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The Journal of Veterinary Medical... Nov 2023Merkel cell carcinoma (MCC) is a rare skin tumor that shares a similar immunophenotype with Merkel cells, although its origin is debatable. More than 80% of human MCC... (Review)
Review
Merkel cell carcinoma (MCC) is a rare skin tumor that shares a similar immunophenotype with Merkel cells, although its origin is debatable. More than 80% of human MCC cases are associated with Merkel cell polyomavirus infections and viral gene integration. Recent studies have shown that the clinical and pathological characteristics of feline MCC are comparable to those of human MCC, including its occurrence in aged individuals, aggressive behavior, histopathological findings, and the expression of Merkel cell markers. More than 90% of feline MCC are positive for the Felis catus papillomavirus type 2 (FcaPV2) gene. Molecular changes involved in papillomavirus-associated tumorigenesis, such as increased p16 and decreased retinoblastoma (Rb) and p53 protein levels, were observed in FcaPV2-positive MCC, but not in FcaPV2-negative MCC cases. These features were also confirmed in FcaPV2-positive and -negative MCC cell lines. The expression of papillomavirus E6 and E7 genes, responsible for p53 degradation and Rb inhibition, respectively, was detected in tumor cells by in situ hybridization. Whole genome sequencing revealed the integration of FcaPV2 DNA into the host feline genome. MCC cases often develop concurrent skin lesions, such as viral plaque and squamous cell carcinoma, which are also associated with papillomavirus infection. These findings suggest that FcaPV2 infection and integration of viral genes are involved in the development of MCC in cats. This review provides an overview of the comparative pathology of feline and human MCC caused by different viruses and discusses their cell of origin.
Topics: Humans; Cats; Animals; Carcinoma, Merkel Cell; Tumor Suppressor Protein p53; Papillomaviridae; Merkel Cells; Skin Neoplasms; Cat Diseases
PubMed: 37743525
DOI: 10.1292/jvms.23-0322 -
Cell Death & Disease Mar 2023Multiciliated cells (MCCs) project dozens to hundreds of motile cilia from their apical surface to promote the movement of fluids or gametes in the mammalian brain,...
Multiciliated cells (MCCs) project dozens to hundreds of motile cilia from their apical surface to promote the movement of fluids or gametes in the mammalian brain, airway or reproductive organs. Differentiation of MCCs requires the sequential action of the Geminin family transcriptional activators, GEMC1 and MCIDAS, that both interact with E2F4/5-DP1. How these factors activate transcription and the extent to which they play redundant functions remains poorly understood. Here, we demonstrate that the transcriptional targets and proximal proteomes of GEMC1 and MCIDAS are highly similar. However, we identified distinct interactions with SWI/SNF subcomplexes; GEMC1 interacts primarily with the ARID1A containing BAF complex while MCIDAS interacts primarily with BRD9 containing ncBAF complexes. Treatment with a BRD9 inhibitor impaired MCIDAS-mediated activation of several target genes and compromised the MCC differentiation program in multiple cell based models. Our data suggest that the differential engagement of distinct SWI/SNF subcomplexes by GEMC1 and MCIDAS is required for MCC-specific transcriptional regulation and mediated by their distinct C-terminal domains.
Topics: Animals; Nuclear Proteins; Gene Expression Regulation; Cell Differentiation; Mammals
PubMed: 36932059
DOI: 10.1038/s41419-023-05720-4 -
International Journal of Molecular... Jun 2021Merkel cell carcinoma (MCC) is an uncommon and highly aggressive skin cancer. It develops mostly within chronically sun-exposed areas of the skin. MCPyV is detected in... (Review)
Review
Merkel cell carcinoma (MCC) is an uncommon and highly aggressive skin cancer. It develops mostly within chronically sun-exposed areas of the skin. MCPyV is detected in 60-80% of MCC cases as integrated within the genome and is considered a major risk factor for MCC. Viral negative MCCs have a high mutation burden with a UV damage signature. Aberrations occur in , , and genes as well as in the PI3K-AKT-mTOR pathway. MCC is highly immunogenic, but MCC cells are known to evade the host's immune response. Despite the characteristic immunohistological profile of MCC, the diagnosis is challenging, and it should be confirmed by an experienced pathologist. Sentinel lymph node biopsy is considered the most reliable staging tool to identify subclinical nodal disease. Subclinical node metastases are present in about 30-50% of patients with primary MCC. The basis of MCC treatment is surgical excision. MCC is highly radiosensitive. It becomes chemoresistant within a few months. MCC is prone to recurrence. The outcomes in patients with metastatic disease are poor, with a historical 5-year survival of 13.5%. The median progression-free survival is 3-5 months, and the median overall survival is ten months. Currently, immunotherapy has become a standard of care first-line therapy for advanced MCC.
