Genome-wide identification and analysis of epithelial-mesenchymal transition-related RNA-binding proteins and alternative splicing in a human breast cancer cell line.

Exploring the mechanism of breast cancer metastasis and searching for new drug therapeutic targets are still the focuses of current research. RNA-binding proteins (RBPs) may affect breast cancer metastasis by regulating alternative splicing (AS) during epithelial-mesenchymal transition (EMT). We hypothesised that during EMT development in breast cancer cells, the expression level of RBPs and the gene AS pattern in the cell were significantly changed on a genome-wide scale. Using GEO database, this study identified differentially expressed RBPs and differential AS events at different stages of EMT in breast cancer cells. By establishing the correlation network of differential RBPs and differential AS events, we found that RBM47, PCBP3, FRG1, SRP72, RBMS3 and other RBPs may regulate the AS of ITGA6, ADGRE5, TNC, COL6A3 and other cell adhesion genes. By further analysing above EMT-related RBPs and AS in breast cancer tissues in TCGA, it was found that the expression levels of ADAT2, C2orf15, SRP72, PAICS, RBMS3, APOBEC3G, NOA1, ACO1 and the AS of TNC and COL6A3 were significantly correlated with the prognosis of breast cancer patients. The expression levels of all 8 RBPs were significantly different in breast cancer tissues without metastasis compared with normal breast tissues. Conclusively, eight RBPs such as RBMS3 and AS of TNC and COL6A3 could be used as predictors of breast cancer prognosis. These findings need to be further explored as possible targets for breast cancer treatment.

Comprehensive Analysis of Expression and Pathway for CD27 in Esophageal Cancer.

CD27 as a marker of memory B cells is belong to the tumor necrosis factor receptor (TNFR) superfamily, CD27 is ligated by CD70, they can co-stimulate T-cell growth and differentiation through their interaction. Uncertainty surrounds CD27's function in esophageal cancer (EC). This study investigated the role of CD27 in the prognosis of EC using the TCGA, cbioportal, linkedomics and GEPIA databases as well as the proliferation assay was applied. CD27 differential expression may be a key factor in the development of EC. different level of CD27 expression in EC has profound impacts on TOR complex, and many kinds of kinase (KIT proto-oncogene receptor tyrosine kinase, transforming growth factor beta receptor 1, and G protein-coupled receptor kinase 3.), as well as the cell membrane, and survival analysis revealed that it had a significant impact on both the overall survival and disease-free survival of EC. CD27 overexpression will suppress the viability of the KYSE150 and TE3 cells. Our findings suggested that the degree of CD27 expression could serve as an esophageal cancer prognosis biomarker.

Preoperative Prognostic Nutritional Index is a Significant Predictor of Survival in Esophageal Squamous Cell Carcinoma Patients.

Background: Preoperative assessment of patients is meaningful to predict survival in patients with malignant tumors. The prognostic nutritional index (PNI) is one of the most significant factors related to the prognosis in various types of cancer; however, its role in esophageal cancer is still inconclusive. The aim of this study was to identify the prognostic value of PNI in predicting overall survival (OS) in esophageal squamous cell carcinoma (ESCC).Methods: This retrospective study included 4146 ESCC patients, 3812 who underwent esophagectomy for ESCC. Other 334 had no surgery. The Preoperative PNI was measured before any therapies and calculated as 10 × serum albumin (g/dL) + 0.005 × total lymphocyte count (per mm3). We classified the patients into three categories according to the PNI, >50, 45-50, and <45.Results: Our study showed that PNI was associated with age (P<0.0001), gender(P<0.001),tumor length (P<0.0001), T grade (P = 0.001), N staging (P = 0.017),and M staging (P<0.0001). Multivariate analysis showed that PNI was a significant predictor of overall survival Lower PNI vs. Higher PNI group had significantly increased the hazard ratio of ESCC survival (OR = 1.2, 95% CI= 1.05-1.5, p = 0.01). The Kaplan-Meier curve suggested that high PNI group will significantly increase the OS in both surgical and non-surgical group.Conclusion: PNI is a useful predictive factor for long-term survival in ESCC. The survival rate of ESCC can be discriminated between three groups, PNI, >50, 45-50, and <45. The prognostic value of PNI can be applied for both surgical and non-surgical ESCC patients.

