Genetic susceptibility to prostate cancer in Taiwan: A genome-wide association study.

We conducted the first genome-wide association study (GWAS) of prostate cancer (PCa) in Taiwan with 1844 cases and 80,709 controls. Thirteen independent single-nucleotide polymorphisms (SNPs) reached genome-wide significance (p < 5 × 10-8 ). Among these, three were distinct from previously identified loci: rs76072851 in CORO2B gene (15q23), odds ratio (OR) = 1.54, 95% confidence interval (CI), 1.36-1.76, p = 5.30 × 10-11 ; rs7837051, near two long noncoding RNA (lncRNA) genes, PRNCR1 and PCAT2 (8q24.21), OR = 1.41 (95% CI, 1.31-1.51), p = 8.77 × 10-21 ; and rs56339048, near an lncRNA gene, CASC8 (8q24.21), OR = 1.25 (95% CI, 1.16-1.35), p = 2.14 × 10-8 . We refined the lead SNPs for two previously identified SNPs in Taiwanese: rs13255059 (near CASC8), p = 9.02 × 10-43 , and rs1456315 (inside PRNCR1), p = 4.33 × 10-42 . We confirmed 35 out of 49 GWAS-identified East Asian PCa susceptibility SNPs. In addition, we identified two SNPs more specific to Taiwanese than East Asians: rs34295433 in LAMC1 (1q25.3) and rs6853490 in PDLIM5 (4q22.3). A weighted genetic risk score (GRS) was developed using the 40 validated SNPs and the area under the receiver-operating characteristic curve for the GRS to predict PCa was 0.67 (95% CI, 0.63-0.71). These identified SNPs provide valuable insights into the molecular mechanisms of prostate carcinogenesis in Taiwan and underscore the significant role of genetic susceptibility in regional differences in PCa incidence.

TP53R175H mutation promotes breast cancer cell proliferation through CORO1A-P38 MAPK pathway regulation.

Breast cancer is the most commonly diagnosed cancer in women. Among all types, triple-negative breast cancer is particularly challenging to cure because of its high recurrence rates and invasive and metastatic capacity. Although numerous studies have explored the role of TP53 mutations in cancer, there is a dearth of research regarding the correlation between TP53 mutations and breast cancer cell proliferation. In this study, our aim was to examine the impact of TP53 mutations on the prognosis of patients with breast cancer bioinformatics techniques. To detect cell proliferation, a CCK8 assay was performed, and western blotting was used to identify the expression of p53, p38, and p-p38 proteins. Cellular mRNA sequencing was used to screen target genes of TP53 mutations, and molecular docking was performed to identify the drugs that could hinder the proliferation of breast cancer cells.The results showed that the TP53 mutation rate is higher in patients with triple-negative breast cancer than non-triple-negative breast cancer, and those with TP53 mutations tended to have a poorer prognosis than those without. Patients with R175H site mutations also had shorter survival times than those without. Cytological experiments revealed that the TP53R175H mutation increases the rate of breast cancer cell proliferation. In conjunction with this, CORO1A was found to be a downstream target of TP53 mutations, and it was determined to promote breast cancer cell proliferation. Moreover, CORO1A overexpression resulted in the downregulation of p-p38 levels. Molecular docking studies further revealed that tea polyphenols can inhibit breast cancer proliferation by binding to p53.

De Novo Variants Found in Three Distinct Schizophrenia Populations Hit a Common Core Gene Network Related to Microtubule and Actin Cytoskeleton Gene Ontology Classes.

Schizophrenia (SZ) is a heterogeneous and debilitating psychiatric disorder with a strong genetic component. To elucidate functional networks perturbed in schizophrenia, we analysed a large dataset of whole-genome studies that identified SNVs, CNVs, and a multi-stage schizophrenia genome-wide association study. Our analysis identified three subclusters that are interrelated and with small overlaps: GO:0007017~Microtubule-Based Process, GO:00015629~Actin Cytoskeleton, and GO:0007268~SynapticTransmission. We next analysed three distinct trio cohorts of 75 SZ Algerian, 45 SZ French, and 61 SZ Japanese patients. We performed Illumina HiSeq whole-exome sequencing and identified de novo mutations using a Bayesian approach. We validated 88 de novo mutations by Sanger sequencing: 35 in French, 21 in Algerian, and 32 in Japanese SZ patients. These 88 de novo mutations exhibited an enrichment in genes encoding proteins related to GO:0051015~actin filament binding (p = 0.0011) using David, and enrichments in GO: 0003774~transport (p = 0.019) and GO:0003729~mRNA binding (p = 0.010) using Amigo. One of these de novo variant was found in CORO1C coding sequence. We studied Coro1c haploinsufficiency in a Coro1c+/- mouse and found defects in the corpus callosum. These results could motivate future studies of the mechanisms surrounding genes encoding proteins involved in transport and the cytoskeleton, with the goal of developing therapeutic intervention strategies for a subset of SZ cases.

