FOXC1 Research Articles

LINC01614 Promotes Oral Squamous Cell Carcinoma by Regulating FOXC1

Background: Long non-coding RNAs (lncRNAs) are pivotal mediators during the development of carcinomas; however, it remains to be investigated whether lncRNAs are implicated in oral squamous cell carcinoma (OSCC). Methods: In this study, quantitative real-time PCR was conducted for detecting the expression of LINC01614 in OSCC cell lines. The biological functions of LINC01614 were assessed by loss- and gain-of-function experiments conducted both in vivo and in vitro. Cellular proliferation, migration, and invasion were investigated herein, and dual luciferase reporter assays were additionally performed to explore the relationships among LINC01614, miR-138-5p, and Forkhead box C1 (FOXC1). Results: The research presented herein revealed that OSCC cells express high levels of LINC01614. Functional experiments employing cellular and animal models demonstrated that LINC01614 knockdown repressed the malignant phenotypes of OSCC cells, including their growth, invasiveness, and migration. Further investigation revealed that LINC01614 absorbs miR-138-5p miRNA by functioning as a competing endogenous RNA to downregulate the abundance of FOXC1. Conclusions: The findings revealed that LINC01614 contributes to the progression of OSCC by targeting the FOXC1 signaling pathway. The study provides insights into a novel mechanistic process to regulate the development of OSCC, and established a possible target for the therapeutic management of OSCC.

Mitochondrial-Derived Signaling Mediates Differentiation of Parietal Epithelial Cells into Podocytes.

Aims: Parietal epithelial cells (PECs) are potential stem cells within the glomerulus, migrating into site of podocyte loss to differentiate into podocytes. Little is known about the mechanism mediating differentiation of PECs into podocytes. Results: In vitro differentiation of PECs into podocytes led to upregulation of podocyte markers such as Wilms' tumor gene 1 (WT-1), Forkhead box C1 (FOXC1), synaptopodin and podocin, accompanied by increased mitochondrial abundance. Preincubation with a mitochondrial reactive oxygen species (ROS) inhibitor prevented all these events in PECs. In vivo, adriamycin (ADR)-treated mice exhibited albuminuria, decreased WT1 positive cells, and claudin-1 expressed in glomerular capillary tuft, as well as peroxisome proliferator-activated receptor-γ coactivator-1α (PGC1α) overproduction in PECs. Expression of the ROS-related molecule nuclear factor erythroid 2-related factor 2 (Nrf2) and its target protein Brahma-related gene 1 (Brg1) increased during differentiation of PECs into podocytes. Suppressing Nrf2 or Brg1 reduced the differentiation of PECs, whereas overexpression had the opposite effect. Brg1 directly regulated WT-1 transcription in PECs. Activation of Nrf2 with bardoxolone-methyl (CDDO-Me) resulted in less proteinuria and more WT1 positive cells in ADR mice. PECs conditional human Nrf2 knock-in mice showed increased WT1 cell numbers. Conclusion: It concluded that mitochondria-derived ROS mediated differentiation of PECs into podocytes via Nrf2 and Brg1 signaling.

Forkhead box C1 promotes the pathology of osteoarthritis in subchondral bone osteoblasts via the Piezo1/YAP axis

Subchondral bone sclerosis is a key characteristic of osteoarthritis (OA). Prior research has shown that Forkhead box C1 (FoxC1) plays a role in the synovial inflammation of OA, but its specific role in the subchondral bone of OA has not been explored. Our research revealed elevated expression levels of FoxC1 and Piezo1 in OA subchondral bone tissues. Further experiments on OA subchondral bone osteoblasts with FoxC1 or Piezo1 overexpression showed increased cell proliferation activity, expression of Yes-associated Protein 1 (YAP) and osteogenic markers, and secretion of proinflammatory factors. Mechanistically, the overexpression of FoxC1 through Piezo1 activation, in combination with downstream YAP signaling, led to increased levels of alkaline phosphatase (ALP), collagen type 1 (COL1) A1, RUNX2, Osteocalcin, matrix metalloproteinase (MMP) 3, and MMP9 expression. Notably, inhibition of Piezo1 reversed the regulatory function of FoxC1. The binding of FoxC1 to the targeted area (ATATTTATTTA, residues +612 to +622) and the activation of Piezo1 transcription were verified by the dual luciferase assays. Additionally, Reduced subchondral osteosclerosis and microangiogenesis were observed in knee joints from FoxC1-conditional knockout (CKO) and Piezo1-CKO mice, indicating reduced lesions. Collectively, our study reveals the significant involvement of FoxC1 in the pathologic process of OA subchondral bone via the Piezo1/YAP signaling pathway, potentially establishing a novel therapeutic target.