Patients with Dipper and Nondipper High-Normal Blood Pressure Were Associated with Left Ventricular Mass.

PURPOSE: High-normal blood pressure has been suggested to associate with target organ damage and higher left ventricular mass index (LVMI). Our aim is to find the association between people with high-normal blood pressure and their left ventricular mass index. MATERIALS AND METHODS: Given a total of 181 people with office blood pressure, 24-hour ambulatory blood pressure monitoring, 35 of them are normotensive (BP < 130/85 mm Hg), and 146 people with high-normal blood pressure (BP 130-139/85-89 mm Hg), divide the high-normal blood pressure group into dipper and nondipper according to their ABPM in 24 hours. All of them were performed with echocardiography to calculate LVMI. RESULTS: After adjusting for potential confounding factors, mean systolic blood pressure (BP) of the nondipper group is (119 + 9) mmHg in 24 h, which is significantly higher (p < 0.05) than in the dipper group (116 + 11) mmHg, indicating the mean systolic BP is associated with the dipper type (p < 0.05); furthermore, the higher nocturnal blood pressure is associated with the nondipper group significantly (p < 0.05), and LVMI ((121 ± 11) g/m2) of the nondipper group is also significantly higher than in the dipper group's LVMI ((108 ± 12) g/m2) (p < 0.05). The multivariate linear regression analyses revealed significant and independent associations of LVMI with these factors: triglyceride (TG), total cholesterol (TC), low-density lipoprotein (LDL-C), and coefficient of variation of systolic and diastolic blood pressure in 24 hours. CONCLUSION: After multiple relevant clinical confounding factors were adjusted, patients with dipper and nondipper high-normal blood pressure had higher LVMI. Abnormalities in circadian blood pressure variability may be associated with the left ventricular hypertrophy.

TBC1D25 Regulates Cardiac Remodeling Through TAK1 Signaling Pathway.

Cardiac remodeling is a major early event of heart failure, which is regulated by multiple signaling pathways. Here, we demonstrate that TBC1D25 is upregulated during pathological cardiac remodeling. The aim of this study is to determine the role of TBC1D25 in cardiac remodeling and to illustrate the underlying molecular mechanism. Specifically, cardiac remodeling was induced in TBC1D25-KO mice and their wild-type control mice through partial transverse aortic constriction (TAC) of aortic arch. Knockout TBC1D25 exacerbated cardiac hypertrophy, fibrosis and dysfunction. Meanwhile, TBC1D25 overexpression in both H9C2 cells and NRCMs alleviate Angiotensin II-induced cardiomyocyte hypertrophy in vitro. Moreover, TBC1D25 deficiency increases the phosphorylation levels of TAK1 and its downstream molecular (JNK and p38), whereas overexpressed TBC1D25 inhibits phosphorylation of TAK1, JNK and p38. And TAK1 is the key molecule in this process. Furthermore, we demonstrated that TBC1D25 could directly interacts with TAK1 by immunoprecipitation assay and GST pull-down assay, and the interaction needs the amino acids from at least 138 to 226 in the C-terminal region of TBC1D25 and from 1 to 300 in the C-terminal region of TAK1. We conclude that TBC1D25 suppresses pathological cardiac remodeling via regulating TAK1-JNK/p38 signaling pathway, which suggests that TBC1D25 will likely become a promising therapeutic target for heart failure.

Single-nucleotide polymorphism rs13426236 contributes to an increased prostate cancer risk via regulating MLPH splicing variant 4.