Exploring Potential Biomarkers of Early Thymoma based on Serum Proteomics.

BACKGROUND: Early diagnosis remains difficult because the early symptoms of thymoma are atypical. OBJECTIVES: This study aimed to analyze the changes of serum proteins in the early stage of thymoma (stage I/II) by proteomics method and to screen and validate candidate biomarkers. METHODS: Proteins were extracted from 8 sera patients with stage I/II thymoma and 9 healthy controls. The levels of serum proteins were detected by data-independent acquisition (DIA) quantitative proteomics techniques, and the differential proteins were identified. The proteomic results were verified by enzyme-linked immunosorbent assay. Additionally, differentially expressed proteins were analyzed using receiver operating characteristic curves (ROC). RESULTS: There were 80 differentially expressed proteins between the patients with thymoma and the healthy control group, among which 39 were up-regulated and 41 were down-regulated. Differential protein enrichment is involved in environmental information processing, signaling molecules and interactions, and in the body system and the immune system. The analysis of receptor working characteristic curves showed that the areas under the curve of CORO1A, SAA1 and LTA4H were all larger than 0.8, indicating that these proteins had good diagnostic value. CONCLUSION: CORO1A, SAA1 and LTA4H may be new biomarkers for early screening of thymoma.

Circular RNA circ-SLC7A5 Functions as a Competing Endogenous RNA to Impact Cell Biological Behaviors in Esophageal Squamous Cell Carcinoma (ESCC).

BACKGROUND: Circular RNAs (circRNAs) have profound effects on establishment and pathogenesis of esophageal squamous cell carcinoma (ESCC). Here, we defined whether circRNA solute carrier family 7 member 5 (circ-SLC7A5, also called hsa_circ_0040796) is causally involved in the pathogenesis of ESCC. METHODS: Circ-SLC7A5, microRNA (miR)-874-3p and coronin-1C (CORO1C) expression levels were gauged by qRT-PCR or immunoblotting. Cell functional phenotypes were tested by colony formation, EdU, flow cytometry, transwell and wound-healing assays. RNA immunoprecipitation (RIP) and dual-luciferase reporter assays were applied to ascertained circ-SLC7A5/miR-874-3p and miR-874-3p/CORO1C relationships. RESULTS: Circ-SLC7A5 was highly expressed in human ESCC. Circ-SLC7A5 depletion impaired cell growth, migration, invasiveness, and promoted apoptosis. Circ-SLC7A5 knockdown diminished ESCC cell tumorigenicity. Mechanistically, circ-SLC7A5 contained a binding site for miR-874-3p. Also, miR-874-3p was responsible for circ-SLC7A5's function in ESCC cells. CORO1C was a direct miR-874-3p target. Circ-SLC7A5 functioned as a competing endogenous RNA (ceRNA) to control CORO1C by competing for shared miR-874-3p. Furthermore, CORO1C knockdown phenocopied miR-874-3p overexpression in impacting the biological behaviors of ESCC cells. CONCLUSION: These findings identify circ-SLC7A5 as a crucial modulator of ESCC cells and establish a novel circ-SLC7A5/miR-874-3p/CORO1C ceRNA network in ESCC.

Uso de anticoagulantes parenterales en pacientes con síndromes coronarios / Use of parenteral anticoagulants in patients with coro nary syndromes

Resumen El tratamiento anticoagulante, en conjunto con la anti agregación, cumple un rol de suma importancia en el tratamiento de los síndromes coronarios agudos. Su uso está asociado a reducción de nuevos eventos isquémicos, trombosis del stent e incluso menor morta lidad. No obstante, en la práctica clínica existe una gran heterogeneidad en su utilización, llevando a resultados subóptimos en el tratamiento. Este trabajo ofrece una revisión narrativa sobre el uso de anticoagulantes parenterales en pacientes con sín dromes coronarios agudos, dependiendo del escenario clínico, así como también de la estrategia de revascula rización implementada y el riesgo hemorrágico. Se abordan los diferentes esquemas anticoagulantes disponibles en síndromes coronarios agudos con y sin elevación del segmento ST, basados en la evidencia ac tualizada hasta la fecha. Finalmente, se desarrollan herramientas para la es tratificación del riesgo de sangrado y su manejo tera péutico.

