Abstract
BackgroundClaudins are tight junction proteins that are involved in tight junction formation and function. Previous studies have shown that claudin-7 is frequently upregulated in epithelial ovarian cancer (EOC) along with claudin-3 and claudin-4. Here, we investigate in detail the expression patterns of claudin-7, as well as its possible functions in EOC.Methodology/Principal FindingsA total of 95 ovarian tissue samples (7 normal ovarian tissues, 65 serous carcinomas, 11 clear cell carcinomas, 8 endometrioid carcinomas and 4 mucinous carcinomas) were studied for claudin-7 expression. In real-time RT-PCR analysis, the gene for claudin-7, CLDN7, was found to be upregulated in all the tumor tissue samples studied. Similarly, immunohistochemical analysis and western blotting showed that claudin-7 protein was significantly overexpressed in the vast majority of EOCs. Small interfering RNA-mediated knockdown of claudin-7 in ovarian cancer cells led to significant changes in gene expression as measured by microarrays and validated by RT-PCR and immunoblotting. Analyses of the genes differentially expressed revealed that the genes altered in response to claudin-7 knockdown were associated with pathways implicated in various molecular and cellular functions such as cell cycle, cellular growth and proliferation, cell death, development, and cell movement. Through functional experiments in vitro, we found that both migration and invasion were altered in cells where CLDN7 had been knocked down or overexpressed. Interestingly, claudin-7 expression was associated with a net increase in invasion, but also with a decrease in migration.Conclusion/SignificanceOur work shows that claudin-7 is significantly upregulated in EOC and that it may be functionally involved in ovarian carcinoma invasion. CLDN7 may therefore represent potential marker for ovarian cancer detection and a target for therapy.
Highlights
Ovarian cancer is the sixth leading cause of cancer deaths in women worldwide [1]
CLDN7 mRNA was found to be highly up-regulated in all four major ovarian cancer subtypes compared with normal ovarian tissues (Figure 1A)
Our data show that CLDN7 is elevated at both mRNA and protein levels in most ovarian cancer tissues and cell lines
Summary
Ovarian cancer is the sixth leading cause of cancer deaths in women worldwide [1]. Ovarian cancer is typically diagnosed as advanced disease when therapeutic options are limited and the prognosis very poor. The past several years have witnessed a number of advances in our understanding of the molecular mechanisms involved in ovarian cancer progression [2],[3], much of the details remain unknown. Among the genes whose expression is frequently altered in ovarian cancer are those encoding the claudin family of tight junction proteins [4]–[7]. Normal TJ function and structure are typically altered and the TJs themselves are frequently disassembled [11],[12]. Recent gene expression profiling studies have reported altered expression of a number of TJ proteins in multiple cancers, including several claudin proteins [4],[6]. Previous studies have shown that claudin-7 is frequently upregulated in epithelial ovarian cancer (EOC) along with claudin-3 and claudin-4. We investigate in detail the expression patterns of claudin-7, as well as its possible functions in EOC
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