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Claudin 5 expression in pulmonary squamous cell carcinoma. Stronger expression is found in the central areas of the tumor cell islands.
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Tight junctions are structures located in the apicobasal region of the cell membranes. They regulate paracellular solute and electrical permeability of cell layers. Additionally, they influence cellular polarity, form a paracellular fence to molecules and pathogens and divide the cell membranes to apical and lateral compartments. Tight junctions ad...
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... immunohistochemical expression of claudins 1, 2, 3, 4, 5 and 7 on lung carcinomas based on our studies the three primary lung epithelial tumors (SQCC, AC and SCC) showed significantly stronger claudin 1 positivity than other types of lung tumors [60,61] (Figure 1 and 2). Squamous cell carcinomas and adenocarcino- mas (including bronchioloalveolar carcinomas) had significantly more cases with claudin 2 posi- tivity than small cell carcinomas or carcinoid tumors. Squamous cell and large cell carcino- mas showed a lower claudin 3 positivity com- pared to adenocarcinomas, small cell carcino- mas, bronchioloalveolar carcinomas, carcinoid tumors and adenosquamous carcinomas. Adenocarcinomas displayed most claudin 5 positive cases, followed by squamous cell carci- nomas and small cell carcinomas (Figure 4). Others tumors were mainly weak or negative in regard to claudin 5 expression. Compared to other claudins studied, claudin 5 was clearly the most weakly expressed and expression was significantly lower compared to the expression of other claudins. Interestingly also, bron- chioloalveolar carcinomas had a similar expres- sion of claudins as adenocarcinomas in general except for the fact that they had a lower expres- sion of claudin 5. This indicates that in situ type of adenocarcinomas as bronchioloalveolar car- cinomas mostly are according to a modern clas- sification [1,2] show a lower expression of this claudin than invasive tumors suggesting that upregulation of claudin 5 might indicate lung adenocarcinoma ...
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An intact intestinal barrier is crucial for immune homeostasis and its impairment activates the immune system and may result in chronic inflammation. The epithelial cells of the intestinal barrier are connected by tight junctions, which form an anastomosing network sealing adjacent epithelial cells. Tight junctions are composed of transmembrane and...
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The two compositionally distinct extracellular cochlear fluids, endolymph and perilymph, are separated by tight junctions that outline the scala media and reticular lamina. Mutations in TRIC (also known as MARVELD2), which encodes a tricellular tight junction protein known as tricellulin, lead to nonsyndromic hearing loss (DFNB49). We generated a k...
Citations
... The observed decrease in these species' abundances may suggest their relation to EMT and to the pathology of bladder cancer as a whole. The adherens junction pathway has been previously implicated in many other cancer types, including colorectal cancer, breast cancer, and lung cancer [58][59][60][61][62]. Moreover, dysbiosis of the gut microbiome has also been shown to contribute to epithelial dysregulation [63]. ...
Simple Summary
Current means of bladder cancer diagnosis are invasive or lack sensitivity. Dysbiosis of the urinary microbiome has been implicated in the development of bladder cancer, though its potential as a diagnostic tool is unknown. This study attempts to characterize bladder cancer-specific dysbiosis of the urinary microbiome to explore its diagnostic potential. Numerous species were observed to be differentially abundant between the urine samples of patients with bladder cancer and healthy individuals. Specific immune modulations were observed with respect to these species, as was the enrichment of select pathways known to be implicated in the progression of bladder cancer. The study suggests that the urinary microbiome may reflect dysregulations of the tumor microenvironment. Further investigation may reveal the potential of the identified species as urinary biomarkers of this disease. In this way, the urinary microbiome may allow for the noninvasive and earlier detection of bladder cancer, regardless of stage or subtype.