Exploring the genetic expression of Sdf1, Foxc1 and histologic changes following mandibular advancement and recovery phase in Wistar rats.

PurposeThis study evaluated the impact of mandibular advancement on Sdf1 and Foxc1 gene expression in the mandibular condylar cartilage of young Wistar rats. By examining the changes that occur during a unique one-month recovery period, it highlights the critical role of gene expression and condylar adaptation during the recovery phase. The analysis focused on whether, during the recovery period, reversal changes occur when functional appliances are removed and whether genetic expression important for condyle growth and adaptation downregulates. Material and MethodsThe study involved 30 male Wistar rats divided into 2 control groups Appliance Control and Recovery Control groups, and 2 experimental groups, the Appliance group with mandibular advancement bite-jumping appliance for 30 days, and the Recovery group with appliance for 30 days followed by a 30-day recovery. Molecular analysis of condylar cartilage using real-time RT-PCR and histological assessments was conducted. ResultsSignificant genetic expression alterations were noted in both the experimental groups for Sdf1 (p < 0.05) and Foxc1 (p < 0.05). According to histological investigations, significant alterations with an increase in the proliferative and hypertrophic layer in condylar cartilage were seen. ConclusionMandibular advancement bite-jumping appliances induce proliferative and hypertrophic layer changes in mandibular condylar cartilage, shown by elevated Foxc1 levels and decreased Sdf1 levels. Post-appliance removal, persistent gene expression reveals a true joint stimulation.

The Influence of FOXC1 Gene on Development, Organogenesis, and Functions

The Influence of FOXC1 Gene on Development, Organogenesis, and Functions

Mutations of CYP1B1 and FOXC1 genes for childhood glaucoma in Japanese individuals.

To explore the frequency and positions of genetic mutations in CYP1B1 and FOXC1 in a Japanese population. Molecular genetic analysis. Genomic DNA was extracted from 31 Japanese patients with childhood glaucoma (CG) from 29 families. We examined the CYP1B, FOXC1, and MYOC genes using Sanger sequencing and whole-exome sequencing (WES). For CYP1B1, we identified 9 families that harbored novel mutations, p.A202T, p.D274E, p.Q340*, and p.V420G; the remaining mutations had been previously reported. When mapped to the CYP1B1 protein structure, all mutations appeared to influence the enzymatic activity of CYP1B1 by provoking structural deformity. Five patients were homozygotes or compound heterozygotes, supporting the recessive inheritance of the CYP1B1 mutations in CG. In contrast, four patients were heterozygous for the CYP1B1 mutation, suggesting the presence of regulatory region mutations or strong modifiers. For the FOXC1 gene, we identified 3 novel mutations, p.Q23fs, p.Q70R, and p.E163*, all of which were identified in a heterozygous state. No mutation was found in the MYOC gene in these CG patients. All individuals with CYP1B1 and FOXC1 mutations were severely affected by early-onset CG. In the CYP1B1-, FOXC1-, and MYOC-negative families, we also searched for variants in the other candidate genes reported for CG through WES, but could not find any mutations in these genes. Our analyses of 29 CG families revealed 9 families with point mutations in the CYP1B1 gene, and four of those patients appeared to be heterozygotes, suggesting the presence of complex pathogenic mechanisms. FOXC1 appears to be another major causal gene of CG, indicating that panel sequencing of CYP1B1 and FOXC1 will be useful for diagnosis of CG in Japanese individuals.

HTB50-2 Inhibits Growth and Migration of Triple-negative Breast Cancer via FOSL2/FOXC1 Signaling Axis and Subsequent Ferroptosis.

