TEAD4: A key regulator of tumor metastasis and chemoresistance - Mechanisms and therapeutic implications.

Cancer metastasis is a complex process influenced by various factors, including epithelial-mesenchymal transition (EMT), tumor cell proliferation, tumor microenvironment, and cellular metabolic status, which remains a significant challenge in clinical oncology, accounting for a majority of cancer-related deaths. TEAD4, a key mediator of the Hippo signaling pathway, has been implicated in regulating these factors that are all critical in the metastatic cascade. TEAD4 drives tumor metastasis and chemoresistance, and its upregulation is associated with poor prognosis in many types of cancers, making it an attractive target for therapeutic intervention. TEAD4 promotes EMT by interacting with coactivators and activating the transcription of genes involved in mesenchymal cell characteristics and extracellular matrix remodeling. Additionally, TEAD4 enhances the stemness of cancer stem cells (CSCs) by regulating the expression of genes associated with CSC maintenance. TEAD4 contributes to metastasis by modulating the secretion of paracrine factors and promoting heterotypic cellular communication. In this paper, we highlight the central role of TEAD4 in cancer metastasis and chemoresistance and its impact on various aspects of tumor biology. Understanding the mechanistic basis of TEAD4-mediated processes can facilitate the development of targeted therapies and combination approaches to combat cancer metastasis and improve treatment outcomes.

HDAC11: A novel target for improved cancer therapy.

Histone deacetylase 11 (HDAC11) is a unique member of the histone deacetylase family that plays an important role in the regulation of gene expression and protein function. In recent years, research on the role of HDAC11 in tumors has attracted increasing attention. This review summarizes the current knowledge on the subcellular localization, structure, expression, and functions of HDAC11 in tumors, as well as the regulatory mechanisms involved in its network, including ncRNA and substrates. Moreover, we focus on the progress made in targeting HDAC11 to overcome tumor therapy resistance, and the development of HDAC11 inhibitors for cancer treatment. Collectively, this review provides comprehensive insights into the potential clinical implications of HDAC11 for cancer therapy.

New insights into the roles of peroxiredoxins in cancer.

Oxidative stress is one of the hallmarks of cancer. Tumorigenesis and progression are accompanied by elevated reactive oxygen species (ROS) levels and adaptive elevation of antioxidant expression levels. Peroxiredoxins (PRDXs) are among the most important antioxidants and are widely distributed in a variety of cancers. PRDXs are involved in the regulation of a variety of tumor cell phenotypes, such as invasion, migration, epithelial-mesenchymal transition (EMT) and stemness. PRDXs are also associated with tumor cell resistance to cell death, such as apoptosis and ferroptosis. In addition, PRDXs are involved in the transduction of hypoxic signals in the TME and in the regulation of the function of other cellular components of the TME, such as cancer-associated fibroblasts (CAFs), natural killer (NK) cells and macrophages. This implies that PRDXs are promising targets for cancer treatment. Of course, further studies are needed to realize the clinical application of targeting PRDXs. In this review, we highlight the role of PRDXs in cancer, summarizing the basic features of PRDXs, their association with tumorigenesis, their expression and function in cancer, and their relationship with cancer therapeutic resistance.

Hypoxia-induced alterations of transcriptome and chromatin accessibility in HL-1 cells.

Cardiac hypoxia plays a significant role in various types of heart disease, and improper treatment of hypoxia often leads to myocardial cell damage or even death. Transcriptome profiling and open chromatin mapping have been used as powerful tools to understand the development of heart disease, but the interplay between gene expression and chromatin accessibility has not been extensively investigated in hypoxia-induced cardiac damage. In this study, with HL-1 cardiomyocytes as a model, we performed temporal profiling of transcriptome and chromatin accessibility to show the cardiac responses to hypoxia (for 4 and 8 hr) and reoxygenation (for 24 hr). With RNA-seq and ATAC-seq, we identified a total of 2,912 differentially expressed genes and 3,004 differential peaks across the whole genome and showed that these data were in good agreement with each other. For hypoxia-related genes, we also discovered high correlations between their ATAC-seq signals and mRNA levels, such as VEGF, Angpt1, Slc2a1, Bnip3, and Casp3 with Pearson correlations >0.7. Interestingly, after 24 hr reoxygenation, the expression levels of 235 genes were still significantly different from the counterparts in the control, suggesting that these genes need a longer recovery time after reoxygenation. In conclusion, our study shows the close relationship between alterations of transcriptome and chromatin accessibility after hypoxia exposure and reoxygenation, emphasizing the importance of open chromatin profiling in related studies. In addition, the profiled molecular responses here will be valuable resources for better understanding of the mechanisms responsible for hypoxia-induced heart disease in future.

