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Frontiers in Genetics 2023Hereditary spastic paraplegia (HSP) is a progressive upper-motor neurodegenerative disease. Mutations in the gene are associated with autosomal dominant HSP, spastic...
Hereditary spastic paraplegia (HSP) is a progressive upper-motor neurodegenerative disease. Mutations in the gene are associated with autosomal dominant HSP, spastic paraplegia 8 (SPG8). However, due to the small number of reported cases, the exact mechanism remains unclear. We report a Chinese family with HSP. The proband was referred to our hospital due to restless leg syndrome and insomnia. The preliminary clinical diagnosis of the proband was spastic paraplegia. Whole-exome sequencing (WES) and RNA splicing analysis were conducted to evaluate the genetic cause of the disease in this family. A novel splice-altering variant (c.712-2A>G) in the gene was detected and further verified by RNA splicing analysis and Sanger sequencing. Real-time qPCR analysis showed that the expression of genes involved in the Wiskott-Aldrich syndrome protein and SCAR homolog (WASH) complex and endosomal and lysosomal systems was altered due to this variant. A novel heterozygous splice-altering variant (c.712-2A>G) in the gene was detected in a Chinese family with HSP. Our study provided data for genetic counseling to this family and offered evidence that this splicing variant in the gene is significant in causing HSP.
PubMed: 38028608
DOI: 10.3389/fgene.2023.1205052 -
IScience Nov 2023Wiskott-Aldrich syndrome protein-interacting protein family member 1 (WIPF1) is associated with malignant tumor progression. However, molecular links between WIPF1 and...
Wiskott-Aldrich syndrome protein-interacting protein family member 1 (WIPF1) is associated with malignant tumor progression. However, molecular links between WIPF1 and gastric cancer (GC) remain elusive. The expression of WIPF1 was detected in GC tissues and cells. WIPF1 was overexpressed in GC tissues and cells and high expression of WIPF1 was an independent risk factor for a poor prognosis in patients with GC. Further experiments indicated that WIPF1 promoted the proliferation, invasion, and migration of GC cells . WIPF1-regulated genes were closely related to cell proliferation and migration in GC, and silencing WIPF1 significantly repressed PI3K/AKT signaling pathway activation. WIPF1 was activated by myocardin (MYOCD) translation. Rescue experiments confirmed that MYOCD promotes the proliferation, invasion, and migration of GC cells in a WIPF1-dependent manner and activates the PI3K/AKT signaling pathway. MYOCD may transactivate WIPF1 and facilitate GC cell growth and metastasis by activating the PI3K/AKT signaling pathway.
PubMed: 38026208
DOI: 10.1016/j.isci.2023.108273 -
Medical Journal, Armed Forces India 2023
PubMed: 37981929
DOI: 10.1016/j.mjafi.2023.08.006 -
Medical Journal, Armed Forces India 2023We describe two young patients with Wiskott-Aldrich Syndrome (WAS) who were treated by T-replete hematopoietic stem cell transplantation (HSCT) from the HLA...
We describe two young patients with Wiskott-Aldrich Syndrome (WAS) who were treated by T-replete hematopoietic stem cell transplantation (HSCT) from the HLA haploidentical father according to a modified Baltimore protocol. Whereas similar protocols have been successfully used in various malignant and non-malignant diseases, this is the first report for this particular disease. The data being presented pertains to the report about two successful haploidentical transplants with post transplant cyclophosphamide (PTCY) after busulfan-based conditioning.
PubMed: 37981926
DOI: 10.1016/j.mjafi.2023.08.015 -
The Kaohsiung Journal of Medical... Jan 2024Long noncoding RNA MYLK antisense RNA 1 (MYLK-AS1) is the crux in multiple diseases. Therefore, the purpose of this study was to investigate the possible mechanism of...
LncRNA MYLK antisense RNA 1 activates cell division cycle 42/Neutal Wiskott-Aldrich syndrome protein pathway via microRNA-101-5p to accelerate epithelial-to-mesenchymal transition of colon cancer cells.