Topics: Carcinoma, Merkel Cell; Humans; Immune Evasion; Merkel cell polyomavirus; Signal Transduction; Skin Neoplasms; Tumor Burden
PubMed: 34208339
DOI: 10.3390/ijms22126305 -
Frontiers in Immunology 2024Idiopathic pulmonary fibrosis (IPF) is characterized by progressive lung dysfunction due to excessive collagen production and tissue scarring. Despite recent...
INTRODUCTION
Idiopathic pulmonary fibrosis (IPF) is characterized by progressive lung dysfunction due to excessive collagen production and tissue scarring. Despite recent advancements, the molecular mechanisms remain unclear.
METHODS
RNA sequencing identified 475 differentially expressed genes (DEGs) in the TGF-β1-induced primary lung fibrosis model. Gene expression chips GSE101286 and GSE110147 from NCBI gene expression omnibus (GEO) database were analyzed using GEO2R, revealing 94 DEGs in IPF lung tissue samples. The gene ontology (GO) and pathway enrichment, Protein-protein interaction (PPI) network construction, and Maximal Clique Centrality (MCC) scoring were performed. Experimental validation included RT-qPCR, Immunohistochemistry (IHC), and Western Blot, with siRNA used for gene knockdown. A co-expression network was constructed by GeneMANIA.
RESULTS
GO enrichment highlighted significant enrichment of DEGs in TGF-β cellular response, connective tissue development, extracellular matrix components, and signaling pathways such as the AGE-RAGE signaling pathway and ECM-receptor interaction. PPI network analysis identified hub genes, including FN1, COL1A1, POSTN, KIF11, and ECT2. CALD1 (Caldesmon 1), CDH2 (Cadherin 2), and POSTN (Periostin) were identified as dysregulated hub genes in both the RNA sequencing and GEO datasets. Validation experiments confirmed the upregulation of CALD1, CDH2, and POSTN in TGF-β1-treated fibroblasts and IPF lung tissue samples. IHC experiments probed tissue-level expression patterns of these three molecules. Knockdown of CALD1, CDH2, and POSTN attenuated the expression of fibrotic markers (collagen I and α-SMA) in response to TGF-β1 stimulation in primary fibroblasts. Co-expression analysis revealed interactions between hub genes and predicted genes involved in actin cytoskeleton regulation and cell-cell junction organization.
CONCLUSIONS
CALD1, CDH2, and POSTN, identified as potential contributors to pulmonary fibrosis, present promising therapeutic targets for IPF patients.
Topics: Humans; Antigens, CD; Cadherins; Calmodulin-Binding Proteins; Cell Adhesion Molecules; Collagen; Fibroblasts; Gene Expression; Idiopathic Pulmonary Fibrosis; Transforming Growth Factor beta1
PubMed: 38370408
DOI: 10.3389/fimmu.2024.1275064 -
Cancers Jun 2022Chemotherapy is a mainstay of colorectal cancer treatment, and often involves a combination drug regime. CpG island methylator phenotype (CIMP)-positive tumors are...
Chemotherapy is a mainstay of colorectal cancer treatment, and often involves a combination drug regime. CpG island methylator phenotype (CIMP)-positive tumors are potentially more responsive to the topoisomerase-inhibitor irinotecan. The mechanistic basis of the increased sensitivity of CIMP cancers to irinotecan is poorly understood. Mutated in Colorectal Cancer () is emerging as a multifunctional tumor suppressor gene in colorectal and liver cancers, and has been implicated in drug responsiveness. Here, we found that CIMP tumors undergo loss almost exclusively via promoter hypermethylation rather than copy number variation or mutations. A subset of cancers display hypomethylation which is also associated with low expression, particularly in rectal cancer, where CIMP is rare. knockdown or deletion was found to sensitize cells to SN38 (the active metabolite of irinotecan) or the PARP-inhibitor Olaparib. A synergistic effect on cell death was evident when these drugs were used concurrently. The improved SN38/irinotecan efficacy was accompanied by the down-regulation of DNA repair genes. Thus, differential methylation of is potentially a valuable biomarker to identify colorectal cancers suitable for irinotecan therapy, possibly in combination with PARP inhibitors.