Relationship between Long Noncoding RNA H19 Polymorphisms and Risk of Coronary Artery Disease in a Chinese Population: A Case-Control Study.

METHODS: We collected 732 samples from Liaoning Province, China, and three polymorphisms in long noncoding RNA H19 were genotyped using the KASP platform. RESULTS: Our data showed that H19 rs2735971 and rs3024270 variant genotypes were associated with a decreased risk of CAD (rs2735971, P = 0.003, odds ratio (OR) = 0.6195, 95% confidence interval = 0.44 - 0.84; rs3024270, P = 0.030, OR = 0.65, 95% confidence interval = 0.44 - 0.96). No significant association with the risk of CAD was found for H19 rs2839698 polymorphism (P > 0.05). In haplotype analysis, H19 polymorphisms of rs2735971-rs2839698-rs3024270 A-C-C haplotype reduced the risk of CAD by 0.61-fold (P = 0.004, OR = 0.61, 95% confidence interval = 0.43-0.86). In addition, we found that rs2839698 interacted with smoking (P interaction = 0.027), and according to multifactor dimensionality reduction analysis, the three-factor model including H19 rs2839698-smoking-drinking was the best model for the risk of CAD (testing balanced accuracy = 0.6979). CONCLUSION: Our study demonstrated that some genotypes of H19 rs2735971 and rs3024270 polymorphisms, as well as rs2735971-rs2839698-rs3024270 A-C-C haplotype, were associated with the risk of CAD in a Chinese population, and these genotypes have the potential to be biomarkers for predicting CAD risk. We also found that rs2735971-rs2839698-rs3024270 A-C-C may have a significantly lower risk of CAD. The recessive genetic model of rs3024270 could predict the severity of CAD.

LncRNA MALAT1 gene polymorphisms in coronary artery disease: a case-control study in a Chinese population.

Background: Coronary artery disease (CAD) is one of the main fatal diseases all over the world. CAD is a complex disease, which has multiple risk factors mechanisms. In recent years, genome-wide association study (GWAS) had revealed single nucleotide polymorphism genes (SNPs) which were closely related with CAD risks. The relationship between long non-coding RNA (lncRNA) MALAT1 (metastasis-associated lung adenocarcinoma transcript 1) and CAD risk is largely unknown. To our knowledge, this is the first study which demonstrated the interaction effects of SNP-SNP and SNP-environment with CAD risk. In general, our case-control study is to detect the association between MALAT1 (rs619586, rs4102217) SNPs and CAD risk. Methods: Three hundred and sixty-five CAD patients and three hundred and eighty-four matched control participants blood samples were collected in Liaoning province, China. Two polymorphisms (rs619586, rs4102217) in lncRNA MALAT1 were genotyped by KASP platform. Results: In a stratified analysis, we found that non-drinkers with GC genotype and the recessive model of rs4102217 had higher CAD risk (P=0.010, odds ratio (OR): 1.96, 95% confidence interval (CI) = 1.17-3.28; P=0.026, OR: 1.73, 95% CI = 1.07-2.79) and diabetes mellitus (DM) history group (P=0.010, OR: 4.07, 95% CI = 1.41-11.81; P=0.019, OR: 3.29, 95% CI = 1.22-8.88). In SNP-SNP interactions analysis between MALAT1 and CAD risk, we found rs4102217 had an increase in smokers (GG: OR: 2.04, 95% CI = 1.42-2.92; CC+GC: OR: 2.64, 95% CI = 1.64-4.26) and a decrease in drinkers (CC+GC: OR: 0.33, 95% CI = 0.20-0.55). Smokers with MALAT1 rs619586 AA genotype (OR: 2.20, 95% CI = 1.57-3.07) and GG+AG genotype (OR: 2.11, 95% CI = 1.17-3.81) had a higher risk of CAD. Moreover, drinkers with AA genotype (OR: 0.22, 95% CI = 0.10-0.48) and GG+AG genotype (OR: 0.38, 95% CI = 0.22-0.65) had a lower risk of CAD. According to the MDR software, MALAT1 rs4102217 polymorphism-smoking-drinking was the best interaction model, which has higher risk of CAD (Testing Bal.ACC. = 0.6979). Conclusion: Our study demonstrated that the GC genotype and the recessive model of rs4102217 potentially increased CAD risk in some specific group.

