USP53 Affects the Proliferation and Apoptosis of Breast Cancer Cells by Regulating the Ubiquitination Level of ZMYND11.

Breast cancer is the most common female malignancy worldwide. Ubiquitin-specific peptidase 53 (USP53) has been shown to exert cancer-suppressing functions in several solid tumors, but its role and the underlying mechanism in breast cancer has not been clearly elucidated. Therefore, we have carried out a series of detailed studies on this matter at the levels of bioinformatics, clinical tissue, cell function and animal model. We found that USP53 expression was downregulated in breast cancer specimens and was negatively correlated with the clinical stages. Gain- and loss-of-function experiments demonstrated USP53 inhibited proliferation, clonogenesis, cell cycle and xenograft growth, as well as induced apoptosis and mitochondrial damage of breast cancer cells. Co-immunoprecipitation data suggested that USP53 interacted with zinc finger MYND-type containing 11 (ZMYND11), and catalyzed its deubiquitination and stabilization. The 33-50 amino acid Cys-box domain was key for USP53 enzyme activity, but not essential for its binding with ZMYND11. The rescue experiments revealed that the anti-tumor role of USP53 in breast cancer cells was at least partially mediated by ZMYND11. Both USP53 and ZMYND11 were prognostic protective factors for breast cancer. USP53-ZMYND11 axis may be a good potential biomarker or therapeutic target for breast cancer, which can provide novel insights into the diagnosis, treatment and prognosis.

SORBS1 inhibits epithelial to mesenchymal transition (EMT) of breast cancer cells by regulating PI3K/AKT signaling and macrophage phenotypic polarization.

This study aimed to explore the regulatory role of SORBS1 in macrophage polarization and the PI3K/AKT signaling pathway, as well as analyze its mechanism in epithelial-mesenchymal transition (EMT) of breast cancer cells. We established SORBS1-overexpressing and knockout cell lines and verified the effects of SORBS1 on cell viability, invasion, and migration by phenotyping experiments and assaying the expression of associated proteins. Furthermore, we established a breast cancer cell and macrophage co-culture system to validate the effect of SORBS1 expression on macrophage polarization and killing of breast cancer cells. Bioinformatics analysis showed that SORBS1 was lowly expressed in breast cancer (BRCA) samples and highly expressed in healthy tissues. Decreased SORBS1 expression was associated with poor prognosis, and the PI3K/AKT signaling pathway was the most significantly enriched pathway. In vitro experiments showed that high expression of SORBS1 inhibited the migration of breast cancer cells, as well as the PI3K/AKT signaling pathway, and blocked EMT of these cells. In addition, SORBS1 induced macrophage polarization to the M1-type and enhanced the killing effect on breast cancer cells in the co-culture system. In conclusion, we successfully verified that SORBS1 inhibits the invasion and migration of breast cancer cells, induces macrophage M1-type polarization, and blocks EMT of breast cancer cells, and it may act by regulating the PI3K/AKT signaling pathway.

A photoelectrochemical aptasensor based on double Z-scheme α-Fe2O3/MoS2/Bi2S3 ternary heterojunction for sensitive detection of circulating tumor cells.

A novel photoelectrochemical (PEC) aptasensor based on a dual Z-scheme α-Fe2O3/MoS2/Bi2S3 ternary heterojunction for the ultrasensitive detection of circulating tumor cells (CTCs) was developed. The α-Fe2O3/MoS2/Bi2S3 nanocomposite was prepared via a step-by-step route, and the photoproduced electron/hole transfer path was speculated by conducting trapping experiments of reactive species. α-Fe2O3/MoS2/Bi2S3-modified electrodes exhibited greatly enhanced photocurrent under visible light due to the double Z-scheme charge transfer process, which met the requirement of the PEC sensor for detecting larger targets. After the aptamer was conjugated on the photoelectrode through chitosan (CS) and glutaraldehyde (GA), when MCF-7 cells were presented and captured, the photocurrent of the PEC biosensing system decreased due to steric hindrance. The current intensity had a linear relationship with the logarithm of MCF-7 cell concentration ranging from 10 to 1×105 cells mL-1, with a low detection limit of 3 cell mL-1 (S/N = 3). The dual Z-scheme α-Fe2O3/MoS2/Bi2S3 ternary heterojunction-modified PEC aptasensor exhibited high sensitivity and excellent specificity and stability. Additionally, MCF-7 cells in human serum were determined by this PEC aptasensor, exhibiting great potential as a promising tool for clinical detection.