Abstract
There are a total of 82,290 new cases and 16,710 deaths estimated for bladder cancer in the United States in 2023. Currently, urine cytology tests are widely used for bladder cancer diagnosis, though they suffer from variable sensitivity, ranging from 45 to 97%. More recently, the microbiome has become increasingly recognized for its role in human diseases, including cancers. This study attempts to characterize urinary microbiome bladder cancer-specific dysbiosis to explore its diagnostic potential. RNA-sequencing data of urine samples from patients with bladder cancer (n = 18) and matched controls (n = 12) were mapped to bacterial sequences to yield species-level abundance approximations. Urine samples were analyzed at both the population and species level to reveal dysbiosis associated with bladder cancer. A panel of 35 differentially abundant species was discovered, which may be useful as urinary biomarkers for this disease. We further assessed whether these species were of similar significance in a validation dataset (n = 81), revealing that the genera Escherichia, Acinetobacter, and Enterobacter were consistently differentially abundant. We discovered distinct patterns of microbial-associated immune modulation in these samples. Several immune pathways were found to be significantly enriched with respect to the abundance of these species, including antigen processing and presentation, cytosolic DNA sensing, and leukocyte transendothelial migration. Differential cytokine activity was similarly observed, suggesting the urinary microbiome’s correlation to immune modulation. The adherens junction and WNT signaling pathways, both implicated in the development and progression of bladder cancer, were also enriched with these species. Our findings indicate that the urinary microbiome may reflect both microbial and immune dysregulations of the tumor microenvironment in bladder cancer. Given the potential biomarker species identified, the urinary microbiome may provide a non-invasive, more sensitive, and more specific diagnostic tool, allowing for the earlier diagnosis of patients with bladder cancer.
... Therefore, we determined the protein expression levels of key markers of epithelial phenotype (ZO-1) and mesenchymal phenotype (ZEB1, beta-catenin, vimentin) in U-87 MG and NCH421k cells. ZO-1 is one of the scaffold proteins in the tight junctions and transduces signals to the cell interior [46]. Our immunostaining results show that there were no differences in signal intensity in U-87 MG, but the signal in the membrane was stronger in the presence of Nb79 than in the control. ...
Purpose:
Glioblastoma (GBM) is the most common primary brain tumour and one of the deadliest cancers. In addition to late diagnosis and inadequate treatment, the extremely low survival rate is also due to the lack of appropriate therapeutic biomarkers and corresponding therapeutic agents. One of the potential therapeutic biomarkers is the intermediate filament vimentin, which is associated with epithelial-mesenchymal transition (EMT). The purpose of this study was to analyse the effect of the anti-vimentin nanobody Nb79 on cell invasion in vitro and in vivo. To further our understanding of the mechanism of action, we investigated the association between Nb79 and EMT in GBM and GBM stem cells by analysing the expression levels of key EMT-related proteins.
Methods:
The expression of vimentin in glioma tissues and cells was determined by RT-qPCR. An invasion assay was performed on differentiated glioblastoma cell line U-87 MG and stem cell line NCH421k in vitro as well as in vivo in zebrafish embryos. The effect of Nb79 on expression of EMT biomarkers beta-catenin, vimentin, ZEB-1 and ZO1 was determined by Western blot and immunocytochemistry.
Results:
Our study shows that vimentin is upregulated in glioblastoma tissue compared to lower grade glioma and non-tumour brain tissue. We demonstrated that treatment with Nb79 reduced glioblastoma cell invasion by up to 64% in vitro and up to 21% in vivo. In addition, we found that the tight junction protein ZO-1 had higher expression on the cell membrane, when treated with inhibitory anti-vimentin Nb79 compared to control.
Conclusion:
In conclusion, our results suggest that anti-vimentin nanobody Nb79 is a promising tool to target glioblastoma cell invasion.
... Thus, tight junction proteins like Claudin, Occludin, and Zo-1 are essential components of intestinal epithelia and produce synergistic effects to maintain physiological homeostasis in mammals (Pearce et al., 2018). Recent evidence from rat and cellular models demonstrates that α-tocopherol repairs hyperoxiaand hyperchromium-induced tight junction protein damage (Simon et al., 1999;Soini, 2012;Zahraoui, 2004). However, it has not yet been determined whether α-tocopherol affects intestinal tight junction proteins under normal physiological conditions. ...
