Claudin-1 and claudin-5 expression patterns differentiate lung squamous cell carcinomas from adenocarcinomas.

Department of Molecular Biology, Faculty of Sciences, University of Geneva, Geneva, Switzerland.
Modern Pathology (Impact Factor: 6.36). 10/2007; 20(9):947-54. DOI: 10.1038/modpathol.3800835
Source: PubMed

ABSTRACT We investigated the expression of tight junction proteins in human lung squamous cell carcinomas and adenocarcinomas by immunohistochemistry and quantitative real-time reverse transcription-polymerase chain reaction (RT-PCR). We found a statistically significant correlation between diagnosis and positivity of tumors with either claudin (CLDN)-1 or CLDN-5. Squamous cell carcinomas and basal cells of bronchial epithelium were positive for CLDN-1 and negative for CLDN-5, whereas adenocarcinomas, normal cylindrical cells and pneumocytes were positive for CLDN-5 and negative for CLDN-1, suggesting different pathways in tumor development and progression. CLDN-4 and ZO-1 staining were detected in both types of tumors, whereas cingulin (CGN) was not detected in squamous cell carcinomas. Quantitative RT-PCR was used to evaluate changes in transcript levels for a large panel of tight junction proteins. In squamous cell carcinomas, we observed statistically significant decreases in the mRNA levels of JAM-1, occludin, CLDN-3, CLDN-4, CLDN-7, CGN, ZO-2 and ZO-3, and an increase in CLDN-1 mRNA. In adenocarcinomas, when transcript levels were compared with bronchial cells, we observed statistically significant decreases in the mRNA levels of CLDN-1, CLDN-3, CLDN-4, CLDN-7, ZO-2 and ZO-3. These results indicate that characterization of tight junction protein expression in human lung tumors can be an additional diagnostic tool and provide new insights on their histogenesis.

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    ABSTRACT: Objectives We previously reported low expression of miR-375 in squamous-cell carcinoma (SCC) and high expression in adenocarcinoma (AC) of the lung. miR-375's target genes and its function in non-small-cell lung cancer (NSCLC) have not been elucidated. Therefore, the present study was designed to identify the targets of miR-375 and to characterize its function in NSCLC Materials and Methods Candidate targets of miR-375 were determined using a prediction database and previous data on differential gene expression between SCC and AC. We evaluated miR-375 and target-gene expression levels in 12 NSCLC cell lines. The effect of miR-375 overexpression and knockdown was evaluated in NSCLC cell lines by transfecting them with an miR-375 precursor or inhibitor. A luciferase-reporter assay was performed to confirm a direct interaction between miR-375 and its target gene. Further, a wound-healing assay was performed to evaluate the effect of miR-375 overexpression on the migration of SK-MES-1 cells. Finally, to assess the clinical relevance, 63 clinical NSCLC samples were analyzed. Results Claudin-1 (CLDN1) has 4 putative miR-375 target sites in its 3′-untranslated region, and this gene was determined to be a target of miR-375. CLDN1 messenger RNA and protein expression were attenuated by overexpression of miR-375 and increased by knockdown of miR-375 in NSCLC cell lines. In a luciferase-reporter assay, miR-375 overexpression resulted in a 3-fold repression of luciferase activity (P < 0.001). Cell migration was promoted by miR-375 overexpression, suggesting a high potential for invasion and metastasis in NSCLC expressing high levels of miR-375. In clinical NSCLC samples, there was a negative correlation between miR-375 and CLDN1 expression (r = -0.35, P = 0.005). In addition, high miR-375 expression was correlated with a shorter survival time among the clinical samples (P = 0.043). Conclusion CLDN1 is a novel target of miR-375, and high miR-375 expression shortens survival in NSCLC.
    Lung Cancer 09/2014; · 3.74 Impact Factor
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    ABSTRACT: We investigated the role of Toll-like receptor (TLR) 2 in maintaining the integrity of the airway epithelial barrier using the human bronchial epithelial cell line Calu-3. Activation of TLR2 by its ligands, Pam3CysSK4 and Peptidoglycan showed a concentration dependent increase in epithelial barrier function, as measured by transepithelial electrical resistance (TEER). This was confirmed by a decrease in paracellular flux of fluorescein sodium. This TLR2 induced increase in TEER was significantly reduced by pretreatment with polyclonal anti-human TLR2-neutralizing antibody. TLR2 stimulation in Calu-3 cell monolayers resulted in an increased expression of the tight junction proteins claudin-1 and ZO-1, and a decreased expression of occludin, at both the mRNA and protein levels. A pseudosubstrate inhibitor to PKCζ significantly prevented the TLR2 mediated increase in barrier function. It also prevented the increase in claudin-1 in a concentration dependent manner up to 1 µM. TLR2 stimulation led to an increase in phosphorylation of atypical PKC ζ, which was prevented by the pseudosubstrate inhibitor in a concentration dependent manner. Taken together, our observations support a model whereby increased tight junction barrier function induced by activation of TLR2 occurs through increased expression of claudin-1, and through modulation of PKC ζ activity.
    Tissue barriers. 05/2014; 2:e29166.
  • Frontiers in Bioscience 01/2011; 16(1):1069. · 4.25 Impact Factor

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