Claudin gene expression profiles and clinical value in colorectal tumors classified according to their molecular subtype

Cancer Management and Research Dovepress open access to scientific and medical research O r i g i n a l R e s e a rc h Cancer Management and Research downloaded from https://www.dovepress.com/ by 88.198.20.149 on 28-Sep-2019 For personal use only. Open Access Full Text Article Claudin gene expression profiles and clinical value in colorectal tumors classified according to their molecular subtype This article was published in the following Dove Medical Press journal: Cancer Management and Research Sara Cherradi Pierre Martineau Céline Gongora Maguy Del Rio Institut de Recherche en Cancérologie de Montpellier (IRCM), INSERM U1194, Université de Montpellier, Institut régional du Cancer de Montpellier, Montpellier F-34298, France Purpose: Colorectal cancer (CRC) is a heterogeneous disease that can be classified into distinct molecular subtypes. The aims of this study were 1) to compare claudin (CLDN) gene expression in CRC samples and normal colon mucosa, and then in the different CRC molecular subtypes, and 2) to assess their prognostic value. Patients and methods: CLDN expression in CRC samples was analyzed using gene expression data for a cohort of 143 primary CRC samples, and compared in the same CRC samples classified into different molecular subtypes (C1 to C6 according to the Marisa’s classification, and CMS1 to CMS4 of the consensus classification). Comparison of CLDN expression in normal and tumor colon samples was also made on a smaller number of samples. Then, the relationship between CLDN expression profiles and overall survival (OS) and progression-free survival was examined. Results: Compared with normal mucosa, CLDN1 and CLDN2 were upregulated, whereas CLDN5, 7, 8, and 23 were downregulated in CRC samples. Variations in CLDN expression profiles were observed mainly in the CMS2/C1 and CMS4/C4 subtypes. Overall, expression of CLDN2 or CLDN4 alone had a strong prognostic value that increased when they were associated. In the CMS4/C4 subtypes, lower expressions of CLDN11, CLDN12, and CLDN23 were associated with longer OS. Conversely, in the CMS2 and C1 subtypes, low CLDN23 expression was associated with shorter OS and progression-free survival, suggesting a dual role for CLDN23 as a tumor suppressor/promoter in CRC. CLDN6 and CLDN11 had a prognostic value in the CMS2 and C4 subtypes, respectively. Conclusion: This analysis of CLDN gene expression profiles and prognostic value in CRC samples classified according to their molecular subtype shows that CRC heterogeneity must be taken into account when assessing CLDN potential value as prognostic markers or therapeutic targets. Keywords: colon, cancer, classification, prognosis, claudin, target, tight junction, heterogeneity Introduction Correspondence: Maguy Del Rio Institut de Recherche en Cancérologie de Montpellier (IRCM), INSERM U1194 -ICM, 208 Avenue des Apothicaires, F-34298 Montpellier Cedex 5, France Tel +33 46761 2416 Email 1337 submit your manuscript | www.dovepress.com Cancer Management and Research 2019:11 1337–1348 Dovepress © 2019 Cherradi et al. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms. php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). http://dx.doi.org/10.2147/CMAR.S188192 Powered by TCPDF (www.tcpdf.org) Colorectal cancer (CRC) originates from the oncogenic transformation of the intestinal epithelium that physiologically acts as a functional barrier between the intestinal mucosa and the luminal environment. It is now becoming clear that epithelial cell polarity is a major gatekeeper against cancer initiation and metastasis formation.1 Epithelial cell polarity depends on the establishment of the apical junctional complex that includes tight junctions (TJs) and adherens junctions.2 TJs, the most apical of these intercellular junctions, play an essential role in maintaining cell polarity and in Dovepress Cancer Management and Research downloaded from https://www.dovepress.com/ by 88.198.20.149 on 28-Sep-2019 For personal use only. Cherradi et al the regulation of paracellular permeability.3 Alterations in TJs by downregulation or upregulation of TJ proteins can trigger malignant transformation and influence cancer progression.4 Claudins (CLDNs) are TJ core components5 that are essential for TJ formation6 and contribute to their selectivity.7 In mammals, the CLDN family includes 27 members divided into two groups: classic and nonclassic CLDNs.8 Almost all CLDNs have a short intracellular N-terminal domain, four transmembrane domains, two extracellular loops, and an intracellular C-terminal domain that contains a PDZ-domainbinding motif for linking to TJ-associated proteins, such as MUPP1, PATJ, ZO-1, ZO-2 and ZO-3, MAGUKs, PAR3, PAR6, and PALS.9,10 These proteins function as adaptors at the cytoplasmic surface of TJ strands and can directly or indirectly interact with cytosolic and nuclear proteins, for instance cytoskeletal molecules, regulatory proteins, tumor suppressors, and transcription factors.11 Finally, some CLDNs interact with cell adhesion proteins (eg, EPCAM) or receptors (eg, EPHA and EPHB).12 The cytoplasmic tail of most CLDNs contains a large number of predicted phosphorylation sites that could be involved in molecular interactions.13 Accumulated evidence indicates that CLDNs are associated with various pathways, including the WNT/β-catenin, JAK-STAT3, and Notch signaling cascades.7,13,14 CLDNs are expressed in a cell- and tissue-specific manner. In the intestine, CLDNs display specific spatiotemporal expression profiles with variations along the crypt–lumen axis.15 Their expression can be regulated by various mechanisms at the transcriptional or posttranscriptional level, but also via mRNA stability modulation16 and through epigenetic mechanisms.16–19 CLDN expression is altered in several cancer types in a tumor-specific manner, and can vary according to the tumor stage.11 CLDN aberrant expression in tumors may have opposite functions (promotion of tumorigenesis and metastasis formation, or suppressive effects).13,20 For example, CLDN-1 is a cancer invasion/metastasis suppressor in lung adenocarcinoma,21 while in CRC, CLDN1 expression enhances the invasive ability and metastatic properties.22 Moreover, some CLDNs have an important regulatory role in the epithelial–mesenchymal transition (EMT).23–25 CLDNs can also serve as a hub for different signaling proteins, and therefore could have a critical role in the regulation of carcinogenesis or (...truncated)