The manipulation of ferroptosis in cancer cells is a possible therapeutic technique that has been investigated for use in the treatment of cancer. Consequently, ferroptosis-inducing medications have recently received increased interest in cancer therapy. In this research, we assessed the anticancer efficacy of 14β-hydroxy- 3β-(β-D-Glucopyranosyloxy)-5α-bufa-20,22-dienolide (HTB50-2), a natural product derived from the plant Helleborus thibetanus Franch, in Triple-Negative Breast Cancer (TNBC). Moreover, we also studied its potential mechanisms. The biological effects of HTB50-2 in a series of breast cancer cell lines were analyzed using sulforhodamine B (SRB) and other methods. The migration ability was analyzed using three methods: wound healing assay, transwell assay, and Western blot. Meanwhile, the potential therapeutic value of HTB50-2 was evaluated in BALB/c mice by orthotopic transplantation. Transcriptome sequencing was conducted to explore the FOS-like antigen 2 (FOSL2) gene, and its role in ferroptosis was verified by Western blot and immunohistochemistry. The association of FOSL2 and ferroptosis-related genes was analyzed using NetworkAnalyst databases, and a TF-Gene interaction network was constructed. Ferroptosis was found to be induced in TNBC cells by HTB50-2. Furthermore, HTB50-2 inhibited tumor development by inducing ferroptosis in TNBC in vivo. Mechanistically, we demonstrated that a transcription factor FOSL2 mediated ferroptosis by HTB50-2. Additionally, it was found that Forkhead box C1 (FOXC1) was regulated by FOSL2 and correlated with ferroptosis. Our data suggest that HTB50-2 exerts its anti-cancer properties by ferroptosis via FOSL2/FOXC1 signaling pathway. Hence, HTB50-2 has an important application potential in the treatment of TNBC.

Exploring the Genetic Landscape of Childhood Glaucoma.

Childhood glaucoma, a significant cause of global blindness, represents a heterogeneous group of disorders categorized into primary or secondary forms. Primary childhood glaucoma stands as the most prevalent subtype, comprising primary congenital glaucoma (PCG) and juvenile open-angle glaucoma (JOAG). Presently, multiple genes are implicated in inherited forms of primary childhood glaucoma. This comprehensive review delves into genetic investigations into primary childhood glaucoma, with a focus on identifying causative genes, understanding their inheritance patterns, exploring essential biological pathways in disease pathogenesis, and utilizing animal models to study these mechanisms. Specifically, attention is directed towards genes such as CYP1B1 (cytochrome P450 family 1 subfamily B member 1), LTBP2 (latent transforming growth factor beta binding protein 2), TEK (TEK receptor tyrosine kinase), ANGPT1 (angiopoietin 1), and FOXC1 (forkhead box C1), all associated with PCG; and MYOC (myocilin), associated with JOAG. Through exploring these genetic factors, this review aims to deepen our understanding of the intricate pathogenesis of primary childhood glaucoma, thereby facilitating the development of enhanced diagnostic and therapeutic strategies.

Context-Responsive Nanoparticle Derived from Synthetic Zwitterionic Ionizable Phospholipids in Targeted CRISPR/Cas9 Therapy for Basal-like Breast Cancer.

The majority of triple negative breast cancers (TNBCs) are basal-like breast cancers (BLBCs), which tend to be more aggressive, proliferate rapidly, and have poor clinical outcomes. A key prognostic biomarker and regulator of BLBC is the Forkhead box C1 (FOXC1) transcription factor. However, because of its functional placement inside the cell nucleus and its structural similarity with other related proteins, targeting FOXC1 for therapeutic benefit, particularly for BLBC, continues to be difficult. We envision targeted nonviral delivery of CRISPR/Cas9 plasmid toward the efficacious knockdown of FOXC1. Keeping in mind the challenges associated with the use of CRISPR/Cas9 in vivo, including off-targeting modifications, and effective release of the cargo, a nanoparticle with context responsive properties can be designed for efficient targeted delivery of CRISPR/Cas9 plasmid. Consequently, we have designed, synthesized, and characterized a zwitterionic amino phospholipid-derived transfecting nanoparticle for delivery of CRISPR/Cas9. The construct becomes positively charged only at low pH, which encourages membrane instability and makes it easier for nanoparticles to exit endosomes. This has enabled effective in vitro and in vivo downregulation of protein expression and genome editing. Following this, we have used EpCAM aptamer to make the system targeted toward BLBC cell lines and to reduce its off-target toxicity. The in vivo efficacy, biodistribution, preliminary pharmacokinetics, and biosafety of the optimized targeted CRISPR nanoplatform is then validated in a rodent xenograft model. Overall, we have attempted to knockout the proto-oncogenic FOXC1 expression in BLBC cases by efficient delivery of CRISPR effectors via a context-responsive nanoparticle delivery system derived from a designer lipid derivative. We believe that the nonviral approach for in vitro and in vivo delivery of CRISPR/Cas9 targeted toward FOXC1, studied herein, will greatly emphasize the therapeutic regimen for BLBC.

