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The level of claudin-7 is reduced as an early event in colorectal carcinogenesis.

Bornholdt J, Friis S, Godiksen S, Poulsen SS, Santoni-Rugiu E, Bisgaard HC, Lothe IM, Ikdahl T, Tveit KM, Johnson E, Kure EH, Vogel LK - BMC Cancer (2011)

Bottom Line: We found in an in-silico search tight co-regulation between matriptase and claudin-7 expression.A 2.7-fold reduction in the claudin-7 mRNA level was found when comparing the biopsies from healthy individuals with the biopsies of carcinomas (p < 0.001).The decrease at mRNA level was confirmed at the protein level by immunohistochemical stainings.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Cellular and Molecular Medicine, Faculty of Health Science, University of Copenhagen, Denmark.

ABSTRACT

Background: Compromised epithelial barriers are found in dysplastic tissue of the gastrointestinal tract. Claudins are transmembrane proteins important for tight junctions. Claudins regulate the paracellular transport and are crucial for maintaining a functional epithelial barrier. Down-regulation of the oncogenic serine protease, matriptase, induces leakiness in epithelial barriers both in vivo and in vitro. We found in an in-silico search tight co-regulation between matriptase and claudin-7 expression. We have previously shown that the matriptase expression level decreases during colorectal carcinogenesis. In the present study we investigated whether claudin-7 expression is likewise decreased during colorectal carcinogenesis, thereby causing or contributing to the compromised epithelial leakiness of dysplastic tissue.

Methods: The mRNA level of claudin-7 (CLDN7) was determined in samples from 18 healthy individuals, 100 individuals with dysplasia and 121 colorectal cancer patients using quantitative real time RT-PCR. In addition, immunohistochemical stainings were performed on colorectal adenomas and carcinomas, to confirm the mRNA findings.

Results: A 2.7-fold reduction in the claudin-7 mRNA level was found when comparing the biopsies from healthy individuals with the biopsies of carcinomas (p < 0.001). Reductions in the claudin-7 mRNA levels were also detected in mild/moderate dysplasia (p < 0.001), severe dysplasia (p < 0.01) and carcinomas (p < 0.01), compared to a control sample from the same individual. The decrease at mRNA level was confirmed at the protein level by immunohistochemical stainings.

Conclusions: Our results show that the claudin-7 mRNA level is decreased already as an early event in colorectal carcinogenesis, probably contributing to the compromised epithelial barrier in adenomas.

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Related in: MedlinePlus

In-silico analysis showing the ST14 co-expressed gene network. The figure shows a modified version of the analysis performed using the COXPRESdb version 4.0 http://coxpresdb.jp/. Each gene is represented by a node. Lines between nodes indicate co-expression. The genes with direct ST14 co-expression are marked with a line to the ST14 node. These genes are SPINT1 (encoding HAI-1), CLDN7 (encoding claudin-7), LSR (encoding lipolysis stimulated lipoprotein receptor) and MAPK13 (encoding mitogen-activated protein kinase 13). Bold lines indicate a mutual ratio (MR) below 5 and normal lines indicate a MR between 5 and 30.
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Figure 1: In-silico analysis showing the ST14 co-expressed gene network. The figure shows a modified version of the analysis performed using the COXPRESdb version 4.0 http://coxpresdb.jp/. Each gene is represented by a node. Lines between nodes indicate co-expression. The genes with direct ST14 co-expression are marked with a line to the ST14 node. These genes are SPINT1 (encoding HAI-1), CLDN7 (encoding claudin-7), LSR (encoding lipolysis stimulated lipoprotein receptor) and MAPK13 (encoding mitogen-activated protein kinase 13). Bold lines indicate a mutual ratio (MR) below 5 and normal lines indicate a MR between 5 and 30.

Mentions: In order to identify genes co-regulated with the ST14 gene, encoding matriptase, an in-silico analysis was performed. The analysis, performed on COXPRESSdb version 4.0 database, shows a network of co-expressed genes including the ST14 gene (Figure 1). Many of these genes are already known to be either inhibitors or substrates of matriptase, such as SPINT1 and SPINT2, encoding the inhibitors of matriptase, HAI-1 and HAI-2 respectively, and the PRSS8 gene encoding the matriptase substrate, prostasin. ST14 has the highest degree of co-regulation with its inhibitor SPINT1 (correlation coefficient = 0.70 (Pearson's) and a MR = 2.0). In addition to these previously described molecules in the matriptase pathway, we found a new gene, CLDN7, that encodes claudin-7 (correlation coefficient = 0.69 and MR = 2.8) to be co-regulated with the ST14 gene. Moreover, the analysis showed that claudin-7 and matriptase have conserved co-expression between human and mouse orthologs. As claudin-7 is involved in the regulation of the epithelial permeability, we found it plausible that the increased epithelial leakiness observed during carcinogenesis could be mediated through a decreased level of claudin-7.


