lnc­MICAL2­1 sponges miR­25 to regulate DKK3 expression and inhibits activation of the Wnt/ß­catenin signaling pathway in breast cancer.

The Dickkopf 3 (DKK3) protein antagonizes the Wnt receptor complex in the Wnt signaling pathway; however, to date, there have been no relevant studies investigating its upstream regulatory mechanism in breast cancer (BC), to the best of our knowledge. The present study aimed to explore whether long non­coding RNA MICAL2­1 (lnc­MICAL2­1) sponged microRNA (miR)­25 to regulate DKK3 and inhibit activation of the Wnt/ß­catenin signaling pathway. The Atlas of non­coding RNA in Cancer database was used to measure the expression levels of lnc­MICAL2­1 and their correlation with DKK3 expression levels. In addition, cell proliferation, invasion and migration were determined following the silencing or overexpression of lnc­MICAL2­1. The binding between lnc­MICAL2­1 and miR­25, or miR­25 and DKK3 was verified using RNA pull­down and dual­luciferase reporter assays. The effects of overexpression or knockdown of lnc­MICAL2­1 on DKK3 expression and the Wnt signaling pathway were further evaluated in a nude mouse xenograft model. The results revealed that, compared with in adjacent normal tissue, the expression levels of lnc­MICAL2­1 were downregulated in BC tissues, and the expression levels of lnc­MICAL2­1 were found to be positively correlated with DKK3 expression. The overexpression of lnc­MICAL2­1 in BC cells upregulated the mRNA expression levels of DKK3 and inhibited their proliferation. Results from the RNA pull­down and dual luciferase reporter assays validated that lnc­MICAL2­1 could bind to miR­25, which targets DKK3. The in vivo experimental data demonstrated that lnc­MICAL2­1 inhibited tumor growth via regulating the Wnt signaling pathway. In conclusion, the findings of the present study highlighted a novel molecular mechanism through which lnc­MICAL2­1 may regulate the DKK3­mediated Wnt signaling pathway in BC, highlighting potential targets for the treatment of the disease.

Long-Term Survival Among Histological Subtypes in Advanced Epithelial Ovarian Cancer: Population-Based Study Using the Surveillance, Epidemiology, and End Results Database.

BACKGROUND: Actual long-term survival rates for advanced epithelial ovarian cancer (EOC) are rarely reported. OBJECTIVE: This study aimed to assess the role of histological subtypes in predicting the prognosis among long-term survivors (≥5 years) of advanced EOC. METHODS: We performed a retrospective analysis of data among patients with stage III-IV EOC diagnosed from 2000 to 2014 using the Surveillance, Epidemiology, and End Results cancer data of the United States. We used the chi-square test, Kaplan-Meier analysis, and multivariate Cox proportional hazards model for the analyses. RESULTS: We included 8050 patients in this study, including 6929 (86.1%), 743 (9.2%), 237 (2.9%), and 141 (1.8%) patients with serous, endometrioid, clear cell, and mucinous tumors, respectively. With a median follow-up of 91 months, the most common cause of death was primary ovarian cancer (80.3%), followed by other cancers (8.1%), other causes of death (7.3%), cardiac-related death (3.2%), and nonmalignant pulmonary disease (3.2%). Patients with the serous subtype were more likely to die from primary ovarian cancer, and patients with the mucinous subtype were more likely to die from other cancers and cardiac-related disease. Multivariate Cox analysis showed that patients with endometrioid (hazard ratio [HR] 0.534, P<.001), mucinous (HR 0.454, P<.001), and clear cell (HR 0.563, P<.001) subtypes showed better ovarian cancer-specific survival than those with the serous subtype. Similar results were found regarding overall survival. However, ovarian cancer-specific survival and overall survival were comparable among those with endometrioid, clear cell, and mucinous tumors. CONCLUSIONS: Ovarian cancer remains the primary cause of death in long-term ovarian cancer survivors. Moreover, the probability of death was significantly different among those with different histological subtypes. It is important for clinicians to individualize the surveillance program for long-term ovarian cancer survivors.

Determination of IL-1B (rs16944) and IL-6 (rs1800796) genetic polymorphisms in IgA nephropathy in a northwest Chinese Han population.

IgA nephropathy (IgAN) is the most common form of primary glomerulonephritis worldwide, but etiology and pathogenesis continue to be poorly understood. Polymorphisms in the cytokine genes may play a role in the etiology and pathogenesis of IgAN. The incidence of different between diverse ethnic groups suggested important genetic influences on its pathogenesis. We genotype 10 single nucleotide polymorphisms (SNPs) in IL-1B and IL-6 gene using Sequenom Mass-ARRAY technology from 417 IgAN patients and 463 healthy controls of the Chinese Han population. We evaluated these SNPs associated with IgAN utilising the chi-square tests and genetic model analysis. We identified that the minor alleles of rs16944 ("A"), rs1800796 ("G") in IL-1B, IL-6 were involved in an increasingly risk of IgAN in allelic model analysis, respectively. The rs16944 in IL-1B and rs1800796 in IL-6 were associated with 1.23-fold (95% CI, 1.02-1.48, P = 0.031) and 1.33-fold (95% CI, 1.11-1.66, P = 0.003) increases in the risk of developing IgAN, respectively. There was only rs1800796 still correlated with IgAN in the allelic model after adjustment by age and gender and the Bonferroni correction. In addition, Haplotype Grs1800796A rs2069837G rs2069840 (P = 0.037) and G rs1800796A rs2069837C rs2069840 (P = 0.042) in IL-6were considered to be associated with increased IgAN risk. This study verified the IL-6, IL-1B genetic variants polymorphisms contributed to IgAN susceptibility in a Chinese Han population. Although we identified SNPs susceptibility, however, replication studies and functional research are required to confirm the genetic contribution in IgAN.