Alpha (α)‐tocopherol is a major component of dietary vitamin E. Despite being one of the most widely used food supplements in both animals and humans, its role in intestinal functions remains unknown. We were able to examine and accurately demonstrate its permeability effect in vitro and its differentiated effect on tight junction expression in different segments of the intestine in vivo using cultured intestinal porcine epithelial cell line (IPEC‐J2) and piglets. A cultured IPEC‐J2 demonstrated that α‐tocopherol upregulated the expression of tight junction proteins and improved their integrity, with a maximum effect at concentrations ranging from 20 to 40 μmol/L. In vivo data from weaned pigs fed different doses of α‐tocopherol for 2 weeks revealed that α‐tocopherol effectively increases the expression of tight junction proteins in all sections of the intestinal mucosa, with the highest effect on the duodenum at an optimum dose of 20–50 mg/kg. In contrast, α‐tocopherol did not affect intestinal inflammation. These findings suggest that α‐tocopherol maintains intestinal integrity and increases the expression of tight junction proteins both in vitro and in vivo. we disclose that α‐tocopherol has profound effect on enhancing expression of tight junction proteins in the intestinal tract and inhibiting permeability in the intestine in normal healthy conditions, both in vivo and in vitro. The detailed mechanisms how α‐tocopherol exerts effect on the intestinal barrier and intestinal inflammation in diseased conditions deserve further study.
... Indeed, tight junctions are closely associated with various types of cancers and drug delivery. Since the drug must pass through the epithelium and the inner membrane to reach the target tissue, that is, the ability of the drug to pass through these membranes is directly related to the effectiveness of the drug [53][54][55]. Therefore, we conducted a hypothesis that the level of methylation may affect the expression of EGFR inhibitors of responsive genes, and then influence the effectiveness of drugs in cancer. ...
The emergence of drug resistance is one of the main obstacles to the treatment of lung cancer patients with EGFR inhibitors. Here, to further understand the mechanism of EGFR inhibitors in lung cancer and offer novel therapeutic targets for anti-EGFR-inhibitor resistance via the deep mining of pharmacogenomics data, we associated DNA methylation with drug sensitivities for uncovering the methylation sites related to EGFR inhibitor sensitivity genes. Specifically, we first introduced a grouped regularized regression model (Group Least Absolute Shrinkage and Selection Operator, group lasso) to detect the genes that were closely related to EGFR inhibitor effectiveness. Then, we applied the classical regression model (lasso) to identify the methylation sites associated with the above drug sensitivity genes. The new model was validated on the well-known cancer genomics resource: CTRP. GeneHancer and Encyclopedia of DNA Elements (ENCODE) database searches indicated that the predicted methylation sites related to EGFR inhibitor sensitivity genes were related to regulatory elements. Moreover, the correlation analysis on sensitivity genes and predicted methylation sites suggested that the methylation sites located in the promoter region were more correlated with the expression of EGFR inhibitor sensitivity genes than those located in the enhancer region and the TFBS. Meanwhile, we performed differential expression analysis of genes and predicted methylation sites and found that changes in the methylation level of some sites may affect the expression of the corresponding EGFR inhibitor-responsive genes. Therefore, we supposed that the effectiveness of EGFR inhibitors in lung cancer may be improved by methylation modification in their sensitivity genes.
... Deregulation of junctions is widely documented in many cancers (Jaggi et al., 2005;Kinugasa et al., 2012;Kurrey et al., 2005;Martin et al., 2010;Orbán et al., 2008;Soini, 2012;Tobioka et al., 2004) (summarized in Table 5), affecting AJs, TJs and desmosomes. ...