Long noncoding RNA MYLK antisense RNA 1 (MYLK-AS1) is the crux in multiple diseases. Therefore, the purpose of this study was to investigate the possible mechanism of MYLK-AS1. A total of 62 colon cancer (CC) specimens and paired adjacent normal tissues were collected, and the expression of MYLK-AS1, microRNA (miR)-101-5p/cell division cycle 42 (CDC42) was detected. CC cell lines were transfected with MYLK-AS1, miR-101-5p, CDC42-related plasmids, and the biological functions and markers of epithelial-mesenchymal transition (EMT) were analyzed. The binding relationship between MYLK-AS1, miR-101-5p, and CDC42 was evaluated. In CC tissues and cell lines, MYLK-AS1 and CDC42 were highly expressed, and miR-101-5p was lowly expressed. Inhibition of MYLK-AS1 or upregulation of miR-101-5p can inhibit CC cell growth and EMT. miR-101-5p inhibited CDC42/N-wasp axis activation in CC cells by targeting CDC42. Knockdown of CDC42 or upregulation of miR-101-5p partially reversed the effects caused by upregulation of MYLK-AS1. MYLK-AS1, which is significantly upregulated in CC, may be a molecular sponge for miR-101-5p, and MYLK-AS1 promotes the activation of the CDC42/N-wasp axis in CC cells by targeting CDC42 through miR-101-5p, which in turn promotes tumor development. MYLK-AS1 may be a potential biomarker and target for CC therapy.
Topics: Humans; MicroRNAs; RNA, Long Noncoding; Wiskott-Aldrich Syndrome Protein; Epithelial-Mesenchymal Transition; Colonic Neoplasms; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Gene Expression Regulation, Neoplastic; Cell Movement; Calcium-Binding Proteins; Myosin-Light-Chain Kinase
PubMed: 37950620
DOI: 10.1002/kjm2.12773 -
Applied Biochemistry and Biotechnology Nov 2023Wiskott-Aldrich syndrome protein family verprolin-homologous domain-containing protein 3 (WAVE3) is reported as an oncogene regulating cell proliferation and motility in...
Wiskott-Aldrich syndrome protein family verprolin-homologous domain-containing protein 3 (WAVE3) is reported as an oncogene regulating cell proliferation and motility in multiple malignancies, while its role in tongue squamous cell carcinoma (TSCC) remains unknown. This study aimed to explore the expression and mechanism of WAVE3 in TSCC. We enrolled 64 TSCC patients admitted between June 2013 and February 2014 and collected their cancerous and adjacent normal tissues to determine WAVE3 expression by immunohistochemistry. The correlation of WAVE3 expression with TSCC patients' pathological characteristics was analyzed. Then, a 7-year follow-up was conducted to observe the value of WAVE3 in evaluating patient outcomes. In addition, human TSCC SCC9, SCC25, and CAL27 cells were purchased and detected by Cell Counting Kit-8 (CCK-8), Transwell, and scratch-wound assays for their proliferation, invasion, and migration capacities, while real-time quantitative PCR (qRT-PCR) and Western blotting were utilized to quantify WAVE3 and epithelial-mesenchymal transition (EMT)-related protein expression, respectively. The most active cell lines were selected to be infected with lentiviral vectors that silenced WAVE3 (named WAVE3-sh group) and overexpressed WAVE3 cDNA (named WAVE3-OE group) to observe the impacts of interfering WAVE3 expression on TSCC cell biological behavior. The positive expression of WAVE3 in TSCC tissue was found to be obviously enhanced and predominantly located in the cytoplasm. In addition, close correlations were identified between WAVE3 and T staging, clinical staging, lymphatic metastasis, distant metastasis, and differentiation degree (P < 0.05). Increased WAVE3 expression predicted an elevated risk of death, as indicated by the follow-up analysis (P < 0.05). SCC9 was selected for subsequent experiments among various TSCC cell lines studied because it showed the most potent ability to proliferate, invade, and migrate (P < 0.05). Silencing WAVE3 expression in SCC9 cells decreased cell proliferation, invasion, migration, and EMT-related protein expression (P < 0.05), while increasing WAVE3 expression promoted SCC9 viability. WAVE3, which was highly expressed in TSCC, promoted EMT in tumor cells and accelerated their proliferation, invasion, and migration, which might provide a new theoretical basis for molecular targeted therapy of TSCC in the future.