PubMed: 35740525
DOI: 10.3390/cancers14122859 -
Epigenomes Sep 2022The polycomb group (PcG) proteins are a subset of transcription regulators highly conserved throughout evolution. Their principal role is to epigenetically modify... (Review)
Review
The polycomb group (PcG) proteins are a subset of transcription regulators highly conserved throughout evolution. Their principal role is to epigenetically modify chromatin landscapes and control the expression of master transcriptional programs to determine cellular identity. The two mayor PcG protein complexes that have been identified in mammals to date are Polycomb Repressive Complex 1 (PRC1) and 2 (PRC2). These protein complexes selectively repress gene expression via the induction of covalent post-translational histone modifications, promoting chromatin structure stabilization. PRC2 catalyzes the histone H3 methylation at lysine 27 (H3K27me1/2/3), inducing heterochromatin structures. This activity is controlled by the formation of a multi-subunit complex, which includes enhancer of zeste (EZH2), embryonic ectoderm development protein (EED), and suppressor of zeste 12 (SUZ12). This review will summarize the latest insights into how PRC2 in mammalian cells regulates transcription to orchestrate the temporal and tissue-specific expression of genes to determine cell identity and cell-fate decisions. We will specifically describe how PRC2 dysregulation in different cell types can promote phenotypic plasticity and/or non-mutational epigenetic reprogramming, inducing the development of highly aggressive epithelial neuroendocrine carcinomas, including prostate, small cell lung, and Merkel cell cancer. With this, EZH2 has emerged as an important actionable therapeutic target in such cancers.
PubMed: 36135315
DOI: 10.3390/epigenomes6030028 -
Medicine Nov 2021To provide reliable molecular markers and effective therapeutic targets for chondrosarcoma and glioma.Gene Set Enrichment (GSE) 29745 and GSE48420 were downloaded from...
To provide reliable molecular markers and effective therapeutic targets for chondrosarcoma and glioma.Gene Set Enrichment (GSE) 29745 and GSE48420 were downloaded from the Gene Expression Omnibus (GEO) database. Differently expressed genes (DEGs) were identified by the GEO2R. We annotated the function of common DEGs through Digital Audio/Video Interactive Decoder (DAVID) and Metascape. Protein-protein interaction network construction was performed through STRING. Hub genes were identified by the two different algorithms (MCC, EPC). DDX10 and BYSL were key factors in embryo implantation and development, and plays a role in a variety of cancers. The role of the DDX10 and BYSL on the glioma derived from the chondrosarcoma would be explored by the clinical samples.A total of 1442 DEGs were identified. The variations in DEGs were mainly enriched in vasculature development, cell motion, blood vessel development, cell migration, regulation of cell proliferation, regulation of cell proliferation, wound healing, biological adhesion, growth factor binding, identical pathways in cancer, and p53 signaling pathway. Dead-box helicase 10 (DDX10), Bystin-like (BYSL), and WD repeat domain 12 (WDR12) were identified as the hub genes, and the three hub genes were up-regulated in the chondrosarcoma. Chondrosarcoma patients with high expression levels of DDX10 (Logrank P = .0052; HR (high) = 1.8; n (high) = 131, 50%), and BYSL (P = 6.5e-05; HR (high) = 2.3; n (high) = 131, 50%) had poorer overall survival times than those with low expression levels.DDX10 and BYSL genes may provide reliable molecular markers and effective therapeutic targets for chondrosarcoma and glioma.
Topics: Cell Adhesion Molecules; Chondrosarcoma; Computational Biology; DEAD-box RNA Helicases; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Glioma; Humans; Protein Interaction Maps
PubMed: 34797290
DOI: 10.1097/MD.0000000000027669 -
Medicine Apr 2023Merkel cell carcinoma (MCC), a rare primary cutaneous neuroendocrine neoplasm, is extremely aggressive and has a higher mortality rate than melanoma. Based on Merkel... (Review)
Review
Merkel cell carcinoma (MCC), a rare primary cutaneous neuroendocrine neoplasm, is extremely aggressive and has a higher mortality rate than melanoma. Based on Merkel cell polyomavirus (MCPyV) status and morphology, MCCs are often divided into several distinct subsets: pure MCPyV-positive, pure MCPyV-negative, and combined MCC. MCPyV-positive MCC develops by the clonal integration of viral DNA, whereas MCPyV-negative MCC is induced by frequent ultraviolet (UV)-mediated mutations, that are characterized by a high mutational burden, UV signature mutations, and many mutations in TP53 and retinoblastoma suppressor gene (RB1). Combined MCC consists of an intimate mix of MCC and other cutaneous tumor populations, and is usually MCPyV-negative, with rare exceptions. Based on the existing subsets of MCC, it is speculated that there are at least 4 stages in the natural history of stem cell differentiation: primitive pluripotent stem cells, divergent differentiated stem cells, unidirectional stem cells, and Merkel cells (or epidermal/adnexal cells). In the first stage, MCPyV may integrate into the genome of primitive pluripotent stem cells, driving oncogenesis in pure MCPyV-positive MCC. If MCPyV integration does not occur, the stem cells enter the second stage and acquire the ability to undergo multidirectional neuroendocrine and epidermal (or adnexal) differentiation. At this stage, accumulated UV-mediated mutations may drive the development of combined MCC. In the third stage, the stem cells differentiate into unidirectional neuroendocrine stem cells, UV-mediated mutations can induce carcinogenesis in pure MCPyV-negative MCC. Therefore, it has been speculated that several subsets of MCCs arise from different stages of differentiation of common stem cells.