Identification of crosstalk genes relating to ECM-receptor interaction genes in MASH and DN using bioinformatics and machine learning.

This study aimed to identify genes shared by metabolic dysfunction-associated fatty liver disease (MASH) and diabetic nephropathy (DN) and the effect of extracellular matrix (ECM) receptor interaction genes on them. Datasets with MASH and DN were downloaded from the Gene Expression Omnibus (GEO) database. Pearson's coefficients assessed the correlation between ECM-receptor interaction genes and cross talk genes. The coexpression network of co-expression pairs (CP) genes was integrated with its protein-protein interaction (PPI) network, and machine learning was employed to identify essential disease-representing genes. Finally, immuno-penetration analysis was performed on the MASH and DN gene datasets using the CIBERSORT algorithm to evaluate the plausibility of these genes in diseases. We found 19 key CP genes. Fos proto-oncogene (FOS), belonging to the IL-17 signalling pathway, showed greater centrality PPI network; Hyaluronan Mediated Motility Receptor (HMMR), belonging to ECM-receptor interaction genes, showed most critical in the co-expression network map of 19 CP genes; Forkhead Box C1 (FOXC1), like FOS, showed a high ability to predict disease in XGBoost analysis. Further immune infiltration showed a clear positive correlation between FOS/FOXC1 and mast cells that secrete IL-17 during inflammation. Combining the results of previous studies, we suggest a FOS/FOXC1/HMMR regulatory axis in MASH and DN may be associated with mast cells in the acting IL-17 signalling pathway. Extracellular HMMR may regulate the IL-17 pathway represented by FOS through the Mitogen-Activated Protein Kinase 1 (ERK) or PI3K-Akt-mTOR pathway. HMMR may serve as a signalling carrier between MASH and DN and could be targeted for therapeutic development.

Statement of Retraction: Forkhead-box C1 attenuates high glucose-induced trophoblast cell injury during gestational diabetes mellitus via activating adenosine monophosphate-activated protein kinase through regulating fibroblast growth factor 19

Statement of Retraction: Forkhead-box C1 attenuates high glucose-induced trophoblast cell injury during gestational diabetes mellitus via activating adenosine monophosphate-activated protein kinase through regulating fibroblast growth factor 19

Reciprocal regulation of forkhead box C1 and L1 cell adhesion molecule contributes to triple-negative breast cancer progression

PurposeThe potential of targeting forkhead box C1 (FOXC1) as a therapeutic approach for triple-negative breast cancer (TNBC) is promising. However, a comprehensive understanding of FOXC1 regulation, particularly upstream factors, remains elusive. Expression of the L1 cell adhesion molecule (L1CAM), a transmembrane glycoprotein associated with brain metastasis, was observed to be positively associated with FOXC1 transcripts. Thus, this study aims to investigate their relationship in TNBC progression.MethodsPublicly available FOXC1 and L1CAM transcriptomic data were obtained, and their corresponding proteins were analyzed in four TNBC cell lines. In BT549 cells, FOXC1 and L1CAM were individually silenced, while L1CAM was overexpressed in BT549-shFOXC1, MDA-MB-231, and HCC1937 cells. CCK-8, transwell, and wound healing assays were performed in these cell lines, and immunohistochemical staining was conducted in tumor samples.ResultsA positive correlation between L1CAM and FOXC1 transcripts was observed in publicly available datasets. In BT549 cells, knockdown of FOXC1 led to reduced L1CAM expression at both the transcriptional and protein levels, and conversely, silencing of L1CAM decreased FOXC1 protein levels, but interestingly, FOXC1 transcripts remained largely unaffected. Overexpressing L1CAM resulted in increased FOXC1 protein expression without significant changes in FOXC1 mRNA levels. This trend was also observed in BT549-shFOXC1, MDA-MB-231-L1CAM, and HCC1937-L1CAM cells. Notably, alterations in FOXC1 or L1CAM levels corresponded to changes in cell proliferation, migration, and invasion capacities. Furthermore, a positive correlation between L1CAM and FOXC1 protein expression was detected in human TNBC tumors.ConclusionFOXC1 and L1CAM exhibit co-regulation at the protein level, with FOXC1 regulating at the transcriptional level and L1CAM regulating at the post-transcriptional level, and together they positively influence cell proliferation, migration, and invasion in TNBC.