Associations between circulating IgG antibodies to Apolipoprotein B100-derived peptide antigens and acute coronary syndrome in a Chinese Han population.

Objectives: Acute coronary syndrome (ACS) is the major cause of mortality worldwide and caused mainly by atherosclerosis of coronary arteries. Apolipoprotein B100 (ApoB100) is a major component of low-density lipoprotein (LDL) and its oxidation can trigger inflammation in vascular endothelial cells leading to atherosclerosis. The association between antibodies to ApoB100-derived antigens and atherosclerotic diseases has been studied in recent years, but the findings appear to be controversial. The present study developed an ELISA in-house with ApoB100-derived peptide antigens to circulating anti-ApoB100 IgG antibodies in patients with ACS. Methods: Fifteen ApoB100-derived peptide antigens (Ag1-Ag15) were designed to develop an in-house ELISA for the detection of circulating anti-ApoB100 IgG levels in 350 patients with ACS and 201 control subjects amongst a Chinese population. Binary logistic regression was applied to examine the differences in anti-ApoB IgG levels between the patient group and the control group with adjustment for a number of confounding factors; the correlation between anti-ApoB100 IgG levels and clinical characteristics was also tested. Results: Patients with ACS had significantly higher levels of plasma IgG for Ag1 (adjusted P<0.001) and Ag10 antigens (adjusted P<0.001). There was no significant increase in the levels of IgG to the other 13 antigens in these ACS patients. In the control group, anti-Ag10 IgG levels were positively correlated with age, high-density lipoprotein (HDL), and ApoA levels (P≤0.001 for all) and negatively correlated with blood triglyceride (TG) (P=0.008); in the patient group, anti-Ag10 IgG levels were positively correlated with LDL (P=0.003), and negatively correlated with ApoA (P=0.048) and systolic blood pressure (SBP) (P=0.036). The area under ROC (receiver operator characteristic) curve (AUC) was 0.612 (95% confidence interval (CI): 0.560-0.664; P<0.001) in anti-Ag1 IgG assay and 0.621 (95% CI: 0.569-0.672; P<0.001) in anti-Ag10 IgG assay. Conclusion: Circulating IgG for ApoB100-derived peptide antigens may be a useful biomarker of ACS, although anti-ApoB IgG levels were not associated with the coronary artery plaque burden characterized by the coronary Gensini score.

A brief review: the therapeutic potential of bone marrow mesenchymal stem cells in myocardial infarction.

Myocardial infarction (MI) results in dysfunction and irreversible loss of cardiomyocytes and is among the most serious health threats today. Bone marrow mesenchymal stem cells (BMSCs), with their capacity for multidirectional differentiation, low immunogenicity, and high portability, can serve as ideal seed cells in cardiovascular disease therapy. In this review, we examine recent literature concerning the application of BMSCs for the treatment of MI and consider the following aspects: activity of transplanted cells, migration and homing of BMSCs, immunomodulatory and anti-inflammatory effects of BMSCs, anti-fibrotic activity of BMSCs, the role of BMSCs in angiogenesis, and differentiation of BMSCs into cardiomyocyte-like cells and endothelial cells. Each aspect is complementary to the others and together they promote the repair of cardiomyocytes by BMSCs after MI. Although transplantation of BMSCs has enabled new options for MI treatment, the critical issue we must now address is the reduced viability of transplanted BMSCs due to inadequate blood supply, poor nourishment of cells, and generation of free radicals. More clinical trials are needed to prove the therapeutic potential of BMSCs in MI.

Common polymorphisms in the interleukin-6 gene and myocardial infarction risk: a meta-analysis.

BACKGROUND: Interleukin-6 (IL-6) plays a critical role in the development and progression of cardiovascular disease. Emerging evidence suggests that two common polymorphisms (-174 G/C and -572 G/C) in the IL-6 gene might have an impact on an individual's susceptibility to myocardial infarction (MI), but individually published results are inconclusive. This meta-analysis aimed to derive a more precise estimation of the relationship between IL-6 -174 G/C and -572 G/C polymorphisms and MI risk. METHOD: An extensive literary search for relevant studies was conducted in PubMed, Embase, Web of Science, Cochrane Library, CISCOM, CINAHL, Google Scholar, China BioMedicine (CBM), and China National Knowledge Infrastructure (CNKI) databases from their inception through August 1st, 2013. A meta-analysis was then performed using the STATA 12.0 software. The crude odds ratios (OR) with 95% confidence intervals (CI) were calculated. RESULTS: Eleven case-control studies were included with a total of 10,252 subjects, including 5429 MI patients and 4823 healthy controls. Our meta-analysis results indicated that IL-6 -174 G/C polymorphism may increase the risk of MI (C allele vs. G allele: OR=1.07, 95% CI: 1.01-1.14, p=0.018; GC+CC vs. GG: OR=1.14, 95% CI: 1.04-1.24, p=0.003; respectively). However, our results showed no significant association between IL-6 -572 G/C polymorphism and MI risk (C allele vs. G allele: OR=0.88, 95% CI: 0.75-1.03, p=0.098; GC+CC vs. GG: OR=0.87, 95% CI: 0.70-1.07, p=0.173; respectively). No publication bias was detected in this meta-analysis. CONCLUSION: The current meta-analysis suggests that IL-6 -174 G/C polymorphism may contribute to MI susceptibility. Thus, detection of IL-6 -174 G/C polymorphisms may be a promising biomarker for the early detection of MI. However, IL-6 -572 G/C polymorphism may not associate with the risk of MI.