Abstract Anticoagulant treatment, together with antiplatelet therapy, plays an important role in the treatment of acute coronary syndromes. Its use is associated with a reduction in new ischemic events, stent thrombosis, and lower mortality. However, in clinical practice there is great heterogene ity in its use, leading to suboptimal results in treatment. This paper conducts a narrative review on the use of parenteral anticoagulants in patients with acute coronary syndromes, depending on the clinical scenario, as well as the revascularization strategy used and the bleeding risk. The different anticoagulant schemes available in acute coronary syndromes with and without segment ST elevation are addressed, based on the updated evidence. Finally, evidence-based strategies for risk stratifi cation for bleeding and therapeutic management are developed.

A Mendelian Randomization-Based Causal Investigation on Bacterial Infection-Related Genes and Neurodegenerative Diseases.

Neurodegenerative diseases remain the most prevalent and unsolved health problems in human society, especially Alzheimer's disease (AD) and Parkinson's disease (PD). The pathogenesis, pathology, and potential clinical treatments of neurodegenerative diseases still require in-depth research. In the wake of the association between pandemics and a growing number of neurodegeneration patients, there has been growing speculation that infections are linked to AD and PD. The Aß peptide is an important causal-related biomarker of AD and is reported to share structural and functional similarities with certain antimicrobial peptides, suggesting that it has a role in eliciting an immune response against microbes. But how neurodegeneration is related to bacterial chronic infection has not been thoroughly investigated. Using the data from genome-wide association studies (GWAS), we performed Mendelian Randomization (MR) and map 7 genes in multiple bacterial infection pathways as exposure, which show a significant association with the outcome of AD or PD. As co-verification, we perform Gene Set Enrichment Analysis (GSEA) on selected genetic variants incorporating their perturb-seq gene list (combining single-cell RNA-seq and CRISPR-based perturbations). We observed clustering of the differentially expressed genes (DEGs) in the upstream and downstream of AD and PD-related KEGG pathways, hence confirming their causal association with AD and PD and providing new perspectives on the true cause of neurodegeneration.

Identification of molecular signatures in acute myocardial infarction based on integrative analysis of proteomics and transcriptomics.

BACKGROUND: Myocardial infarction (MI) is one of the most serious cardiovascular diseases, characterized by a rapid and irreversible decline in myocardial function. Early detection of patients with MI and prolonging the optimal therapeutic window of acute myocardial infarction (AMI) are particularly important. This study aimed to identify the diagnostic biomarkers and novel therapeutic targets for acute myocardial infarction. METHOD: We generated the AMI mouse models by ligating the proximal left anterior descending coronary artery. Six time points-Sham, AMI 10-min, 1-h, 6-h, 24-h, and 72-h-were chosen to examine the molecular changes that occur during the AMI process. RNA-seq and DIA-MS were performed on the infarcted left ventricular tissues of AMI mice at each time point. Co-expression pattern genes were screened from myocardial infarction samples at different time points by time-series analysis. Gene Ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were used to examine these genes. Using the Interactive Gene/Protein Retrieval Tool (STRING) database, the protein-protein interaction network (PPI) was constructed and the hub genes were identified. In order to evaluate the diagnostic value of hub genes, a receiver operating characteristic (ROC) curve was constructed. An independent data set, GSE163772, confirmed the diagnostic value of hub genes further. RESULT: We obtained the expression profiles at different time points after the occurrence of heart failure through high-throughput sequencing, and found 167 genes with similar expression patterns through time series analysis. The immune response and immune-related pathways had the greatest enrichment of these genes. Among them, Itgb2 Syk, Tlr4, Tlr2, Itgax, and Lcp2 may play key roles as hub genes. Combined with the results of proteomic analysis, it was found that the expression of Coro1a in both omics increased with time. The results of external validation showed that TLR2, ITGAX, and LCP2 had good predictive ability for AMI diagnosis. CONCLUSION: Itgb2, Syk, Tlr4, Tlr2, Itgax, Lcp2 and Coro1a are considered to be the seven key genes significantly associated with AMI. Our results may provide potential targets for the prevention of adverse ventricular remodeling and the treatment of AMI.