Importance of genetic studies in the diagnosis of glaucoma

Glaucoma is the world's leading cause of irreversible blindness being a known family grouping disease with a strong hereditary component. Based on the age of onset and other clinical characteristics, glaucoma has been classified into primary congenital glaucoma (PCG), juvenile glaucoma (JG), and primary open‐angle glaucoma (POAG), the latter occurring in adulthood. Early‐onset forms of glaucoma such as, PCG and JG, are typically monogenic diseases inherited as Mendelian autosomal dominant or recessive traits, whereas adult glaucoma is a complex trait, with multifactorial inheritance.Genetic variants causing early‐onset glaucoma are highly penetrant. Some examples include dominant negative pathogenic variants in the MYOC gene accounting for 10% of JG cases or biallelic pathogenic variants in CYP1B1 gene mainly associated with PCG. In our cohort of 32 patients with a diagnosis of PCG or JG, we have identified two JOAG patients with two different pathogenic variants in the olfactomedin/like domain of MYOC gene and one PGC patient with two heterozygote pathogenic variants in CYP1B1 gene. Familiar segregation studies of these genetic variants in the three families confirm their pathogenicity. On the one hand, segregation studies of both variants identified in MYOC gene revealed its presence in those relatives with a clinical diagnosis of glaucoma and its absence in healthy individuals. On the other hand, parental screening of both variants identified in CYP1B1 showed that each parent is an asymptomatic carrier of one of the variants confirming that our patient present both variants in CYP1B1 gene in compound heterozygosis. Furthermore, heterozygote pathogenic variants in FOXC1 and COL2A1 genes associated with Axenfeld‐Rieger syndrome type 3 and Stickler syndrome type 1, respectively, have been identified in two different patients with PGC. In these cases, glaucoma is a phenotypic trait of both syndromes inherited in an autosomal dominant manner.Family grouping is a known risk factor for glaucoma in the adult, with a risk 7–10 times greater than the observed in general population. The genetic study of adult glaucoma is complex since its transmission mechanisms are sometimes unclear and have variable penetrance and late onset. In our cohort of 65 patients diagnosed with adult glaucoma, we have identified rare genetic variants with uncertain clinic significance in CYP1B1, SIX6, CARD10, MFN1, OPTC, OPTN, and WDR36 glaucoma‐related genes. Some of these variants are classified as hypomorphic alleles that reduce but do not eliminate gene's functionality and they can contribute to late‐onset disorders.Glaucoma is a treatable disease if detected in early stages and treatment can stop visual loss, however if damage has already occurred it cannot be reverted. Therefore, to identify a genetic cause associated with glaucoma is not only beneficial for the patient but also to detect asymptomatic carriers of the disease in the family‐relatives, which will be susceptible for early treatment. Therefore, proper genetic analysis may provide more accurate information on the prognosis and the adequacy of the therapeutic approach to personalize the treatment of glaucoma.