Multigene testing panels reveal pathogenic variants in sporadic breast cancer patients in northern China.

Background: Breast cancer, the most prevalent malignancy in women worldwide, presents diverse onset patterns and genetic backgrounds. This study aims to examine the genetic landscape and clinical implications of rare mutations in Chinese breast cancer patients. Methods: Clinical data from 253 patients, including sporadic and familial cases, were analyzed. Comprehensive genomic profiling was performed, categorizing identified rare variants according to the American College of Medical Genetics (ACMG) guidelines. In silico protein modeling was used to analyze potentially pathogenic variants' impact on protein structure and function. Results: We detected 421 rare variants across patients. The most frequently mutated genes were ALK (22.2%), BARD1 (15.6%), and BRCA2 (15.0%). ACMG classification identified 7% of patients harboring Pathogenic/Likely Pathogenic (P/LP) variants, with one case displaying a pathogenic BRCA1 mutation linked to triple-negative breast cancer (TNBC). Also identified were two pathogenic MUTYH variants, previously associated with colon cancer but increasingly implicated in breast cancer. Variants of uncertain significance (VUS) were identified in 112 patients, with PTEN c.C804A showing the highest frequency. The role of these variants in sporadic breast cancer oncogenesis was suggested. In-depth exploration of previously unreported variants led to the identification of three potential pathogenic variants: ATM c.C8573T, MSH3 c.A2723T, and CDKN1C c.C221T. Their predicted impact on protein structure and stability suggests a functional role in cancer development. Conclusion: This study reveals a comprehensive overview of the genetic variants landscape in Chinese breast cancer patients, highlighting the prevalence and potential implications of rare variants. We emphasize the value of comprehensive genomic profiling in breast cancer management and the necessity of continuous research into understanding the functional impacts of these variants.

Comprehensive analysis of N6-methylandenosine regulators and m6A-related RNAs as prognosis factors in colorectal cancer.

Colorectal cancer (CRC) is one of the most common malignancies and has been a leading cause of cancer-related death worldwide in recent years. N6-methyladenosine (m6A) methylation is the most abundant epigenetic modification of various types of RNAs, and it plays a vital role in promoting cancer development. Here, we obtained SNV and transcriptome data of CRC from The Cancer Genome Atlas (TCGA). We demonstrated that most m6A methylation regulators were aberrantly expressed in individuals with CRC. The abnormal expression of m6A regulators was caused by their different copy number variation (CNV) patterns, and alteration of m6A regulators was significantly correlated with prognosis and tumor stage. By using weighted coexpression network analysis (WGCNA), we identified m6A-related long noncoding RNAs (lncRNAs) and mRNAs; then we used least absolute shrinkage and selection operator (LASSO) Cox regression analysis to construct m6A-related lncRNA and mRNA prognostic signatures in the TCGA dataset. Furthermore, a nomogram with clinicopathological features, lncRNA risk scores, and mRNA risk scores was established, which showed a strong ability to forecast the overall survival of the individuals with CRC in training and testing sets. In conclusion, m6A methylation regulators played a vital role in affecting the prognosis of subjects with CRC, and m6A-related lncRNAs and mRNAs revealed underlying mechanisms in CRC tumorigenesis and progression.

Adenosine A3 receptor activated in H2O2 oxidative stress of primary open-angle glaucoma.