Wip1 inhibits neutrophil extracellular traps to promote abscess formation in mice by directly dephosphorylating Coronin-1a.

Neutrophil extracellular traps (NETs) participate in the rapid inhibition and clearance of pathogens during infection; however, the molecular regulation of NET formation remains poorly understood. In the current study, we found that inhibition of the wild-type p53-induced phosphatase 1 (Wip1) significantly suppressed the activity of Staphylococcus aureus (S. aureus) and accelerated abscess healing in S. aureus-induced abscess model mice by enhancing NET formation. A Wip1 inhibitor significantly enhanced NET formation in mouse and human neutrophils in vitro. High-resolution mass spectrometry and biochemical assays demonstrated that Coro1a is a substrate of Wip1. Further experiments also revealed that Wip1 preferentially and directly interacts with phosphorylated Coro1a than compared to unphosphorylated inactivated Coro1a. The phosphorylated Ser426 site of Coro1a and the 28-90 aa domain of Wip1 are essential for the direct interaction of Coro1a and Wip1 and for Wip1 dephosphorylation of p-Coro1a Ser426. Wip1 deletion or inhibition in neutrophils significantly upregulated the phosphorylation of Coro1a-Ser426, which activated phospholipase C and subsequently the calcium pathway, the latter of which promoted NET formation after infection or lipopolysaccharide stimulation. This study revealed Coro1a to be a novel substrate of Wip1 and showed that Wip1 is a negative regulator of NET formation during infection. These results support the potential application of Wip1 inhibitors to treat bacterial infections.

Molecular characterization of the unusual peptide CORO1C-47aa encoded by the circular RNA and docking simulations with its binding partner.

Circular RNAs, which have covalently closed ends, are in the class of non-coding RNAs. Recent studies reveal that they are associated with various biochemical pathways. One such involvement of circular RNAs is in the onset of different types of cancers. Though the circular RNAs are known as non-coding RNAs, some of them are found to possess the capacities to code for proteins. One such circular RNA is hsa-circ-0000437 which is known to code for a short peptide referred to as CORO1C-47aa. The peptide has anti-angiogenic activity and is associated with the prevention of endometrial cancer. The peptide binds to the PAS-B domain of the Aryl hydrocarbon Receptor Nuclear Translocator (ARNT). However, till date only the amino acid sequence of the peptide is known and no structural details of the peptide are available. Therefore, in this work, our aim was to predict how the peptide would fold and what could be its possible ligand binding sites. We used computational tools to determine the structure of the peptide refined further by molecular dynamics simulations. We then performed molecular docking simulations of the peptide with its known binding partner ARNT to gain an insight into the modes of binding as the process is associated with endometrial cancer. The possible ligand binding sites along-with the natures of the possible other different ligands of the peptide were analyzed further. From this structure function analysis study, we tried to elucidate the plausible mechanism of the involvements of the peptide in the onset of endometrial cancer. This is the first report on the structural characterization of the peptide and its modes of interactions with the partner protein ARNT. This study may therefore be useful in determining the structures of new drug candidates for the treatment of endometrial cancer.

[Anomalous connections of coronary arteries : About 4 cases and litterature review]. / Les anomalies de connexion coronaires : à propos de 4 cas et revue de la littérature.

Coronary connection anomalies are a rare congenital anatomical aberration with an angiographic incidence of around 1%. In the majority of cases, these anomalies are incidentally discovered during coronary angiography or coro CT and remain silent without clinical translation, while in a certain number of cases, they can be responsible for serious clinical manifestations of up to sudden death. Coronary CT is crucial in the management of its patients since it makes it possible to objectify the presence of a pre-aortic course or the existence of an intramural aortic trajectory, two characteristics associated with the occurrence of sudden death. Through four clinical cases we illustrate the different situations in which we had to manage these anomalies.

Coronin 1C, Regulated by Multiple microRNAs, Facilitates Cancer Cell Aggressiveness in Pancreatic Ductal Adenocarcinoma.

