CFTR, Cell Junctions and the Cytoskeleton

Pankonien, Ines; Quaresma, Margarida C.; Rodrigues, Cláudia S.; Amaral, Margarida D.

doi:10.3390/ijms23052688

Cited by 13 publications

(11 citation statements)

References 59 publications

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“…However, scant information is available for the repair of a wounded airway epithelium [ 58 , 59 ]. Given the recognized importance of epithelial junctions in the pathophysiology of CF [ 60 ], this gap should be filled. We have previously shown that hAMSCs and CFBE can form CX43-mediated GJs and that this coupling is involved in the rescue of CFTR function and recovery of other defects presented by CFBE cells.…”

Section: Discussionmentioning

confidence: 99%

Human Amniotic Mesenchymal Stem Cells and Fibroblasts Accelerate Wound Repair of Cystic Fibrosis Epithelium

Beccia

Daniello

Laselva

et al. 2022

Life

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Cystic fibrosis (CF) airways are affected by a deranged repair of the damaged epithelium resulting in altered regeneration and differentiation. Previously, we showed that human amniotic mesenchymal stem cells (hAMSCs) corrected base defects of CF airway epithelial cells via connexin (CX)43-intercellular gap junction formation. In this scenario, it is unknown whether hAMSCs, or fibroblasts sharing some common characteristics with MSCs, can operate a faster repair of a damaged airway epithelium. A tip-based scratch assay was employed to study wound repair in monolayers of CFBE14o- cells (CFBE, homozygous for the F508del mutation). hAMSCs were either co-cultured with CFBE cells before the wound or added to the wounded monolayers. NIH-3T3 fibroblasts (CX43+) were added to wounded cells. HeLa cells (CX43-) were used as controls. γ-irradiation was optimized to block CFBE cell proliferation. A specific siRNA was employed to downregulate CX43 expression in CFBE cells. CFBE cells showed a delayed repair as compared with wt-CFTR cells (16HBE41o-). hAMSCs enhanced the wound repair rate of wounded CFBE cell monolayers, especially when added post wounding. hAMSCs and NIH-3T3 fibroblasts, but not HeLa cells, increased wound closure of irradiated CFBE monolayers. CX43 downregulation accelerated CFBE wound repair rate without affecting cell proliferation. We conclude that hAMSCs and fibroblasts enhance the repair of a wounded CF airway epithelium, likely through a CX43-mediated mechanism mainly involving cell migration.

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Section: Discussionmentioning

confidence: 99%

Human Amniotic Mesenchymal Stem Cells and Fibroblasts Accelerate Wound Repair of Cystic Fibrosis Epithelium

Beccia

Daniello

Laselva

et al. 2022

Life

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“…Because of its oncogenic potential, YAP1 is tightly regulated by the cytoskeleton, ECM and cell–cell contacts ( 38 ), with a stiff ECM ( 39 ) and lack of cell–cell contacts ( 40 ) both resulting in YAP1 nuclear activity. Disruption of epithelial structures, particularly increased ECM and abnormal cell junctions, are present in the CF lung ( 14 , 41 , 42 ) and likely lead to nuclear YAP1 expression which further potentiates fibrosis and EMT.…”

Section: Discussionmentioning

confidence: 99%

Exploring YAP1-centered networks linking dysfunctional CFTR to epithelial–mesenchymal transition

et al. 2022

Self Cite

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Mutations in the CFTR anion channel cause cystic fibrosis (CF) and have also been related to higher cancer incidence. Previously we proposed that this is linked to an emerging role of functional CFTR in protecting against epithelial–mesenchymal transition (EMT). However, the pathways bridging dysfunctional CFTR to EMT remain elusive. Here, we applied systems biology to address this question. Our data show that YAP1 is aberrantly active in the presence of mutant CFTR, interacting with F508del, but not with wt-CFTR, and that YAP1 knockdown rescues F508del-CFTR processing and function. Subsequent analysis of YAP1 interactors and roles in cells expressing either wt- or F508del-CFTR reveal that YAP1 is an important mediator of the fibrotic/EMT processes in CF. Alongside, five main pathways emerge here as key in linking mutant CFTR to EMT, namely, (1) the Hippo pathway; (2) the Wnt pathway; (3) the TGFβ pathway; (4) the p53 pathway; and (5) MYC signaling. Several potential hub proteins which mediate the crosstalk among these pathways were also identified, appearing as potential therapeutic targets for both CF and cancer.