BACKGROUND: Primary open-angle glaucoma (POAG), as one of the leading reasons for blindness, is mainly due to trabecular meshwork (TM) dysfunction. Bioinformatics analysis was used to find related genes involved in TM oxidative stress, which is a major cause of TM fibrosis. METHODS: A total of three datasets from the Gene Expression Omnibus (GEO) database were used to identify differentially expressed genes (DEGs). Gene expression relationships were enriched by the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and Gene Ontology (GO) pathways. The interaction network was listed by the protein-protein interaction (PPI) network. The expression of adenosine A3 receptor (ADORA3) was validated in POAG tissue and human trabecular meshwork cells (HTMCs) by western blot (WB) and reverse transcription polymerase chain reaction (RT-PCR). Additionally, WB and RT-PCR were used to measure oxidative stress injury relative protein and gene expression, respectively, such as fibronectin (FN), collagen-I (Col-I), and α-smooth muscle actin (α-SMA). Cell migration function and vitality were tested via transwell migration assay and Cell Counting Kit-8 (CCK-8). The cell vitality was measured using CCK-8. RESULTS: A total of 61 significant DEGs among the three data sources were analyzed. Among all three different datasets, two significant DEGs [ADORA3 and DNA damage-inducible transcript 4 protein (DDIT4)] were identified. The dataset ADORA3 was selected for further analysis. In the POAG TM tissue, ADORA3 was overexpressed at transcriptional and post-transcriptional levels. Overexpression of ADORA3 reduced TMC viability and migration but upregulated the extracellular matrix (ECM) proteins (FN, Col-I, and α-SMA) expression. It was found that ADORA3 can exacerbate oxidative stress injury in normal TMCs. These results indicated that ADORA3 might play an essential role in the occurrence and progression of POAG. CONCLUSIONS: A total of 61 novel common DEGs identified are related to the development and prognosis of POAG. In the POAG, ADORA3 was verified as overexpressed; therefore, it may be associated with an oxidative stress injury in TMCs.

c-FLIP regulates pyroptosis in retinal neurons following oxygen-glucose deprivation/recovery via a GSDMD-mediated pathway.

Cellular FLICE-inhibitory protein (c-FLIP), an anti-apoptotic regulator, shows remarkable similarities to caspase-8, which plays a key role in the cleavage of gasdermin D (GSDMD). It has been reported that the oxygen-glucose deprivation/recovery (OGD/R) model and lipopolysaccharide (LPS)/adenosine triphosphate (ATP) treatment could induce inflammation and pyroptosis. However, the regulatory role of c-FLIP in the pyroptotic death of retinal neurons is unclear. In this study, we hypothesized that c-FLIP might regulate retinal neuronal pyroptosis by GSDMD cleavage. To investigate this hypothesis, we induced retinal neuronal damage in vitro (OGD/R and LPS/ATP) and in vivo (acute high intraocular pressure [aHIOP]). Our results demonstrated that the three injuries triggered the up-regulation of pyroptosis-related proteins, and c-FLIP could cleave GSDMD to generate a functional N-terminal (NT) domain of GSDMD, causing retinal neuronal pyroptosis. In addition, c-FLIP knockdown in vivo ameliorated the already established visual impairment mediated by acute IOP elevation. Taken together, these findings revealed that decreased c-FLIP expression protected against pyroptotic death of retinal neurons possibly by inhibiting GSDMD-NT generation. Therefore, c-FLIP might provide new insights into the pathogenesis of pyroptosis-related diseases and help to elucidate new therapeutic targets and potential treatment strategies.

Targeting Programmed Cell Death to Improve Stem Cell Therapy: Implications for Treating Diabetes and Diabetes-Related Diseases.

Stem cell therapies have shown promising therapeutic effects in restoring damaged tissue and promoting functional repair in a wide range of human diseases. Generations of insulin-producing cells and pancreatic progenitors from stem cells are potential therapeutic methods for treating diabetes and diabetes-related diseases. However, accumulated evidence has demonstrated that multiple types of programmed cell death (PCD) existed in stem cells post-transplantation and compromise their therapeutic efficiency, including apoptosis, autophagy, necroptosis, pyroptosis, and ferroptosis. Understanding the molecular mechanisms in PCD during stem cell transplantation and targeting cell death signaling pathways are vital to successful stem cell therapies. In this review, we highlight the research advances in PCD mechanisms that guide the development of multiple strategies to prevent the loss of stem cells and discuss promising implications for improving stem cell therapy in diabetes and diabetes-related diseases.

Cyto-biological effects of microRNA-424-5p on human colorectal cancer cells.