Coronin proteins are actin-related proteins containing WD repeat domains encoded by seven genes (CORO1A, CORO1B, CORO1C, CORO2A, CORO2B, CORO6, and CORO7) in the human genome. Analysis of large cohort data from The Cancer Genome Atlas revealed that expression of CORO1A, CORO1B, CORO1C, CORO2A, and CORO7 was significantly upregulated in pancreatic ductal adenocarcinoma (PDAC) tissues (p < 0.05). Moreover, high expression of CORO1C and CORO2A significantly predicted the 5 year survival rate of patients with PDAC (p = 0.0071 and p = 0.0389, respectively). In this study, we focused on CORO1C and investigated its functional significance and epigenetic regulation in PDAC cells. Knockdown assays using siRNAs targeting CORO1C were performed in PDAC cells. Aggressive cancer cell phenotypes, especially cancer cell migration and invasion, were inhibited by CORO1C knockdown. The involvement of microRNAs (miRNAs) is a molecular mechanism underlying the aberrant expression of cancer-related genes in cancer cells. Our in silico analysis revealed that five miRNAs (miR-26a-5p, miR-29c-3p, miR-130b-5p, miR-148a-5p, and miR-217) are putative candidate miRNAs regulating CORO1C expression in PDAC cells. Importantly, all five miRNAs exhibited tumor-suppressive functions and four miRNAs except miR-130b-5p negatively regulated CORO1C expression in PDAC cells. CORO1C and its downstream signaling molecules are potential therapeutic targets in PDAC.

Propofol mediates non-small cell lung cancer growth in part by regulating circ_0003028-related mechanisms.

BACKGROUND: Circular RNAs (circRNAs) are associated with propofol-mediated inhibitory effect on non-small cell lung cancer (NSCLC) progression. Circular hsa_circ_0003028 (circ_0003028) exerts a tumor-promoting role in NSCLC. However, it is unclear whether propofol can mediate NSCLC progression via regulating circ_0003028 expression. METHODS: A total of 36 NSCLC patients were recruited in the study. Cell viability, proliferation, apoptosis, migration, and invasion were determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), colony formation, flow cytometry, and transwell assays. Relative expression of circ_0003028 in NSCLC samples and cells was detected by quantitative real-time polymerase chain reaction (RT-qPCR). Analysis of the latent binding of circ_0003028 to miR-1305 was done by bioinformatic analysis and confirmed by luciferase reporter and RNA immunoprecipitation (RIP) assays. Xenografting in mice was done to verify the relationship between propofol and circ_0003028. RESULTS: Significant upregulation of circ_0003028 was detected in NSCLC samples and cells. Functionally, propofol treatment reduced circ_0003028 expression in NSCLC cells, and circ_0003028 overexpression impaired propofol-mediated inhibitory effect on NSCLC cell proliferation, migration, and invasion. Interestingly, circ_0003028 could compete with miR-1305 as a competing endogenous RNA and upregulate CORO1C expression in NSCLC cells. CONCLUSION: Propofol-mediated inhibiting effect on NSCLC growth partly depended on the circ_0003028/miR-1305/CORO1C axis.

Deciphering the Role of microRNA Mediated Regulation of Coronin 1C in Glioblastoma Development and Metastasis.

Glioblastoma multiforme (GBM) is a highly heterogenic and malignant brain tumour with a median survival of 15 months. The initial identification of primary glioblastomas is often challenging. Coronin 1C (CORO1C) is a key player in actin rearrangement and cofilin dynamics, as well as enhancing the processes of neurite overgrowth and migration of brain tumour cells. Different bioinformatic databases were accessed to measure CORO1C expression at the mRNA and protein level in normal and malignant brains. CORO1C expression was observed in brain regions which have retained high synaptic plasticity and myelination properties. CORO1C was also expressed mainly within the hippocampus formation, including the Cornu Ammonis (CA) fields: CA1-CA4. Higher expression was also noticed in paediatric GBM in comparison to their adult counterparts. Pediatric cell populations were observed to have an increased log2 expression of CORO1C. Furthermore, 62 miRNAs were found to target the CORO1C gene. Of these, hsa-miR-34a-5p, hsa-miR-512-3p, hsa-miR-136-5p, hsa-miR-206, hsa-miR-128-3p, and hsa-miR-21-5p have shown to act as tumour suppressors or oncomiRs in different neoplasms, including GBM. The elevated expression of CORO1C in high grade metastatic brain malignancies, including GBM, suggests that this protein could have a clinical utility as a biomarker linked to an unfavorable outcome.