A prostate cancer risk single-nucleotide polymorphism (SNP), rs13426236, is significantly associated with melanophilin (MLPH) expression. To functionally characterize role of the rs13426236 in prostate cancer, we first performed splicing-specific expression quantitative trait loci analysis and refined the significant association of rs13426236 allele G with an increased expression of MLPH splicing transcript variant 4 (V4) (P = 7.61E-5) but not other protein-coding variants (V1-V3) (P > .05). We then performed an allele-specific reporter assay to determine if SNP-containing sequences functioned as an active enhancer. Compared to allele A, allele G of rs13426236 showed significantly higher luciferase activity on the promoter of the splicing transcript V4 (P < .03) but not on the promoter of transcript V1 (P > .05) in two prostate cancer cell lines (DU145 and 22Rv1). Cell transfection assays showed stronger effect of transcript V4 than V1 on promoting cell proliferation, invasion, and antiapoptotic activities. RNA profiling analysis demonstrated that transcript V4 overexpression caused significant expression changes in glycosylation/glycoprotein and metal-binding gene ontology pathways (FDR < 0.01). We also found that both transcripts V4 and V1 were significantly upregulated in prostate adenocarcinoma (P ≤ 2.49E-6) but only transcript V4 upregulation was associated with poor recurrence-free survival (P = .028, hazard ratio = 1.63, 95% confidence interval = 1.05-2.42) in The Cancer Genome Atlas data. This study provides strong evidence showing that prostate cancer risk SNP rs13426236 upregulates expression of MLPH transcript V4, which may function as a candidate oncogene in prostate cancer.

Interaction of 22 risk SNPs with Helicobacter pylori infection and risk of gastric cardia adenocarcinoma.

Aim: To determine the prevalence of Helicobacter pylori infection and correlation between H. pylori infection and single nucleotide polymorphism (SNPs) identified in gastric cardia adenocarcinoma (GCA) patients. Methods: A case control study was performed. 22 risks of GCA-related SNPs were identified by genotyping assay and the relationship between susceptibility loci for GCA and H. pylori infection was further analyzed. Results: Helicobacter pylori infection was associated with GCA significantly (odds ratio: 1.40; 95% CI: 1.29-1.53 p < 0.01). Five GCA risk SNPs had their genotypes significantly different between H. pylori positive patients and H. pylori negative patients. Conclusion: The interaction between SNPs susceptibility loci and H. pylori infection is associated with an increased risk of GCA.

MDM2 and its functional polymorphism SNP309 contribute to the development of esophageal carcinoma.

BACKGROUND: Overexpression of the murine double minute 2 (MDM2) has been explored in many tumors with high proliferation and anti-apoptosis ability. However, the role of MDM2 and its functional single nucleotide polymorphism (SNP) rs2279744 (also known as SNP309) in esophageal squamous cell carcinoma (ESCC) remains unclear. METHODS: We performed a genotype study of blood samples in 360 ESCC patients and 360 healthy control individuals to determine the risk of various rs2279744 in ESCC. To further evaluate the role of rs2279744 in regulating MDM2 expression, we performed an allele-specific reporter assay and investigated whether the SNP-containing sequences functioned as an active enhancer. To examine the functional role of MDM2 on esophageal cancer cell lines, we carried out an MTS assay and flow cytometry analysis. RESULTS: From the genotyping study, we found that GG genotype of SNP309 significantly increased the risk of ESCC in an additive model [odds ratio (OR) = 2.55, 95% confidence interval (CI) = 1.66-3.89, p = 1.50 × 10-5 ) and in a recessive model (OR = 2.44, 95% CI = 1.69-3.51, p = 1.60 × 10-8 ). Furthermore, the G allele was significantly associated with a higher risk of ESCC (OR = 1.56, 95% CI = 1.26-1.92, p = 2.81 × 10-5 ). In multivariate logistic regression analysis, the GG genotype had increased the occurrence of ESCC by 2.39-fold (95% CI = 1.48-3.8). Compared to the T allele, the variant G allele had significantly higher luciferase activity on the promoter of MDM2 in both cell lines. By transfecting the gene to ESCC lines, we showed that overexpression of MDM2 significantly promote cell proliferation and anti-apoptosis. CONCLUSIONS: The MDM2 promoter SNP309 is a risk factor for esophageal cancer. MDM2 promotes the proliferation and anti-apoptosis of ESCC.