The level of claudin-7 is reduced as an early event in colorectal carcinogenesis.

Bornholdt J, Friis S, Godiksen S, Poulsen SS, Santoni-Rugiu E, Bisgaard HC, Lothe IM, Ikdahl T, Tveit KM, Johnson E, Kure EH, Vogel LK - BMC Cancer (2011)

In-silico analysis showing the ST14 co-expressed gene network. The figure shows a modified version of the analysis performed using the COXPRESdb version 4.0 http://coxpresdb.jp/. Each gene is represented by a node. Lines between nodes indicate co-expression. The genes with direct ST14 co-expression are marked with a line to the ST14 node. These genes are SPINT1 (encoding HAI-1), CLDN7 (encoding claudin-7), LSR (encoding lipolysis stimulated lipoprotein receptor) and MAPK13 (encoding mitogen-activated protein kinase 13). Bold lines indicate a mutual ratio (MR) below 5 and normal lines indicate a MR between 5 and 30.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3045986&req=5

Figure 1: In-silico analysis showing the ST14 co-expressed gene network. The figure shows a modified version of the analysis performed using the COXPRESdb version 4.0 http://coxpresdb.jp/. Each gene is represented by a node. Lines between nodes indicate co-expression. The genes with direct ST14 co-expression are marked with a line to the ST14 node. These genes are SPINT1 (encoding HAI-1), CLDN7 (encoding claudin-7), LSR (encoding lipolysis stimulated lipoprotein receptor) and MAPK13 (encoding mitogen-activated protein kinase 13). Bold lines indicate a mutual ratio (MR) below 5 and normal lines indicate a MR between 5 and 30.
Mentions: In order to identify genes co-regulated with the ST14 gene, encoding matriptase, an in-silico analysis was performed. The analysis, performed on COXPRESSdb version 4.0 database, shows a network of co-expressed genes including the ST14 gene (Figure 1). Many of these genes are already known to be either inhibitors or substrates of matriptase, such as SPINT1 and SPINT2, encoding the inhibitors of matriptase, HAI-1 and HAI-2 respectively, and the PRSS8 gene encoding the matriptase substrate, prostasin. ST14 has the highest degree of co-regulation with its inhibitor SPINT1 (correlation coefficient = 0.70 (Pearson's) and a MR = 2.0). In addition to these previously described molecules in the matriptase pathway, we found a new gene, CLDN7, that encodes claudin-7 (correlation coefficient = 0.69 and MR = 2.8) to be co-regulated with the ST14 gene. Moreover, the analysis showed that claudin-7 and matriptase have conserved co-expression between human and mouse orthologs. As claudin-7 is involved in the regulation of the epithelial permeability, we found it plausible that the increased epithelial leakiness observed during carcinogenesis could be mediated through a decreased level of claudin-7.

Bottom Line: We found in an in-silico search tight co-regulation between matriptase and claudin-7 expression.A 2.7-fold reduction in the claudin-7 mRNA level was found when comparing the biopsies from healthy individuals with the biopsies of carcinomas (p < 0.001).The decrease at mRNA level was confirmed at the protein level by immunohistochemical stainings.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Cellular and Molecular Medicine, Faculty of Health Science, University of Copenhagen, Denmark.

ABSTRACT

Background: Compromised epithelial barriers are found in dysplastic tissue of the gastrointestinal tract. Claudins are transmembrane proteins important for tight junctions. Claudins regulate the paracellular transport and are crucial for maintaining a functional epithelial barrier. Down-regulation of the oncogenic serine protease, matriptase, induces leakiness in epithelial barriers both in vivo and in vitro. We found in an in-silico search tight co-regulation between matriptase and claudin-7 expression. We have previously shown that the matriptase expression level decreases during colorectal carcinogenesis. In the present study we investigated whether claudin-7 expression is likewise decreased during colorectal carcinogenesis, thereby causing or contributing to the compromised epithelial leakiness of dysplastic tissue.

Methods: The mRNA level of claudin-7 (CLDN7) was determined in samples from 18 healthy individuals, 100 individuals with dysplasia and 121 colorectal cancer patients using quantitative real time RT-PCR. In addition, immunohistochemical stainings were performed on colorectal adenomas and carcinomas, to confirm the mRNA findings.

Results: A 2.7-fold reduction in the claudin-7 mRNA level was found when comparing the biopsies from healthy individuals with the biopsies of carcinomas (p < 0.001). Reductions in the claudin-7 mRNA levels were also detected in mild/moderate dysplasia (p < 0.001), severe dysplasia (p < 0.01) and carcinomas (p < 0.01), compared to a control sample from the same individual. The decrease at mRNA level was confirmed at the protein level by immunohistochemical stainings.

Conclusions: Our results show that the claudin-7 mRNA level is decreased already as an early event in colorectal carcinogenesis, probably contributing to the compromised epithelial barrier in adenomas.

Show MeSH
Related in: MedlinePlus