%, OR = 1.83, 95% CI: 1.21-2.75, p = 0.004; TC + CC genotype: 81.6% versus 57.1%, OR = 3.32, 95% CI: 1.83-6.06, p < 0.001, respectively). Haplotype analysis showed that the VDR BsmI, ApaI and TaqI polymorphic loci were in a strong linkage disequilibrium. Furthermore, the frequency of AAC haplotype was statistically lower in UC patients than that in the controls (3.8 versus 5.9%, OR = 0.63, 95% CI: 0.39-1.01, p = 0.039). In conclusion, the mutation of FokI gene influenced severity of the disease in UC patients. Moreover, the AAC haplotype formed by the VDR BsmI, ApaI and TaqI gene might engender a reduced risk of UC attack.
Assuntos
Colite Ulcerativa/genética , Polimorfismo de Nucleotídeo Único/genética , Receptores de Calcitriol/genética , Estudos de Casos e Controles , China/epidemiologia , Colite Ulcerativa/epidemiologia , Colite Ulcerativa/patologia , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Fatores de RiscoRESUMO
BACKGROUND AND AIM: FUT2 and FUT3 genes are responsible for the formation of histo-blood group antigens, which act as binding sites for some intestinal microbes. Several studies suggested that FUT2 gene might affect the intestinal microbiota composition and modulate innate immune responses. However, the effect of FUT2 polymorphisms on Crohn's disease (CD) is uncertain. Our study aimed to analyze associations of CD with FUT2 and FUT3 polymorphisms in Chinese population. METHODS: A total of 273 CD patients and 479 controls were recruited. The genotypes of FUT2 (rs281377, rs1047781, and rs601338) and FUT3 (rs28362459, rs3745635, and rs3894326) were detected by SNaPshot analysis. RESULTS: Compared with controls, homozygote TT of FUT2 (rs1047781) was significantly increased in CD patients (TTâ vs others; P = 0.002, odds ratio [OR] = 1.767, 95% confidence interval [CI] = 1.235-2.528). The haplotype TT formed with FUT2 (rs281377) and (rs1047781) was more prevalent in CD patients than in controls (48.9% vs 43.5%, P = 0.046). Mutant T allele and homozygote TT of FUT2 (rs1047781) were increased in colonic CD patients compared with controls (P < 0.001, OR = 1.843, 95% CI = 1.353-2.512; P < 0.001, OR = 2.607, 95% CI = 1.622-4.191, respectively). Although allele and genotypic distributions of FUT3 were not statistically different between CD patients and controls, mutant allele and genotype of FUT3 (rs28362459) and (rs3745635) were significantly discrepant in three subgroups of CD patients according to lesion locations (all P < 0.05). CONCLUSIONS: Our study strongly implicates the polymorphic locus of FUT2 (rs1047781) in CD susceptibility in Chinese population. Mutations of FUT3 (rs28362459) and (rs3745635) might influence the lesion locations in CD patients.
Assuntos
Doença de Crohn/genética , Fucosiltransferases/genética , Mutação/genética , Polimorfismo Genético/genética , Adulto , Povo Asiático , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem , Galactosídeo 2-alfa-L-FucosiltransferaseRESUMO
OBJECTIVE: To explore the correlations of genetic polymorphisms in tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) gene and the plasma levels of soluble TRAIL (sTRAIL) with ulcerative colitis (UC). METHODS: From May 2004 to April 2011, a total of 393 UC patients were recruited from Second and First Affiliated Hospitals of Wenzhou Medical College and Second Renmin Hospital of Wenzhou City. During the same period, a total of 1292 healthy controls were recruited from Physical Examination Center at Second Affiliated Hospital of Wenzhou Medical College. After PCR amplification, the genetic polymorphisms in TRAIL (G1525A, G1588A, C1595T) genes were examined by direct sequencing, and the haplotype analysis were also performed in all study subjects. Furthermore, the plasma levels of sTRAIL were determined by enzyme-linked immunosorbent assay (ELISA). RESULTS: The frequencies of variant genotypes in TRAIL (G1525A, G1588A, C1595T) genes were significantly lower in the UC patients than those in the controls (all P < 0.01). Both of variant allele frequencies in TRAIL G1525A and G1588A were significantly decreased in UC patients (40.08% (315/786) vs 54.95% (1420/2584), 49.49% (389/786) vs 55.53% (1435/2584), both P < 0.01). However, the variant allele frequency in TRAIL C1595T gene was not significantly lower in the UC patients (P = 0.133). According to disease severity, the UC patients were divided into mild, intermediate and severe groups. The frequencies of variant allele (T) and genotype (CT + TT) in TRAIL C1595T gene were also significantly higher in the patients with severe UC than those in others (63.50% (127/200) vs 49.15% (288/586), 77.00% (77/100) vs 61.43% (180/293), both P < 0.01). In haplotype analysis, the frequency of GAT haplotype was significantly higher in the UC patients than that in the controls. However, the frequency of AAT haplotype was significantly lower in the UC patients (both P < 0.01). Furthermore, the plasma levels of sTRAIL were significantly higher in the UC patients than those in the controls ((1.05 ± 0.48) vs (0.96 ± 0.90) ng/L, P < 0.01). CONCLUSION: The genetic polymorphisms of TRAIL (G1525A, G1588A, C1595T) and the plasma levels of sTRAIL are correlated with UC in Chinese patients.
Assuntos
Colite Ulcerativa/genética , Ligante Indutor de Apoptose Relacionado a TNF/sangue , Ligante Indutor de Apoptose Relacionado a TNF/genética , Adulto , Alelos , Estudos de Casos e Controles , Feminino , Frequência do Gene , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , FenótipoRESUMO
OBJECTIVE: To investigate the association between the genetic polymorphisms of methylenetetrahydrofolate reductase (MTHFR) and ulcerative colitis (UC) of Han ethnic population in Zhejiang, China. METHODS: Two hundred and seventy-four consecutive patients with UC and 726 healthy controls (HC) were studied. The genetic polymorphisms of MTHFR (C677T and A1298C) were genotyped using PCR-RELP methods. RESULTS: The frequencies of variant allele and genotype in MTHFR A1298C gene were higher in UC patients than in the HC (35.77% vs 29.96%, P = 0.013; 52.19% vs 44.90%, P = 0.039; respectively). However, there were no significant discrepancies of the allele and genotype frequencies in the MTHFR C677T gene between the UC patients and the HC (P > 0.05). In addition, the MTHFR 677TT homozygote, T allele and 677CT/1298AC compound genotype were more prevalent in patients with extensive colitis than in those with distal colitis (37.66% vs 14.72%, P = 0.0002; 49.35% vs 32.99%, P = 0.0004; 29.87% vs 15.23%, P = 0.006; respectively). Furthermore, the variant allele in the MTHFR A1298C gene (C) in severe UC patients was significantly lower than in mild and moderate UC patients (18.97% vs 33.88%, P = 0.022). CONCLUSION: The genetic polymorphisms of MTHFR C677T and A1298C are obviously associated with Han ethnic population with UC in Zhejiang province.