Glutathione S-transferase M1 polymorphism and coronary heart disease susceptibility: a meta-analysis involving 47,596 subjects.

BACKGROUND: Many studies have investigated the association between glutathione S-transferase M1 (GSTM1) null genotype and the risk of coronary heart disease (CHD). However, the effect of the GSTM1 null genotype on CHD is still unclear because of apparent inconsistencies among those studies. A meta-analysis was performed to characterise the relationship more accurately. METHODS: Pubmed, Embase, and Web of Science were searched. We estimated the summary odds ratio (OR) with a 95% confidence interval (95% CI) to assess the association. RESULTS: Up to 26 case-control studies with 13,929 CHD cases and 33,667 control cases were included into this meta-analysis. Meta-analysis of the 26 studies showed that GSTM1 null genotype was associated with the risk of CHD (random effects OR=1.35, 95% CI 1.00 to 1.83). After adjustment for heterogeneity, meta-analysis showed that GSTM1 null genotype was not associated with increased risk of CHD in the total population (fixed effects OR=1.01, 95% CI 0.95 to 1.07). In the subgroup analysis by ethnicity, increased risks were not found for either Caucasians (OR=1.36, 95% CI=0.96-1.92) or Asians (OR=1.28, 95% CI=0.91-1.80). When stratified by smoking status, in the subgroup of smokers, GSTM1 null genotype was significantly associated with increased CHD risk (random effects OR=1.64, 95% CI 1.02 to 2.64). No evidence of publication bias was observed. CONCLUSION: In conclusion, this meta-analysis suggested that there is overall lack of association between GSTM1 genotypes and CHD risk, however, GSTM1 null genotype when combining with smoking history may contribute to CHD susceptibility.

MiR-17-5p impairs trafficking of H-ERG K+ channel protein by targeting multiple er stress-related chaperones during chronic oxidative stress.

BACKGROUND: To investigate if microRNAs (miRNAs) play a role in regulating h-ERG trafficking in the setting of chronic oxidative stress as a common deleterious factor for many cardiac disorders. METHODS: We treated neonatal rat ventricular myocytes and HEK293 cells with stable expression of h-ERG with H2O2 for 12 h and 48 h. Expression of miR-17-5p seed miRNAs was quantified by real-time RT-PCR. Protein levels of chaperones and h-ERG trafficking were measured by Western blot analysis. Luciferase reporter gene assay was used to study miRNA and target interactions. Whole-cell patch-clamp techniques were employed to record h-ERG K(+) current. RESULTS: H-ERG trafficking was impaired by H2O2 after 48 h treatment, accompanied by reciprocal changes of expression between miR-17-5p seed miRNAs and several chaperones (Hsp70, Hsc70, CANX, and Golga2), with the former upregulated and the latter downregulated. We established these chaperones as targets for miR-17-5p. Application miR-17-5p inhibitor rescued H2O2-induced impairment of h-ERG trafficking. Upregulation of endogenous by H2O2 or forced miR-17-5p expression either reduced h-ERG current. Sequestration of AP1 by its decoy molecule eliminated the upregulation of miR-17-5p, and ameliorated impairment of h-ERG trafficking. CONCLUSIONS: Collectively, deregulation of the miR-17-5p seed family miRNAs can cause severe impairment of h-ERG trafficking through targeting multiple ER stress-related chaperones, and activation of AP1 likely accounts for the deleterious upregulation of these miRNAs, in the setting of prolonged duration of oxidative stress. These findings revealed the role of miRNAs in h-ERG trafficking, which may contribute to the cardiac electrical disturbances associated with oxidative stress.