CORO1C, a novel PAK4 binding protein, recruits phospho-PAK4 at serine 99 to the leading edge and promotes the migration of gastric cancer cells.

Gastric cancer is one of the malignant tumors in the world. PAK4 plays an important role in the occurrence and development of gastric cancer, especially in the process of invasion and metastasis. Here we discover that CORO1C, a member of coronin family that regulates microfilament and lamellipodia formation, recruits cytoplasmic PAK4 to the leading edge of gastric cancer cells by C-terminal extension (CE) domain of CORO1C (353-457 aa). The localization of PAK4 on the leading edge of the cell depends on two necessary conditions: the phosphorylation of PAK4 on serine 99 and the binding to the CE domain of CORO1C. Unphosphorylated PAK4 on serine 99 is closely associated with microtubules by PAK4/GEF-H1/Tctex-1 complex. Once phosphorylated, PAK4 is released from microtubule, and then is recruited by CORO1C to the leading edge and regulates the CORO1C/RCC2 (regulator of chromosome condensation 2) complex, leading to the migration of gastric cancer cells. Our results reveal a new mechanism by which PAK4 regulates the migration potential of gastric cancer cells through microtubule-microfilament cross talk.

Circ_0020123 plays an oncogenic role in non-small cell lung cancer depending on the regulation of miR-512-3p/CORO1C.

BACKGROUND: Non-small cell lung cancer (NSCLC) is one of the leading causes responsible for cancer-associated death globally. The aim of this study was to illustrate the function of circular RNA_0020123 (circ_0020123) in NSCLC progression and its associated mechanism. METHODS: RNA and protein expression was determined by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blot assay. Cell proliferation, migration, invasion, angiogenesis, apoptosis and autophagy were analyzed to assess the role of circ_0020123/microRNA-512-3p (miR-512-3p)/coronin 1C (CORO1C) axis in NSCLC cells. Tumorigenesis in nude mice was analyzed to determine the in vivo role of circ_0020123. The intermolecular target relation was confirmed by dual-luciferase reporter and RNA immunoprecipitation (RIP) assays. RESULTS: Circ_0020123 expression was aberrantly upregulated in NSCLC tissues and cell lines. Circ_0020123 interference markedly restrained cell proliferation, migration, invasion, angiogenesis and autophagy and induced cell apoptosis of NSCLC cells. Circ_0020123 knockdown suppressed xenograft tumor growth in vivo. Circ_0020123 acted as a molecular sponge for miR-512-3p. Circ_0020123 silencing-induced effects in NSCLC cells were largely reversed by the knockdown of miR-512-3p. miR-512-3p interacted with the 3' untranslated region (3'UTR) of CORO1C. CORO1C overexpression largely reversed miR-512-3p accumulation-induced influences in NSCLC cells. Circ_0020123 positively regulated CORO1C expression by sponging miR-512-3p in NSCLC cells. CONCLUSION: Circ_0020123 aggravated NSCLC progression by binding to miR-512-3p to induce CORO1C expression, which provided new potential targets for the treatment of NSCLC.

Identification of key biomarkers and immune infiltration in renal interstitial fibrosis.

Background: Renal interstitial fibrosis (RIF) is the common final pathway that mediates almost all progressive renal diseases. However, the underlying mechanisms of RIF have not been fully elucidated. Therefore, the current study aimed to explore the etiology of RIF and identify the key targets and immune infiltration patterns of RIF. Methods: Ribonucleic acid (RNA)-seq data of RIF and normal samples were downloaded from the Gene Expression Omnibus (GEO) database. Weighted gene co-expression network analysis (WGCNA) was performed to screen relevant modules associated with RIF. Differentially expressed genes (DEGs) between the RIF and normal samples were identified using the limma package. Machine learning methods were used to identify hub gene signatures related to RIF. Further biochemical approaches including quantitative polymerase chain reaction (qPCR), immunoblotting and immunohistochemistry experiments were performed to verify the hub signatures in the RIF samples. Single sample gene set enrichment analysis (ssGSEA) was used to analyze the proportions of 28 immune cells in RIF and normal samples. Results: WGCNA showed 121 RIF-related genes. A total of 523 DEGs were found between the RIF and normal samples. By overlapping these genes, we obtained 78 RIF-related genes, which were mainly enriched in Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways associated with immunity and inflammation. Integrative analysis of machine learning methods showed prominin 1 (PROM1), tryptophan aspartate-containing coat protein (CORO1A), interferon-stimulated exonuclease gene 20 (ISG20), and tissue inhibitor matrix metalloproteinase 1 (TIMP1) as hub gene signatures in RIF. Further, receiver operating curve (ROC) curves implied the diagnostic role of ISG20 and CORO1A in RIF. The expression levels of ISG20 and CORO1A were significantly higher in fibrotic tubular cells and renal tissues based on biochemical approaches. The immune microenvironment was found to be markedly altered in the RIF samples, as 21 differentially infiltrated immune cells (DIICs) were found between RIF and normal samples. Conclusions: This study is the first to find that ISG20 and CORO1A are key biomarkers and to examine the landscape of immune infiltration in RIF. Our findings provide novel insights into the mechanisms and treatment of patients with RIF.