MicroRNA (miR)-424-5p is overexpressed in colorectal cancer (CRC); however, its role, clinical significance and underlying molecular mechanism have remained to be fully elucidated. The aim of the present study was to investigate the roles of miR-424-5p in CRC and the underlying mechanisms. It was demonstrated that miR-424-5p is overexpressed in CRC, based on bioinformatics analysis using The Cancer Genome Atlas TCGA and analysis of tissue samples from patients with CRC from The First Hospital of Hebei Medical University, and the expression of miR-424-5p was associated with the depth of invasion and Dukes' staging. In CRC cells, the oncogenic roles of miR-424-5p were also verified by Cell Counting Kit-8, wound healing and Transwell assays. To identify target genes, all transcripts were compared between miR-424-5p mimic-transfected SW480 cells and mimic control cells by transcriptome sequencing. Subsequently, the differentially expressed genes (DEGs) were subjected to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. The DEGs were revealed to be significantly enriched in the GO terms 'serine hydrolase activity,' 'serine-type peptidase activity' and 'serine-type endopeptidase activity'. KEGG signaling pathway analysis indicated that the DEGs were significantly enriched in 'endocytosis', 'regulation of actin cytoskeleton', 'Wnt signaling pathway' and 'ubiquitin-mediated proteolysis signaling pathway'. These results suggested that miR-424-5p is a potential target in the treatment of CRC.

Significant association between long non-coding RNA H19 polymorphisms and cancer susceptibility: A PRISMA-compliant meta-analysis and bioinformatics prediction.

BACKGROUND: H19, a well-known long non-coding RNA, is involved in carcinogenesis and progression of multiple cancers. Molecular epidemiological research suggests that polymorphisms in H19 are associated with an increased risk of cancer, but the results are inconsistent. Thus, we performed a meta-analysis to estimate the associations between H19 polymorphisms and cancer susceptibility. METHODS: PubMed, Embase, and Web of Science databases were searched. Odds ratios with 95% confidence interval were applied to assess the association between H19 rs2107425, rs217727, rs2839698, rs2735971, rs3024270, and rs3741219 polymorphisms and cancer susceptibility in all 5 models. We also predicted the H19 secondary structure, as well as the generation and abolishment of miRNA binding sites on H19 through the selected SNPs. RESULTS: Eighteen related studies, involving 17,090 patients and 23,532 control samples, were analyzed. The pooled data showed that rs2839698 polymorphism was significantly associated with an increased cancer susceptibility. As for rs217727 and rs3024270 polymorphisms, similarly increased risks were found in specific genetic models and stratified groups. However, significant decreases in cancer risk were observed for rs2107425 and rs2735971 in the total population, as well as in subgroup analyses. In addition, no significant associations were found in all 5 models for rs3741219 polymorphism. Furthermore, RNAfold prediction revealed that the centroid secondary structure was markedly altered in rs217727 and rs2735971. We also identified that rs217727 G>A and rs2839689 G>A alleles could create and destroy miRNA binding sites on H19. CONCLUSION: The results of our meta-analyses suggest that H19 polymorphisms may be associated with the risk of cancer development.

Ferrocene-containing hybrids as potential anticancer agents: Current developments, mechanisms of action and structure-activity relationships.

Cancer is one of the most fatal threatens to human health throughout the world. The major challenges in the control and eradication of cancers are the continuous emergency of drug-resistant cancer and the low specificity of anticancer agents, creating an urgent need to develop novel anticancer agents. Organometallic compounds especially ferrocene derivatives possess remarkable structural and mechanistic diversity, inherent stability towards air, heat and light, low toxicity, low cost, reversible redox, ligand exchange, and catalytic properties, making them promising drug candidates for cancer therapy. Ferrocifen, a ferrocene-phenol hybrid, has demonstrated promising anticancer properties on drug-resistant cancers. Currently, Ferrocifen is in pre-clinical trial against cancers. Obviously, ferrocene moiety is a useful template for the development of novel anticancer agents. This review will provide an overview of ferrocene-containing hybrids with potential application in the treatment of cancers covering articles published between 2010 and 2020. The mechanisms of action, the critical aspects of design and structure-activity relationships are also discussed.

Krüppel-like factor 4 induces apoptosis and inhibits tumorigenic progression in SK-BR-3 breast cancer cells.

Krüppel-like factor 4 (KLF4) functions as either a tumor suppressor or an oncogene in different tissues by regulating the expression of various genes. The aim of this study was to reveal the functions of KLF4 in regulating breast cancer apoptosis, proliferation, and tumorigenic progression. KLF4 expression levels in breast cancer tissues and breast cancer cell lines were found to be much lower than those in nontumorous tissues and a nontransformed mammary epithelial cell line. KLF4 was upregulated in the tumor necrosis factor-α-induced SK-BR-3 breast cancer cell apoptotic process. Overexpression of KLF4 promoted SK-BR-3 breast cancer cell apoptosis and suppressed SK-BR-3 cell tumorigenicity in vivo.