Disrupted tight junctions in the small intestine of cystic fibrosis mice

Lisle, Robert C. De

doi:10.1007/s00441-013-1734-3

Cited by 41 publications

(41 citation statements)

References 69 publications

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“…Foremost is the inflammatory landscape in the GI tract observed in CF patients, a phenotype that is modeled well in Cftr intestinal-specific knockout mice. In both human CF patients and Cftr knockout mice there is impaired mucosal barrier function, including disrupted tight junctions, 28 that leads to compromised resistance to bacterial colonization, 29 infection, and abnormal innate and adaptive immune responses and inflammation, factors that together may promote oncogenesis. 1,21,30,31 Increased epithelial permeability is also a major factor in bicarbonate loss in the inflamed colon.…”

Section: Discussionmentioning

confidence: 99%

CFTR is a tumor suppressor gene in murine and human intestinal cancer

et al. 2016

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CFTR, the cystic fibrosis (CF) gene, encodes for the CFTR protein that plays an essential role in anion regulation and tissue homeostasis of various epithelia. In the gastrointestinal (GI) tract CFTR promotes chloride and bicarbonate secretion, playing an essential role in ion and acid–base homeostasis. Cftr has been identified as a candidate driver gene for colorectal cancer (CRC) in several Sleeping Beauty DNA transposon-based forward genetic screens in mice. Further, recent epidemiological and clinical studies indicate that CF patients are at high risk for developing tumors in the colon. To investigate the effects of CFTR dysregulation on GI cancer, we generated ApcMin mice that carried an intestinal-specific knockout of Cftr. Our results indicate that Cftr is a tumor suppressor gene in the intestinal tract as Cftr mutant mice developed significantly more tumors in the colon and the entire small intestine. In Apc+/+ mice aged to ~ 1 year, Cftr deficiency alone caused the development of intestinal tumors in >60% of mice. Colon organoid formation was significantly increased in organoids created from Cftr mutant mice compared with wild-type controls, suggesting a potential role of Cftr in regulating the intestinal stem cell compartment. Microarray data from the Cftr-deficient colon and the small intestine identified dysregulated genes that belong to groups of immune response, ion channel, intestinal stem cell and other growth signaling regulators. These associated clusters of genes were confirmed by pathway analysis using Ingenuity Pathway Analysis and gene set enrichment analysis (GSEA). We also conducted RNA Seq analysis of tumors from Apc+/+ Cftr knockout mice and identified sets of genes dysregulated in tumors including altered Wnt β-catenin target genes. Finally we analyzed expression of CFTR in early stage human CRC patients stratified by risk of recurrence and found that loss of expression of CFTR was significantly associated with poor disease-free survival.

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Section: Discussionmentioning

confidence: 99%

CFTR is a tumor suppressor gene in murine and human intestinal cancer

et al. 2016

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“…However, little is known about how these cell–cell adhesion molecules are regulated during wound repair. Interestingly, CFTR has been previously shown to be interacting with junctional complexes (Castellani et al, ; Sun et al, ; De Lisle, ) and recently demonstrated to be involved in epithelial‐mesenchymal‐transition (EMT) and cancer metastasis in breast and colon cancer cells (Zhang et al, ; Sun et al, ). These results are consistent with the presently demonstrated important role of CFTR in the regulation of adhesion molecules, such as ZO‐1 and β‐catenin (Fig.…”

Section: Discussionmentioning

confidence: 99%

Dynamically Regulated CFTR Expression and Its Functional Role in Cutaneous Wound Healing