CORO1A regulates lipoprotein uptake in Leydig cells exposed to cadmium.

Cadmium (Cd) is one of the most common environmental pollutants, which has a long biological half-life. Maternal Cd-exposure in the natural environment causes steroidogenesis defects resulting in spermatogenesis disorder in male offspring. For better understanding its underlying mechanism, we have employed iTRAQ to screen the differentially expressed protein and found that the expression of CORO1A and Cofilin 1 was up-regulated approximately 2 fold in Leydig cells of maternal Cd-exposure offspring. As the major source of steroid hormone, cholesterol is transported to cells via receptor-mediated endocytosis which relies on the remodel of cytoskeleton, then stores in lipid droplets (LDs). However, few studies have focused on the role of cytoskeleton in abnormal steroidogenesis. This study was performed to explore the role of CORO1A in androgen deficiency caused by Cd exposure and its involvement of low-density lipoprotein (LDL) uptake and effects on LDs. We found that Cd resulted in the up-regulation of CORO1A and Cofilin 1, and down-regulation of Profilin 1 in the testis of male offspring with maternal exposure. The structure of filamentous actin was broken, disordered and even crumpled up in Cd-treated R2C cells. F-actin disassembly led to a low uptake of LDL with a reduced number of LDs, followed by decreased total cholesterol and low progesterone production. When CORO1A was silenced, the expression of Cofilin 1 was down-regulated and Profilin 1 was up-regulated in Cd-treated R2C cells. The filamentous actin was rescued and the integrated cytoskeleton prompted LDL uptake, which resulted in the increased total cholesterol and high progesterone production. These findings highlight the crucial role of CORO1A as a cytoskeleton regulatory protein in steroidogenesis, which may help to better understand Cd-induced steroid hormone deficiency in children.

CircRNA CORO1C Regulates miR-654-3p/USP7 Axis to Mediate Laryngeal Squamous Cell Carcinoma Progression.

Circular RNAs have attracted the attention in the research on laryngeal squamous cell carcinoma (LSCC) development. But the function and mechanism of circRNA coronin-1C (circ_CORO1C) in LSCC progression are largely unknown. Circ_CORO1C, microRNA (miR)-654-3p, and ubiquitin-specific protease 7 (USP7) levels in LSCC tissues and cells were determined. Quantitative reverse transcription polymerase chain reaction and western blotting assays were conducted to determine the mRNA and protein levels of genes. Functional assays were further investigated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT), EdU staining, flow cytometry, transwell and xenograft assays. The binding relationship was examined by dual-luciferase reporter assay. Circ_CORO1C expression was elevated in LSCC samples and cells. circ_CORO1C silencing constrained cell proliferation and promoted apoptosis via reducing cell proliferation, inducing cell cycle arrest, inhibiting epithelial-mesenchymal transition, and promoting apoptosis, as well as restraining cell migration and invasion. USP7 is highly expressed in LSCC tissues and cells, and its expression was suppressed by circ_CORO1C silencing. Besides, the up-regulation of USP7 attenuated the influence of circ_CORO1C silencing on LSCC cell progression. Both circ_CORO1C and USP7 could bind to miR-654-3p. circ_CORO1C regulated USP7 expression by modulating miR-654-3p. miR-654-3p knockdown mitigated the influence of circ_CORO1C silence on LSCC cell progression. Furthermore, circ_CORO1C silencing reduced tumor growth in vivo. In conclusion, circ_CORO1C is highly expressed in LSCC tissues and cells, and circ_CORO1C silencing repressed LSCC progression via regulating miR-654-3p/USP7 axis.