Molecular Analysis of the First Reported Hereditary Lymphedema-distichiasis Case in Bangladesh

Lymphedema–distichiasis syndrome (LD, OMIM 153400) is hereditary primary lymphedema with autosomal dominant nature of inheritance and variable expression. LD is characterized by late childhood or pubertal onset of lower limb lymphedema and an aberrant second row of eyelashes (distichiasis) arising from the meibomian glands. Among the molecular reasons behind this condition are the mutations in the FOXC2 gene, a forkhead transcription factor, that plays a role in the formation of lymphatic and vascular systems. In this study, we report the first case of LD from Bangladesh with classical lymphedema–distichiasis syndrome with an eight-base-pair deletion in the FOXC2 gene. ClinVar accession code for this deletion is RCV000007679.3. FOXC2 protein is 501 amino acids long. This deletion of 8 bp (ACGCCGCC) causes frameshift of codons after amino acid number 304. The frameshift creates an altered truncated protein with 154 new amino acids after codon 304. We assume that these changes in the protein may affect its function contributing to the disease manifestations. Further research may confirm these assumptions. J. Bangladesh Acad. Sci. 47(2); 205-213: December 2023

The XPO1-FOXC1-HOX Functional Axis Opens New Therapeutic Avenues to Treat DEK-NUP214 AML Patients

Introduction: t(6;9)(p23;q34.1)/DEK-NUP214 patients represent a discrete group of younger AML patients recognised as a separate disease entity in the World Health Organization classification of myeloid neoplasms. They typically display a dismal prognosis, higher relapse rate and a striking co-occurrence with FLT3-ITD mutations in &amp;gt; 70% of cases. DEK is a nuclear factor that has been attributed multifunctional roles, including gene regulation, while its fusion partner, NUP214, plays a pivotal role in nuclear export by interacting with transport receptors such as XPO1. However, the precise mechanism by which DEK-NUP214 drives leukaemia remains unclear. Aims: Application of a multi-omics profiling to understand the oncogenic mechanisms underlying DEK-NUP214 fusion protein and identify potential therapeutical vulnerabilities. Methods: A comprehensive multi-omics screening (whole genome sequencing, targeted sequencing, transcriptomics, (phosphor)proteomics, mass cytometry (CyTOF) and in vitro drug screening) was conducted on 57 untreated primary AML samples from cytogenetically poor-risk AML, including four cases with t(6;9) translocation (complex karyotype (n=20), -7/del(7) (n=15), KMT2A rearrangements (not including t(9;11)) (n=12), t(6;9) (n=4) and other poor-risk karyotypes (inv(3), -5/del(5), t(3;12)/+8 or -17/del(17)) (n=6)). The t(6;9)/DEK-NUP214 cell line FKH-1, was utilised as a model for in vitro experiments and compared with other AML cell lines (OCI-AML3, KASUMI-1, THP-1, P31-FUJ, MV4-11 and K562). In vitro drug treatments were conducted in the cell lines and patient samples using Cell-Titer&amp;Glo, and transcriptional changes were evaluated using qPCR and RNA-seq. To examine the function of selected target genes of DEK-NUP214, we used lentiviral shRNA system followed by cell cycle, apoptosis, differentiation, and cell proliferation assays. Results: An integrative RNA-seq analysis of our cohort and a separate series of 691 AML cases that included three additional t(6;9) cases (Leucegene, https://leucegene.ca/) revealed 128 genes significantly upregulated and 74 downregulated in t(6;9) patients compared to other AML samples. The overexpressed genes included some known leukaemia mediators (FOXC1, HOXA and HOXB genes), the genes previously reported in t(6;9) patients (EYA3, SESN1 and PRDM2) and novel genes with roles in haematopoiesis or cancer cell survival that showed the most significant differences (NFIX and GGT5). The significant overexpression of these genes was also confirmed in the t(6;9) FKH-1 cell line. In vitro drug screening of 527 licenced or investigational drugs allowed us to identify the compounds that were most effective and selective for t(6;9) patients in comparison with other AML cytogenetic groups. The two XPO1 inhibitors (Selinexor and Eltanexor) included in our drug panel were within the four top-ranked compounds. Of note, qPCR and RNA-seq analyses in the cell lines and primary patient samples showed that inhibition of XPO1 resulted in significant downregulation of the expression of FOXC1, NFIX, EYA3, HOXA and HOXB genes, highlighting a functional axis linking these target genes, XPO1 and the fusion. In line with this finding, silencing of FOXC1 in the FKH-1 cells led to an increase in apoptosis, lower cell proliferation and reduced clonogenic capacity, accompanied by a concomitant downregulation of HOXA and HOXB genes. Collectively, these findings support a key role of FOXC1 in DEK-NUP214-driven AML. Conclusion: This study offers valuable insights into the molecular and pathological mechanisms underlying t(6;9)-AML, revealing a functional interaction between DEK-NUP214, XPO1 and FOXC1, and providing evidence to consider XPO1 inhibition as a potential new avenue to treat these patients.