PubMed: 37947948
DOI: 10.1007/s12010-023-04764-8 -
Cellular Immunology 2023Wiskott-Aldrich syndrome (WAS) is a disorder characterized by rare X-linked genetic immune deficiency with mutations in the Was gene, which is specifically expressed in...
Wiskott-Aldrich syndrome (WAS) is a disorder characterized by rare X-linked genetic immune deficiency with mutations in the Was gene, which is specifically expressed in hematopoietic cells. The spleen plays a major role in hematopoiesis and red blood cell clearance. However, to date, comprehensive analyses of the spleen in wild-type (WT) and WASp-deficient (WAS-KO) mice, especially at the transcriptome level, have not been reported. In this study, single-cell RNA sequencing (scRNA-seq) was adopted to identify various types of immune cells and investigate the mechanisms underlying immune deficiency. We identified 30 clusters and 10 major cell subtypes among 11,269 cells; these cell types included B cells, T cells, dendritic cells (DCs), natural killer (NK) cells, monocytes, macrophages, granulocytes, stem cells and erythrocytes. Moreover, we evaluated gene expression differences among cell subtypes, identified differentially expressed genes (DEGs), and performed enrichment analyses to identify the reasons for the dysfunction in these different cell populations in WAS. Furthermore, some key genes were identified based on a comparison of the DEGs in each cell type involved in specific and nonspecific immune responses, and further analysis showed that these key genes were previously undiscovered pathology-related genes in WAS-KO mice. In summary, we present a landscape of immune cells in the spleen of WAS-KO mice based on detailed data obtained at single-cell resolution. These unprecedented data revealed the transcriptional characteristics of specific and nonspecific immune cells, and the key genes were identified, laying a foundation for future studies of WAS, especially studies into novel and underexplored mechanisms that may improve gene therapies for WAS.
Topics: Animals; Mice; Wiskott-Aldrich Syndrome; Spleen; T-Lymphocytes; Killer Cells, Natural
PubMed: 37944382
DOI: 10.1016/j.cellimm.2023.104783 -
Molecular Cancer Research : MCR Mar 2024Coordination of filament assembly and membrane remodeling is required for the directional migration of cancer cells. The Wiskott-Aldrich syndrome protein (WASP) recruits...
UNLABELLED
Coordination of filament assembly and membrane remodeling is required for the directional migration of cancer cells. The Wiskott-Aldrich syndrome protein (WASP) recruits the actin-related protein (ARP) 2/3 complex to assemble branched actin networks. The goal of our study was to assess the potential regulatory role exerted by the novel long noncoding RNA (lncRNA) LINC00869 on hepatocellular carcinoma (HCC) cells. We used HCC cells to overexpress or knockdown LINC00869, analyzed patient data from publicly available databases and Cancer Hospital Affiliated with Zhengzhou University, and used a xenograft mouse model of HCC to study the molecular mechanism associated with LINC00869 expression. We found that high levels of LINC00869 expression were associated with poor prognosis in patients with HCC. Next, we detected an interaction between LINC00869 and both WASP and ARP2 in HCC cells, and observed a modulatory effect of LINC00869 on the phosphorylation of WASP at Y291 and the activity of cell division control protein 42 (CDC42). These modulatory roles were required for WASP/CDC42 activity on F-actin polymerization to enhance membrane protrusion formation and maintain persistent cell polarization. This, in turn, promoted the migration and invasion abilities of HCC cells. Finally, we confirmed the role of LINC00869in vivo, using the tumor xenograft mouse model; and identified a positive correlation between LINC00869 expression levels and the phosphorylation levels of WASP in HCC samples. Overall, our findings suggest a unique mechanism by which LINC00869 orchestrates membrane protrusion during migration and invasion of HCC cells.