Topics: Humans; Carcinoma, Merkel Cell; Skin Neoplasms; Cell Transformation, Neoplastic; Carcinogenesis; Stem Cells; Cell Differentiation; Merkel cell polyomavirus; Polyomavirus Infections; Tumor Virus Infections
PubMed: 37058042
DOI: 10.1097/MD.0000000000033535 -
Genes Mar 2021Cystic fibrosis (CF) is a life-limiting genetic disorder caused by loss-of-function mutations in the gene which codes for the CF transmembrane conductance regulator... (Review)
Review
Cystic fibrosis (CF) is a life-limiting genetic disorder caused by loss-of-function mutations in the gene which codes for the CF transmembrane conductance regulator (CFTR) Cl channel. Loss of Cl secretion across the apical membrane of airway lining epithelial cells results in dehydration of the airway surface liquid (ASL) layer which impairs mucociliary clearance (MCC), and as a consequence promotes bacterial infection and inflammation of the airways. Interventions that restore airway hydration are known to improve MCC. Here we review the ion channels present at the luminal surface of airway epithelial cells that may be targeted to improve airway hydration and MCC in CF airways.
Topics: Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Loss of Function Mutation; Mucociliary Clearance; Respiratory Mucosa
PubMed: 33810137
DOI: 10.3390/genes12030453 -
Scientific Reports Jul 2022Skin cutaneous melanoma is a malignant and highly metastatic skin tumor, and its morbidity and mortality are still rising worldwide. However, the molecular mechanisms...
Skin cutaneous melanoma is a malignant and highly metastatic skin tumor, and its morbidity and mortality are still rising worldwide. However, the molecular mechanisms that promote melanoma metastasis are unclear. Two datasets (GSE15605 and GSE46517) were retrieved to identify the differentially expressed genes (DEGs), including 23 normal skin tissues (N), 77 primary melanoma tissues (T) and 85 metastatic melanoma tissues (M). Gene ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis were performed to explore the functions of the DEGs. We constructed protein-protein interaction network using the STRING database and Cytoscape software. Using the cytoHubba plugin of Cytoscape, we identified the most significant hub genes by five analytical methods (Degree, Bottleneck, MCC, MNC, and EPC). Hub gene expression was validated using the UALCAN website. Clinical relevance was investigated using The Cancer Genome Atlas resources. Finally, we explored the association between metastasis-associated genes and immune infiltrates through the Tumor Immune Estimation Resource (TIMER) database and performed drug-gene interaction analysis using the Drug-Gene Interaction database. A total of 294 specific genes were related to melanoma metastasis and were mainly involved in the positive regulation of locomotion, mitotic cell cycle process, and epithelial cell differentiation. Four hub genes (CDK1, FOXM1, KIF11, and RFC4) were identified from the cytoHubba plugin of Cytoscape. CDK1 was significantly upregulated in metastatic melanoma compared with primary melanoma, and high CDK1 expression was positively correlated with worse overall survival. Immune infiltration analysis revealed that CDK1 expression negatively correlated with macrophage infiltration (Rho = - 0.164, P = 2.02e-03) and positively correlated with neutrophil cells (Rho = 0.269, P = 2.72e-07) in SKCM metastasis. In addition, we identified that CDK1 had a close interaction with 10 antitumor drugs. CDK1 was identified as a hub gene involved in the progression of melanoma metastasis and may be regarded as a therapeutic target for melanoma patients to improve prognosis and prevent metastasis in the future.
Topics: Biomarkers, Tumor; Computational Biology; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Gene Regulatory Networks; Humans; Melanoma; Prognosis; Skin Neoplasms; Melanoma, Cutaneous Malignant
PubMed: 35906389
DOI: 10.1038/s41598-022-17468-6