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“…A function of CFTR is to transport Cl− and HCO 3− , and it also regulates other ion channels (Na+, K+, Ca 2+ , and other Cl− channels) (20)(21)(22). Additionally, CFTR also has roles in osmoregulation, membrane potential maintenance, lipid homeostasis, cell polarity, the metabolism of glucose and other substrates, oxidative stress, inflammation, mucus production, microbiome alterations, pH regulation, cell motility, autophagy, mitochondrial dysfunction, apoptosis, cell polarity, cell-cell contact, stem cell function, and cellular immune responses (23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33). Some studies have shown multiple associations between CFTR and cancer; however, its expression levels vary between different types of tumors.…”

Section: Discussionmentioning

confidence: 99%

Identification of cystic fibrosis transmembrane conductance regulator as a prognostic marker for juvenile myelomonocytic leukemia via the whole-genome bisulfite sequencing of monozygotic twins and data mining

Yi¹,

Yu²,

Liang³

et al. 2022

Transl Pediatr

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Background: Linked deoxyribonucleic acid (DNA) hypermethylation investigations of promoter methylation levels of candidate genes may help to increase the progressiveness and mortality rates of juvenile myelomonocytic leukemia (JMML), which is a unique myelodysplastic/myeloproliferative neoplasm caused by excessive monocyte and granulocyte proliferation in infancy/early childhood. However, the roles of hypermethylation in this malignant disease are uncertain.Methods: Bone marrow samples from a JMML patient and peripheral blood samples from a healthy monozygotic twin and an unrelated healthy donor were collected with the informed consent of the participant's parents. Whole-genome bisulfite sequencing (WGBS) was then performed. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed to analyze specific differentially methylated region (DMG) related genes. The target genes were screened with Cytoscape and Search Tool for the Retrieval of Interacting Genes/Proteins (STRING), which are gene/ protein interaction databases. A data mining platform was used to examine the expression level data of the healthy control and JMML patient tissues in Gene Expression Omnibus data sets, and a survival analysis was performed for all the JMML patients. Results:The STRING analysis revealed that the red node [i.e., the cystic fibrosis transmembrane conductance regulator (CFTR)] was the gene of interest. The gene-expression microarray data set analysis suggested that the CFTR expression levels did not differ significantly between the JMML patients and healthy controls (P=0.81). A statistically significant difference was observed in the CFTR promoter methylation level but not in the CFTR gene body methylation level. The overall survival analysis demonstrated that a high level of CFTR expression was associated with a worse survival rate in patients with JMML (P=0.039).Conclusions: CFTR promoter hypermethylation may be a novel biomarker for the diagnosis, monitoring of disease progression, and prognosis of JMML.

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CFTR, Cell Junctions and the Cytoskeleton

Cited by 13 publications

References 59 publications

Human Amniotic Mesenchymal Stem Cells and Fibroblasts Accelerate Wound Repair of Cystic Fibrosis Epithelium

Human Amniotic Mesenchymal Stem Cells and Fibroblasts Accelerate Wound Repair of Cystic Fibrosis Epithelium

Exploring YAP1-centered networks linking dysfunctional CFTR to epithelial–mesenchymal transition

Identification of cystic fibrosis transmembrane conductance regulator as a prognostic marker for juvenile myelomonocytic leukemia via the whole-genome bisulfite sequencing of monozygotic twins and data mining

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