Alterations of the apical junctional complex and actin cytoskeleton and their role in colorectal cancer progression

Gehren, Adriana S; Rocha, Murilo Ramos; Souza, Waldemir Fernandes de; Morgado‐Díaz, José Andrés

doi:10.1080/21688370.2015.1017688

Cited by 35 publications

(26 citation statements)

References 146 publications

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“…(Assimakopoulos et al 2011). There has been growing interest in studying ZO-1 and E-cadherin proteins due to their critical role in the structural and functional organization of the junctional complexes and subsequent mucosal barrier establishment and stability (Assimakopoulos et al 2011;Gehren et al 2015;Bardag-Gorce et al 2016;Costanzo et al 2016;Lee et al 2016).…”

Section: Introductionmentioning

confidence: 99%

Lactobacillus reuteristrains protect epithelial barrier integrity of IPEC-J2 monolayers from the detrimental effect of enterotoxigenicEscherichia coli

et al. 2018

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Lactobacillus reuteri is an inhabitant of the gastrointestinal (GI) tract of mammals and birds and several strains of this species are known to be effective probiotics. The mechanisms by which L. reuteri confers its health‐promoting effects are far from being fully understood, but protection of the mucosal barrier is thought to be important. Leaky gut is a state of abnormal intestinal permeability with implications for the pathophysiology of various gastrointestinal disorders. Enterotoxigenic Escherichia coli (ETEC) can invade the intestinal mucosa and induce changes in barrier function by producing enterotoxin or by direct invasion of the intestinal epithelium. Our hypothesis was that L. reuteri can protect the mucosal barrier, and the goal of the study was to challenge this hypothesis by monitoring the protective effect of L. reuteri strains on epithelial dysfunction caused by ETEC. Using an infection model based on the porcine intestinal cell line IPEC‐J2, it was demonstrated that pretreatment of the cells with human‐derived L. reuteri strains (ATCC PTA 6475, DSM 17938 and 1563F) and a rat strain (R2LC) reduced the detrimental effect of ETEC in a dose‐dependent manner, as monitored by permeability of FITC‐dextran and transepithelial electrical resistance (TEER). Moreover, the results revealed that ETEC upregulated proinflammatory cytokines IL‐6 and TNF α and decreased expression of the shorter isoform of ZO‐1 (187 kDa) and E‐cadherin. In contrast, pretreatment with L. reuteri DSM 17938 and 1563F downregulated expression of IL‐6 and TNF α, and led to an increase in production of the longer isoform of ZO‐1 (195 kDa) and maintained E‐cadherin expression. Interestingly, expression of ZO‐1 (187 kDa) was preserved only when the infected cells were pretreated with strain 1563F. These findings demonstrate that L. reuteri strains exert a protective effect against ETEC‐induced mucosal integrity disruption.

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Section: Introductionmentioning

confidence: 99%

Lactobacillus reuteristrains protect epithelial barrier integrity of IPEC-J2 monolayers from the detrimental effect of enterotoxigenicEscherichia coli

et al. 2018

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“…Regardless of the subtype, the disruption of the apical junctional complex (AJC), consisting of tight junctions (TJs) and adherens junctions, is frequently observed during CRC progression (6). The functionality of TJs, which constitute the barrier to the paracellular flow of macromolecules and ions, is regulated in part by the levels of its proteins (7,8), and claudins in particular.…”

Section: N-glycosylation and Receptor Tyrosine Kinase Signaling Affecmentioning

confidence: 99%

N‑glycosylation and receptor tyrosine kinase signaling affect claudin‑3 levels in colorectal cancer cells

et al. 2020

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Changes in protein levels in different components of the apical junctional complex occur in colorectal cancer (CRC). Claudin-3 is one of the main constituents of tight junctions, and its overexpression can increase the paracellular flux of macromolecules, as well as the malignant potential of CRC cells. The aim of this study was to investigate the molecular mechanisms involved in the regulation of claudin-3 and its prognostic value in CRC. In silico evaluation in each of the CRC consensus molecular subtypes (CMSs) revealed that high expression levels of CLDN3 (gene encoding claudin-3) in CMS2 and CMS3 worsened the patients' long-term survival, whereas a decrease in claudin-3 levels concomitant with a reduction in phosphorylation levels of epidermal growth factor receptor (EGFR) and insulin-like growth factor 1 receptor (IGF1R) could be achieved by inhibiting N-glycan biosynthesis in CRC cells. We also observed that specific inactivation of these receptor tyrosine kinases (RTKs) led to a decrease in claudin-3 levels, and this regulation seems to be mediated by phospholipase C (PLC) and signal transducer and activator of transcription 3 (STAT3) in CRC cells. RTKs are modulated by their N-linked glycans, and inhibition of N-glycan biosynthesis decreased the claudin-3 levels; therefore, we evaluated the correlation between N-glycogenes and CLDN3 expression levels in each of the CRC molecular subtypes. The CMS1 (MSI immune) subtype concomitantly exhibited low expression levels of CLDN3 and N-glycogenes (MGAT5, ST6GAL1, and B3GNT8), whereas CMS2 (canonical) exhibited high gene expression levels of CLDN3 and N-glycogenes (ST6GAL1 and B3GNT8). A robust positive correlation was also observed between CLDN3 and B3GNT8 expression levels in all CMSs. These results support the hypothesis of a mechanism integrating RTK signaling and N-glycosylation for the regulation of claudin-3 levels in CRC, and they suggest that CLDN3 expression can be used to predict the prognosis of patients identified as CMS2 or CMS3.