During development, the behaviour of cells is tightly regulated ensuring optimal functioning of healthy epithelial tissues. Epithelial cells thus establish well organized intercellular junctions, apico/basal polarity, cytoskeletal architecture, and integrate regulatory and homeostatic inputs relayed by dedicated signalling pathways. Alterations in these processes are most often associated with cancer.My lab is interested in deciphering the mechanisms in which junctional and polarity alterations are able to induce tumorigenesis. Scaffold proteins represent important regulators of these different processes, and alterations to several key epithelial scaffolds have been linked to cancer. Recent work in the team identified Magi, a member of the MAGUK family, as a regulator of E-Caherin-based Adherens Junctions during eye development in Drosophila. The main goal of my thesis was to study the function of MAGI1, the most abundant MAGI family member in human tissues, during cancer, and more specifically its roles in luminal A Breast Cancer cells. Using mainly loss-of-function approaches, we were able to identify a tumour suppressive function of MAGI1 in luminal BCa cells both in vitro cellular assays as well as in xenografted nude mice. Moreover, this work revealed that MAGI1 inhibits an AMOTL2/P38 signalling axis that is activated upon MAGI1 loss and then responsible for the enhanced tumorigenicity phenotype obtained. Interestingly, the loss of MAGI1 induced increased myosin activity, increased compressive behaviours, and associated elevated plasma membrane tension, which we propose to be one of the activator of P38 downstream of MAGI1 loss. Strikingly, even though cells lacking MAGI1 showed increased tumorigenicity, the activity of the YAP onco-protein is lowered in MAGI1-deficient luminal breast cancer cells, suggesting that the relationship between YAP and tumorigenesis could be more complex than commonly assumed.The study of Hippo pathway regulations is indeed a major axis of the team. A secondary objective of my thesis was thus to explore the involvement of YAP/TAZ and of the Hippo pathway during Oxaliplatin exposure in colon cancer cells. As first line chemotherapy along with 5 Fluorouracil, it is important to understand the mechanism of action of Oxaliplatin beyond its major role as inducer of deleterious DNA double strand breaks. HCT116 colon cancer cells treated with relatively modest doses of Oxaliplatin (at IC50), featured a translocation of YAP/TAZ to the nucleus accompanied with increased YAP/TAZ-mediated transcription, as judged by qPCR and RNA-Seq. This effect was coupled with a re-organization of the actin cytoskeleton inside the cell upon the treatment, and many genes affected by oxaliplatin treatment were actin regulators (including several that are also potential YAP/TAZ targets). This study involves YAP/TAZ in HCT116 response to Oxaliplatin treatment, and we propose that it leads to actin re-organization.
... junctions bearing tissues. Their expression was found in many lung cancer histological types, and overexpression could results in tumor spreading (Soini, 2012). In addition, S100 family were highly expressed in P6, whereas P7 has elevated expression of many ribosomal protein genes (RPL and RPS). ...
Metastatic lung cancer accounts for about half of the brain metastases (BM). Development of leptomeningeal metastases (LM) are becoming increasingly common, and its prognosis is still poor despite the advances in systemic and local approaches. Until now, the cytology analysis in the cerebrospinal fluid (CSF) remains the gold diagnostic standard. Although several previous studies performed in CSF have offered great promise for the diagnostics and therapeutics of LM, a comprehensive characterization of CTCs in CSF is still lacking. To fill this critical gap of lung adenocarcinoma leptomeningeal metastases (LUAD-LM), we analyzed the transcriptomes of 1,375 cells from 5 LUAD-LM patient and 3 control samples using single-cell RNA sequencing technology. We defined CSF-CTCs based on abundant expression of epithelial markers and genes with lung origin, as well as the enrichment of metabolic pathway and cell adhesion molecules, which are crucial for the survival and metastases of tumor cells. Elevated expression of CEACAM6 and SCGB3A2 was discovered in CSF-CTCs, which could serve as candidate biomarkers of LUAD-LM. We revealed substantial heterogeneity in CSF-CTCs among LUAD-LM patients and within patient among individual cells. Cell-cycle gene expression profiles and the proportion of CTCs displaying mesenchymal and cancer stem cell properties also vary among patients. In addition, CSF-CTC transcriptome profiling identified one LM case as cancer of unknown primary site (CUP). Our results will shed light on the mechanism of LUAD-LM and provide a new direction of diagnostic test of LUAD-LM and CUP cases from CSF samples.