IMPLICATIONS
LncRNA LINC00869 regulates the activity of CDC42-WASP pathway and positively affects protrusion formation in HCC cells, which expands the current understanding of lncRNA functions as well as gives a better understanding of carcinogenesis.
Topics: Humans; Animals; Mice; Carcinoma, Hepatocellular; Actins; RNA, Long Noncoding; Liver Neoplasms; Phosphorylation; Actin-Related Protein 2-3 Complex; Disease Models, Animal
PubMed: 37934195
DOI: 10.1158/1541-7786.MCR-23-0414 -
Mucosal Immunology Feb 2024Dysregulated B cell responses have been described in inflammatory bowel disease (IBD) patients; however, the role of B cells in IBD pathology remained incompletely...
Dysregulated B cell responses have been described in inflammatory bowel disease (IBD) patients; however, the role of B cells in IBD pathology remained incompletely understood. We here provide evidence for the detrimental role of activated B cells during the onset of autoimmune intestinal inflammation. Using Wiskott-Aldrich Syndrome interacting protein deficient (Wipf1) mice as a mouse model of chronic colitis, we identified clusters of differentiation (CD)86 expression on activated B cells as a crucial factor exacerbating pro-inflammatory cytokine production of intestinal CD4 T cells. Depleting B cells through anti-CD20 antibody treatment or blocking costimulatory signals mediated by CD86 through cytotoxic T lymphocyte antigen-4-immunoglobulin (CTLA-4-Ig) diminished intestinal inflammation in our mouse model of chronic IBD at the onset of disease. This was due to a reduction in aberrant humoral immune responses and reduced CD4 T cell pro-inflammatory cytokine production, especially interferon-g (IFN-g) and granulocyte-macrophage colony-stimulating factor (GM-CSF). Interestingly, in addition to B cells isolated from the inflamed colon of Wipf1 mice, we also found CD86 mRNA and protein expression upregulated on activated B cells isolated from inflamed tissue of human patients with IBD. B cell activation and CD86 expression were boosted by soluble CD40L in vitro, which we found in the serum of mice and human patients with IBD. In summary, our data provides detailed insight into the contribution of B cells to intestinal inflammation, with implications for the treatment of IBD.
Topics: Humans; CD4-Positive T-Lymphocytes; Colitis; Inflammation; Inflammatory Bowel Diseases; Intestinal Mucosa; Intestines
PubMed: 37918715
DOI: 10.1016/j.mucimm.2023.10.005 -
Nature Communications Oct 2023Cortactin coactivates Arp2/3 complex synergistically with WASP-family nucleation-promoting factors (NPFs) and stabilizes branched networks by linking Arp2/3 complex to...
Cortactin coactivates Arp2/3 complex synergistically with WASP-family nucleation-promoting factors (NPFs) and stabilizes branched networks by linking Arp2/3 complex to F-actin. It is poorly understood how cortactin performs these functions. We describe the 2.89 Å resolution cryo-EM structure of cortactin's N-terminal domain (Cort) bound to Arp2/3 complex. Cortactin binds Arp2/3 complex through an inverted Acidic domain (D20-V29), which targets the same site on Arp3 as the Acidic domain of NPFs but with opposite polarity. Sequences N- and C-terminal to cortactin's Acidic domain do not increase its affinity for Arp2/3 complex but contribute toward coactivation with NPFs. Coactivation further increases with NPF dimerization and for longer cortactin constructs with stronger binding to F-actin. The results suggest that cortactin contributes to Arp2/3 complex coactivation with NPFs in two ways, by helping recruit the complex to F-actin and by stabilizing the short-pitch (active) conformation, which are both byproducts of cortactin's core function in branch stabilization.
Topics: Actin-Related Protein 2-3 Complex; Cortactin; Actins; Wiskott-Aldrich Syndrome Protein; Actin-Related Protein 2; Actin-Related Protein 3
PubMed: 37898612
DOI: 10.1038/s41467-023-42229-y