Extraction ofcharacteristic serum microRNAs andprediction oftarget genes in IgG4-related dacryoadenitis and sialadenitis.

To identify the specific microRNAs (miRNAs) in IgG4-related dacryoadenitis and sialadenitis (IgG4-DS) and predict the targeted genes. miRNAs in the serum of nine patients with IgG4-DS, three patients with primary Sjögren's syndrome, and three healthy controls were analysed using the human miRNA chip, and miRNAs that exhibited significant fluctuation in expression in IgG4-DS patients were extracted. The respective target genes were predicted using an existing database, and expression of the target genes was evaluated in actual submandibular gland tissues affected by IgG4-DS. Serum miR-125a-3p and miR-125b-1-3p levels were elevated in IgG4-DS. Six candidate target genes (glypican 4, forkhead box C1, protein tyrosine phosphatase non-receptor type 3, hydroxycarboxylic acid receptor 1, major facilitator superfamily domain containing 11, and tumour-associated calcium signal transducer 2) were downregulated in the affected submandibular gland tissue. Overexpression of miR-125a-3p and miR-125b-1-3p is a hallmark of IgG4-DS. These miRNAs appear to be involved in the pathogenesis of IgG4-DS.

Neuroimaging Findings in Axenfeld-Rieger Syndrome: A Case Series.

Axenfeld-Rieger syndrome is an autosomal dominant condition associated with multisystemic features including developmental anomalies of the anterior segment of the eye. Single nucleotide and copy number variants in the paired-like homeodomain transcription factor 2 (PITX2) and forkhead box C1 (FOXC1) genes are associated with Axenfeld-Rieger syndrome as well as other CNS malformations. We determined the association between Axenfeld-Rieger syndrome and specific brain MR imaging neuroradiologic anomalies in cases with or without a genetic diagnosis. This case series included 8 individuals with pathogenic variants in FOXC1; 2, in PITX2; and 2 without a genetic diagnosis. The most common observation was vertebrobasilar artery dolichoectasia, with 46% prevalence. Other prevalent abnormalities included WM hyperintensities, cerebellar hypoplasia, and ventriculomegaly. Vertebrobasilar artery dolichoectasia and absent/hypoplastic olfactory bulbs were reported in >50% of individuals with FOXC1 variants compared with 0% of PITX2 variants. Notwithstanding the small sample size, neuroimaging abnormalities were more prevalent in individuals with FOXC1 variants compared those with PITX2 variants.

Bioinformatics and Systems Biology Approach to Identify the Pathogenetic Link Between Psoriasis and Cardiovascular Disease.

This study aimed to identify hub genes and common pathways shared between psoriasis and cardiovascular disease (CVD) using bioinformatics analysis and predict the transcription factors (TFs) of hub genes. GSE133555 data from the Gene Expression Omnibus (GEO) database were used to identify differentially expressed genes (DEGs) between involved and uninvolved skin lesions in psoriasis, employing the limma package in R. Additionally, CVD-related genes were obtained from the GeneCards database. The intersection of DEGs and CVD-related genes yielded CVD-DEGs. Gene Ontology and signaling pathway analyses were performed using the clusterProfiler package in R. Hub genes were identified by intersecting six algorithms in the CytoHubba plugin of Cytoscape. To identify potential biomarkers, the GSE14905 dataset was subjected to receiver operating characteristic analysis, resulting in the identification of eight central hub genes. Finally, the NetworkAnalyst web tool was used to identify the TFs of the eight hub genes. We identified 92 significant DEGs out of 1825 CVD-related genes in psoriasis obtained from the GSE13355 and GeneCard data. Functional enrichment analysis revealed the involvement of these genes in various signaling pathways, including the interleukin-17 signaling, tumor necrosis factor signaling, lipid and atherosclerosis, chemokine signaling, and cytokine signaling pathways in the immune system. The eight hub genes identified included interleukin-1 beta, C-X-C motif chemokine ligand 8, signal transducer and activator of transcription 3, C-C motif chemokine ligand 2, arginase 1, C-X-C motif chemokine receptor 4, cyclin D1, and matrix metallopeptidase 9, with forkhead box C1 also identified as an associated TF of these genes. These hub genes and TF may act as key regulators in the context of CVD. This study identified several hub genes and signaling pathways associated with both CVD and psoriasis. These findings lay the groundwork for potential therapeutic interventions for patients with psoriasis affected by CVD.