... Human lung cancer is the second leading cause of mortality in the United States (1). The lung expresses various tight junction (TJ) proteins depending on their compartments, including claudin-1, -2, -3, -5, -7, -8, and -18 (2). TJ proteins are one of the cellular junctional proteins located at the apical side of epithelial cells, and they regulate paracellular permeability between neighboring epithelial cells (3). ...
Claudins are a family of tight junction proteins, and serve important roles in epithelial barrier, selective ion transports and cancer metastasis. Although the exact role of claudin-7 in human lung cancer has not been completely elucidated, recent clinical studies have demonstrated that claudin-7 is associated with the survival of patients with lung cancer. Our previous studies have demonstrated that claudin-7 forms a protein complex with integrin β1 in human lung cancer cells. The knockdown (KD) of claudin-7 by short hairpin RNA (shRNA) reduced integrin β1 expression and increased the cell proliferative rate, whereas claudin-7 re-expression in the KD cells decreased the cell proliferation. It is unknown as to whether claudin-7 and integrin β1 regulate cell proliferation and invasion synergistically or independently. In the present study, it was observed that ectopic expression of integrin β1 in claudin-7 KD lung cancer cells did not reduce the cell proliferation. However, integrin β1-transfected cells migrated more effectively in wound healing and cell invasion assays and were more adhesive in a cell attachment assay when compared with those of claudin-7 KD cells. This indicates that claudin-7 controls cell proliferation, while cell attachment and motility were regulated partially through integrin β1. Additionally, claudin-7 overexpression in claudin-7 KD cells resulted in an improved ability to attach to the surface of cell culture plates and a higher expression of focal adhesion proteins when compared with claudin-7 non-KD control cells, which supports the role of claudin-7 in cell adhesion and motility. Taken together, these data suggest that claudin-7 regulates cell motility through integrin β1, providing additional insight into the roles of claudins in carcinogenesis and cancer cell metastasis.
... In recent decades, researchers have begun to focus on the tight junction as a potential target implicated in the pathogenesis of many respiratory disorders. Initially, tight junctions were believed to be simple paracellular seals; however, our current understanding of the functions of tight junctions now includes the regulation of cell polarity and the modulation of cellular proliferation and differentiation (Gonzalez-Mariscal et al. 2014;Soini 2012;Findley and Koval 2009). Tight junctions have long been viewed as critical in maintaining the permeability barrier; however, they are now also considered an essential component of the overall innate immune system. ...
Claudin-6 (Cldn6) is a tetraspanin transmembrane protein that contributes to tight junctional complexes and has been implicated in the maintenance of lung epithelial barriers. In the present study, we tested the hypothesis that genetic up-regulation of Cldn-6 influences inflammation in mice exposed to short-term environmental diesel particulate matter (DPM). Mice were subjected to ten exposures of nebulized DPM (PM2.5) over a period of 20 days via a nose-only inhalation system (Scireq, Montreal, Canada). Using real-time RT-PCR, we discovered that the Cldn6 gene was up-regulated in control mice exposed to DPM and in lung-specific transgenic mice that up-regulate Cldn-6 (Cldn-6 TG). Interestingly, DPM did not further enhance Cldn-6 expression in Cldn-6 TG mice. DPM caused increased cell diapedesis into bronchoalveolar lavage fluid (BALF) from control mice; however, Cldn-6 TG mice had less total cells and PMNs in BALF following DPM exposure. Because Cldn-6 TG mice had diminished cell diapedesis, other inflammatory intermediates were screened to characterize the impact of increased Cldn-6 on inflammatory signaling. Cytokines that mediate inflammatory responses including TNF-α and IL-1β were differentially regulated in Cldn6 TG mice and controls following DPM exposure. These results demonstrate that epithelial barriers organized by Cldn-6 mediate, at least in part, diesel-induced inflammation. Further work may show that Cldn-6 is a key target in understanding pulmonary epithelial gateways exacerbated by environmental pollution.