Association between MPHOSPH6 gene polymorphisms and IgA nephropathy risk in a Chinese Han population.

Multiple genetic and environmental factors together contribute to the risk of IgA nephropathy (IgAN). MPHOSPH6 play an important role in the recruitment of the exosome to the pre-rRNA. However, to date, little information is found about the association between MPHOSPH6 polymorphisms and the IgAN risk. In this case-control study, we genotyped five single nucleotide polymorphisms (SNPs) in MPHOSPH6 gene in 416 IgAN cases and 495 controls using Sequenom Mass-ARRAY technology and evaluated their association with IgAN using the χ2 and genetic model analysis. In the allelic model analysis, we determined rs1056654 was associated with a 0.774-fold decrease in the risk of IgAN (95%CI= 0.630-0.952; p = 0.015). In the genetic model analysis, we found that the "C/C" genotype of rs1056675 was associated with an increased risk of IgAN based on the codominant model (OR =1.48; 95% CI=1.03-2.13; p=0.033) and recessive model (OR =1.52; 95% CI=1.11-2.09; p=0.0095). The "G/A-A/A" genotype of rs1056654 was associated with a decreased risk of IgAN based on the dominant model (OR =0.75; 95% CI=0.58-0.98; p=0.032) and log-additvie model (OR =0.78; 95% CI=0.64-0.96; p=0.0188). Our data suggested that gene polymorphisms in the MPHOSPH6 may exert influences IgAN susceptibility in a Chinese Han population.

Association of genetic polymorphisms in IL-1R1 and IL-1R2 genes with IgA nephropathy in the Han Chinese population.

AIM: IgA nephropathy (IgAN) is the major cause of end-stage renal disease(ESRD) in Asia and its pathogenesis is influenced by both genetic and environmental factors. Single nucleotide polymorphisms (SNPs) in IL1R1 and IL-1R2 may be associated with susceptibility to IgAN. In this study, we study the association between genetic variants of IL-1R1 and IL-1R2 and IgA nephropathy risk in the Chinese Han population. RESULT: In the allelic model analysis, the rs10490571 and rs3917225 were associated with a 1.40-fold, and 1.31-fold increased risk of IgA nephropathy, respectively. In the genetic model analysis, the rs10490571 in IL1R1 was associated with a 1.46-fold increased risk of IgAN in the dominant model and 1.36-fold increased risk in the Log-additive model, respectively. However, the rs3218977 in IL1R2 was associated with a 0.71-fold decrease risk of IgAN in the dominant model and a 0.71-fold decrease risk in the over-dominant model, respectively. We found four SNPs (rs11674595, rs4851521, rs719250, and rs3218896) constructed four haplotypes in the IL1R2 gene and none of the haplotype was significantly associated with risk of IgAN. MATERIALS AND METHODS: A case-control study was conducted including 426 nephropathy patients and 463 healthy controls. Chi-squared tests and genetic model were used to evaluate associations. >CONCLUSIONS: These findings suggested that IL-1R1 and IL-1R2 polymorphisms may contribute to the development of IgAN.

Fasudil inhibits tissue factor and plasminogen activator Inhibitor-1 secretion by peripheral blood mononuclear cells in CAPD patients.

Disturbances in hemostasis are common complications of kidney diseases and correlate well with cardiovascular mortality. Little is known about the effects of fasudil on tissue factor (TF) and plasminogen activator inhibitor-1 (PAI-1) expression in peripheral blood mononuclear cells (PBMCs) in CAPD patients. PBMCs were isolated from 13 individuals with CAPD and 13 healthy subjects. After 4 h of incubation with or without LPS (10 ng/mL), TF and PAI-1 mRNA of PBMCs were detected by RT-PCR. The levels of TF and PAI-1 in culture supernatants of PBMCs were determined by ELISA. Compared with healthy controls, CAPD patients had increased TF, PAI-1 protein and mRNA expression by PBMCs at baseline and after stimulated by LPS (10 ng/mL) [p < 0.001]. The fasudil treatment resulted in a significant effect in decreasing TF and PAI-1 [p < 0.05] synthesis in PBMCs. TF and PAI-1 mRNA expression and activities in PBMCs were increased in CAPD patients. Fasudil reduced LPS-mediated TF and PAI-1 expression and activity in PBMCs. These effects may partially be relevant to the clinical benefits of fasudil in the treatment of CAPD patients.