Dong

Jiang

Zhang

et al. 2015

Journal Cellular Physiology

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The physiological role of cystic fibrosis transmembrane conductance regulator (CFTR) in keratinocytes and skin wound healing is completely unknown. The present study shows that CFTR is expressed in the multiple layers of keratinocytes in mouse epidermis and exhibits a dynamic expression pattern in a dorsal skin wound healing model, with diminishing levels observed from day 3 to day 5 and re-appearing from day 7 to day 10 after wounding. Knockdown of CFTR in cultured human keratinocytes promotes cell migration but inhibits differentiation, while overexpression of CFTR suppresses migration but enhances differentiation, indicating an important role of CFTR in regulating keratinocyte behavior. In addition, we have demonstrated a direct association of CFTR with epithelial junction formation as knockdown of CFTR downregulates the expression of adhesion molecules, such as E-cadherin, ZO-1 and β-catenin, and disrupts the formation of cell junction, while overexpression of CFTR enhances cell junction formation. More importantly, we have shown that ΔF508cftr-/- mice with defective CFTR exhibit delayed wound healing as compared to wild type mice, indicating that normal function of CFTR is critical for wound repair. Taken together, the present study has revealed a previously undefined role of CFTR in regulating skin wound healing processes, which may have implications in injury repair of other epithelial tissues.

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“…Acting as a hub, CFTR also stabilizes the apical junction complex through actin‐dependent interactions in epithelial cells so that the loss of apical protein networks orchestrated by CFTR has emerged as a common mechanism of increased permeability in CF epithelia, including gut and bile ducts . A disruption of tight junctions that could explain increased permeability has thus been demonstrated in the small intestine of CF mice …”

Section: Discussionmentioning

confidence: 99%

Diet‐Induced Dysbiosis and Genetic Background Synergize With Cystic Fibrosis Transmembrane Conductance Regulator Deficiency to Promote Cholangiopathy in Mice

et al. 2018

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The most typical expression of cystic fibrosis (CF)–related liver disease is a cholangiopathy that can progress to cirrhosis. We aimed to determine the potential impact of environmental and genetic factors on the development of CF‐related cholangiopathy in mice. Cystic fibrosis transmembrane conductance regulator (Cftr)−/− mice and Cftr +/+ littermates in a congenic C57BL/6J background were fed a high medium‐chain triglyceride (MCT) diet. Liver histopathology, fecal microbiota, intestinal inflammation and barrier function, bile acid homeostasis, and liver transcriptome were analyzed in 3‐month‐old males. Subsequently, MCT diet was changed for chow with polyethylene glycol (PEG) and the genetic background for a mixed C57BL/6J;129/Ola background (resulting from three backcrosses), to test their effect on phenotype. C57BL/6J Cftr −/− mice on an MCT diet developed cholangiopathy features that were associated with dysbiosis, primarily Escherichia coli enrichment, and low‐grade intestinal inflammation. Compared with Cftr +/+ littermates, they displayed increased intestinal permeability and a lack of secondary bile acids together with a low expression of ileal bile acid transporters. Dietary‐induced (chow with PEG) changes in gut microbiota composition largely prevented the development of cholangiopathy in Cftr −/− mice. Regardless of Cftr status, mice in a mixed C57BL/6J;129/Ola background developed fatty liver under an MCT diet. The Cftr −/− mice in the mixed background showed no cholangiopathy, which was not explained by a difference in gut microbiota or intestinal permeability, compared with congenic mice. Transcriptomic analysis of the liver revealed differential expression, notably of immune‐related genes, in mice of the congenic versus mixed background. In conclusion, our findings suggest that CFTR deficiency causes abnormal intestinal permeability, which, combined with diet‐induced dysbiosis and immune‐related genetic susceptibility, promotes CF‐related cholangiopathy.

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Disrupted tight junctions in the small intestine of cystic fibrosis mice

Cited by 41 publications

References 69 publications

CFTR is a tumor suppressor gene in murine and human intestinal cancer

CFTR is a tumor suppressor gene in murine and human intestinal cancer

Dynamically Regulated CFTR Expression and Its Functional Role in Cutaneous Wound Healing

Diet‐Induced Dysbiosis and Genetic Background Synergize With Cystic Fibrosis Transmembrane Conductance Regulator Deficiency to Promote Cholangiopathy in Mice

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