... Epithelial-mesenchymal transition (EMT) is associated with multiple pathologies including lung cancer metastasis, during which epithelial cells acquire enhanced mobility and invasiveness by the loss of E-cadherin expression and the increase of mesenchymal marker (N-cadherin and Vimentin) expression. 4,5 Further studies are needed to explore the molecular mechanism that regulates EMT, in order to find therapeutic target for the treatment of tumor invasion and metastasis. Osteopontin (OPN) is an extracellular matrix protein that plays a key role in tumor progression through binding with avβ3-integrin and CD44 receptor. ...
... It is well known that the EMT process plays an important role in the transition of lung cancer from early stage to invasive carcinoma. 4 Taken together, these data suggested that SIRT1 might be a new therapeutic modality in OPN-mediated NSCLC progression. ...
Osteopontin (OPN) is a promoter for tumor progression. It has been reported to promote non-small cell lung cancer (NSCLC) progression via the activation of nuclear factor-κB (NF-κB) signaling. As the increased acetylation of NF-κB p65 is linked to NF-κB activation, the regulation of NF-κB p65 acetylation could be a potential treatment target for OPN-induced NSCLC progression. Sirtuin 1 (SIRT1) is a deacetylase, and the role of SIRT1 in tumor progression is still controversial. The effect and mechanism of SIRT1 on OPN-induced tumor progression remains unknown. The results presented in this research demonstrated that OPN inhibited SIRT1 expression and promoted NF-κB p65 acetylation in NSCLC cell lines (A549 and NCI-H358). In this article, overexpression of SIRT1 was induced by infection of SIRT1-overexpressing lentiviral vectors. The overexpression of SIRT1 protected NSCLC cells against OPN-induced NF-κB p65 acetylation and epithelial-mesenchymal transition (EMT), as indicated by the reduction of OPN-induced changes in the expression levels of EMT-related markers and cellular morphology. Furthermore, SIRT1 overexpression significantly attenuated OPN-induced cell proliferation, migration and invasion. Moreover, overexpression of SIRT1 inhibited OPN-induced NF-κB activation. As OPN induced NSCLC cell EMT through activation of NF-κB signaling, OPN-induced SIRT1 downregulation may play an important role in NSCLC cell EMT via NF-κB signaling. The results suggest that SIRT1 could be a tumor suppressor to attenuate OPN-induced NSCLC progression through the regulation of NF-κB signaling.
... Interestingly, mice with knockout of Cldn15 demonstrated an unexpected phenotype of upper small intestine enlargement (megaintestine) and increased crypt cell proliferation without evidence of inflammation (14). Both up-and downregulation of claudin expression have been observed in a number of cancers, although how these changes contribute to carcinogenesis and/or neoplastic progression remains controversial (15)(16)(17)(18). These studies suggest that, in addition to traditional roles in regulating epithelial barrier function and polarity, claudins also regulate cell functions such as proliferation that might contribute to tumorigenesis. ...
Claudins, the integral tight junction (TJ) proteins that regulate paracellular permeability and cell polarity, are frequently dysregulated in cancer; however, their role in neoplastic progression is unclear. Here, we demonstrated that knockout of Cldn18, a claudin family member highly expressed in lung alveolar epithelium, leads to lung enlargement, parenchymal expansion, increased abundance and proliferation of known distal lung progenitors, the alveolar epithelial type II (AT2) cells, activation of Yes-associated protein (YAP), increased organ size, and tumorigenesis in mice. Inhibition of YAP decreased proliferation and colony-forming efficiency (CFE) of Cldn18-/- AT2 cells and prevented increased lung size, while CLDN18 overexpression decreased YAP nuclear localization, cell proliferation, CFE, and YAP transcriptional activity. CLDN18 and YAP interacted and colocalized at cell-cell contacts, while loss of CLDN18 decreased YAP interaction with Hippo kinases p-LATS1/2. Additionally, Cldn18-/- mice had increased propensity to develop lung adenocarcinomas (LuAd) with age, and human LuAd showed stage-dependent reduction of CLDN18.1. These results establish CLDN18 as a regulator of YAP activity that serves to restrict organ size, progenitor cell proliferation, and tumorigenesis, and suggest a mechanism whereby TJ disruption may promote progenitor proliferation to enhance repair following injury.