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“…The gastrointestinal epithelium forms the body's largest interface between biological compartments and allows for the absorption of nutrients while providing a physical barrier to the permeation of pathogens, toxins, and antigens from the luminal environment across the mucosa and ultimately in the circulatory system (17). The intestinal barrier is composed of epithelial cells linked by apical junctional complexes (AJCs), which are formed by tight junctions (TJs) and adherens junctions (AJs) that also establish apical-basal cell polarity (3,12). The TJ is the most apical component of the AJC acting as a barrier (gate) to the paracellular pathway by regulating passive diffusion of solutes and macromolecules.…”

Section: Introductionmentioning

confidence: 99%

“…The AJs, together with TJs, control epithelial cell-to-cell adherence, cell polarization, and barrier function and also play a vital role in the regulation of the actin cytoskeleton, intracellular signaling pathways, and epithelial transcription. The AJC components also have critical functions during intestinal crypt development and differentiation (12,22).…”

Section: Introductionmentioning

confidence: 99%

Knockout of ClC-2 reveals critical functions of adherens junctions in colonic homeostasis and tumorigenicity

Jin

Ibrahim

Magness

et al. 2018

American Journal of Physiology-Gastrointestinal and Liver Physi

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Adherens junctions (AJs), together with tight junctions (TJs), form an apical junctional complex that regulates intestinal epithelial cell-to-cell adherence and barrier homeostasis. Within the AJ, membrane-bound E-cadherin binds β-catenin, which functions as an essential intracellular signaling molecule. We have previously identified a novel protein in the region of the apical junction complex, chloride channel protein-2 (ClC-2), that we have used to study TJ regulation. In this study, we investigated the possible effects of ClC-2 on the regulation of AJs in intestinal mucosal epithelial homeostasis and tumorigenicity. Mucosal homeostasis and junctional proteins were examined in wild-type (WT) and ClC-2 knockout (KO) mice as well as associated colonoids. Tumorigenicity and AJ-associated signaling were evaluated in a murine colitis-associated tumor model and in a colorectal cancer cell line (HT-29). Colonic tissues from ClC-2 KO mice had altered ultrastructural morphology of intercellular junctions with reduced colonocyte differentiation, whereas jejunal tissues had minimal changes. Colonic crypts from ClC-2 KO mice had significantly higher numbers of less-differentiated forms of colonoids compared with WT. Furthermore, the absence of ClC-2 resulted in redistribution of AJ proteins and increased β-catenin activity. Downregulation of ClC-2 in colorectal cells resulted in significant increases in proliferation associated with disruption of AJs. Colitis-associated tumors in ClC-2 KO mice were significantly increased, associated with β-catenin transcription factor activation. The absence of ClC-2 results in less differentiated colonic crypts and increased tumorigenicity associated with colitis via dysregulation of AJ proteins and activation of β-catenin-associated signaling. NEW & NOTEWORTHY Disruption of adherens junctions in the absence of chloride channel protein-2 revealed critical functions of these junctional structures, including maintenance of colonic homeostasis and differentiation as well as driving tumorigenicity by regulating β-catenin signaling.

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Alterations of the apical junctional complex and actin cytoskeleton and their role in colorectal cancer progression

Cited by 35 publications

References 146 publications

Lactobacillus reuteristrains protect epithelial barrier integrity of IPEC-J2 monolayers from the detrimental effect of enterotoxigenicEscherichia coli

Lactobacillus reuteristrains protect epithelial barrier integrity of IPEC-J2 monolayers from the detrimental effect of enterotoxigenicEscherichia coli

N‑glycosylation and receptor tyrosine kinase signaling affect claudin‑3 levels in colorectal cancer cells

Knockout of ClC-2 reveals critical functions of adherens junctions in colonic homeostasis and tumorigenicity

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