Primary open-angle glaucoma risk prediction with ABCA1 and LOC102723944 variants and their genotype-phenotype correlations in southern Chinese population.

Glaucoma is a leading cause of irreversible visual impairment and blindness worldwide. Previous genome-wide association studies have identified caveolin-1 (CAV1), ATP-binding cassette A1 (ABCA1), and forkhead box C1 (FOXC1) loci associated with primary open angle glaucoma (POAG), a major subtype of glaucoma. This study aimed to fine map the association pattern of FOXC1 locus with POAG and determine the correlations of FOXC1, ABCA1, and CAV1 variants with ocular and lipidemic parameters in southern Chinese population. In total, 1291 unrelated Han Chinese subjects were recruited, including 301 high-tension glaucoma (HTG), 126 normal-tension glaucoma (NTG), and 864 control subjects. Twelve variants in FOXC1 locus, and two variants in ABCA1 and CAV1 genes, were genotyped by TaqMan assays. Genetic risk score and genotype-phenotype correlation analyses were conducted. In the FOXC1 locus, LOC102723944 rs6596830, rather than previously reported rs2745572, showed significant association with POAG (P = 8.61 × 10-4, odds ratio (OR) = 0.75) and HTG (P = 3.68 × 10-3, OR = 0.75). ABCA1 rs2487032 was also significantly associated with POAG (P = 3.00 × 10-5, OR = 0.70) and HTG (P = 2.08 × 10-4, OR = 0.70). Joint analysis showed that carriers of homozygous non-protective alleles of ABCA1 rs2487032 and LOC102723944 rs6596830 had 2.99-fold higher risk of POAG (P = 1.27 × 10-3) when compared to those carrying homozygous non-risk alleles. Patients with POAG carrying ABCA1 rs2487032 G allele had higher HDL cholesterol, and those with LOC102723944 rs6596830 A allele had lower LDL. This study revealed individual and joint association of ABCA1 and LOC102723944 variants with POAG in southern Chinese population. Subjects carrying non-protective alleles had increased risk to POAG, and corresponding genotypes would affect the lipid profiles.

Promotion effect of FOXCUT as a microRNA sponge for miR-24-3p on progression in triple-negative breast cancer through the p38 MAPK signaling pathway.

Triple-negative breast cancer (TNBC) is a type of highly invasive breast cancer with a poor prognosis. According to new research, long noncoding RNAs (lncRNAs) play a significant role in the progression of cancer. Although the role of lncRNAs in breast cancer has been well reported, few studies have focused on TNBC. This study aimed to explore the biological function and clinical significance of forkhead box C1 promoter upstream transcript (FOXCUT) in triple-negative breast cancer. Based on a bioinformatic analysis of the cancer genome atlas (TCGA) database, we detected that the lncRNA FOXCUT was overexpressed in TNBC tissues, which was further validated in an external cohort of tissues from the General Surgery Department of the First Affiliated Hospital of Nanjing Medical University. The functions of FOXCUT in proliferation, migration, and invasion were detected in vitro or in vivo. Luciferase assays and RNA immunoprecipitation (RIP) were performed to reveal that FOXCUT acted as a competitive endogenous RNA (ceRNA) for the microRNA miR-24-3p and consequently inhibited the degradation of p38. lncRNA FOXCUT was markedly highly expressed in breast cancer, which was associated with poor prognosis in some cases. Knockdown of FOXCUT significantly inhibited cancer growth and metastasis in vitro or in vivo. Mechanistically, FOXCUT competitively bounded to miR-24-3p to prevent the degradation of p38, which might act as an oncogene in breast cancer. Collectively, this research revealed a novel FOXCUT/miR-24-3p/p38 axis that affected breast cancer progression and suggested that the lncRNA FOXCUT could be a diagnostic marker and therapeutic target for breast cancer.