Expression of claudin-3 and claudin-4 in normal, hyperplastic, and malignant endometrial tissue

Abstract

To clarify the roles of claudins in endometrial tumorigenesis, we determined levels of protein and messengerRNA (mRNA) expression of claudin-3 and claudin-4 in human endometrial tissue (proliferative phase [PE, n= 25]; secretory phase [SE, n= 25]; simple hyperplasia [SH, n= 20]; complex hyperplasia [CH, n= 12]; atypical hyperplasia [AH, n= 15]; endometrioid adenocarcinoma [EEC, n= 30]) using immunohistochemistry, western blotting, and real-time polymerase chain reaction, respectively. Morphologic changes of tight junctions (TJs) were also observed in normal, hyperplastic, and malignant endometrial tissue. Absence or weak staining for claudin-3 and claudin-4 was observed in PE, SE, SH, and CH, while medium to intense staining was detected in AH and EEC. Staining of claudin-3 and claudin-4 was predominantly localized to the glandular epithelial cell membrane. Expression of claudin-3 and claudin-4 was significantly increased in the groups of AH and EEC in comparison with the groups of CH, SH, and normal cyclic endometrium at both protein and mRNA levels. The highest expression was observed in EEC. Although no relevance was found with regard to FIGO stage and histologic grade, overexpression of claudin-3 and claudin-4, especially claudin-4, significantly correlated with myometrial invasion. Transmission electron microscopy analysis indicated morphologic disruptions of TJs may lag behind the increase of claudins expression. These results demonstrate that claudin-3 and claudin-4 are strongly expressed in AH and EEC, but less frequently in normal endometrium. The upregulation of claudins expression during endometrial carcinogenesis suggests their potential utility as diagnostic and prognostic biomarkers.

Overexpression and delocalization of claudin-3 protein in MCF-7 and MDA-MB-415 breast cancer cell lines

“…The assessment of claudin-3 expression in three breast cancer cell lines revealed that, compared with normal breast epithelial cells (HMEC), there was a considerable overexpression of claudin-3 in two of the cell lines, MCF-7 and MDA-MB-415. By contrast, the third breast (8) and endometrial (11,12) cancers, while claudin-4 overexpression has been reported in breast cancer (4). As previously stated, the MCF-7 and MDA-MB-415 cell lines are metastatic breast adenocarcinomas derived from pleural effusions.…”

Tight junction-based epithelial microenvironment and cell proliferation

“…For example, claudin-1 and -7 reportedly decreased to almost undetectable levels in some cancers from detectable levels in control subjects (Lioni et al, 2007). On the other hand, the expression levels of claudin-1, -2, -3 and -7 were reported to show more than 10-fold differences, and even more than 100-fold differences in some cases, in more than 10 types of cancers (Pan et al, 2007). However, the direct or indirect molecular mechanisms …”

Tight junctions in thyroid carcinogenesis: diverse expression of claudin-1, claudin-4, claudin-7 and occludin in thyroid neoplasms

“…[7][8][9][10] Claudin family consists of 24 members. Different claudins are found at the tight junction of diverse epithelial cells, 11 and this accounts for the observed differences in permeability and electrical resistance of various epithelia. 2,8,10 Previous studies have shown that occludin and claudin-1, -4 and -7 are deregulated in a variety of malignancies; for example, loss of occludin expression or upregulation of claudin-3 and -4 accompanies the progression of endometrial carcinoma, 12,13 reduced expression of claudin-1 correlates with poorer differentiation, disease recurrence and poor survival in stage II colonic cancer, 14 claudin-7 expression has been found reduced in mammary, 15 esophageal, 16 and head and neck carcinomas, 17 whereas claudin-4 overexpression decreases the invasiveness and metastatic potential of pancreatic cancer cells.…”