Sex-biased differences in the correlation between epithelial-to-mesenchymal transition-associated genes in cancer cell lines.

Abstract

There is a wide disparity in the incidence, malignancy and mortality of different types of cancer between each sex. The sex-specificity of cancer seems to be dependent on the type of cancer. Cancer incidence and mortality have been demonstrated as sex-specific in a number of different types of cancer, such as liver cancer, whereas sex-specificity is not noticeable in certain other types of cancer, including colon and lung cancer. The present study aimed to elucidate the molecular basis for sex-biased gene expression in cancer. The mRNA expression of the epithelial-to-mesenchymal transition-associated genes was investigated, including E-cadherin (also termed CDH1), vimentin (VIM), discoidin domain receptor 1 (DDR1) and zinc finger E-box binding homeobox 1 (ZEB1) in female- and male-derived cancer cell lines by reverse transcription (RT)-PCR and the Broad-Novartis Cancer Cell Line Encyclopedia (CCLE) database analysis. A negative correlation was observed between DDR1 and ZEB1 only in the female-derived cancer cell lines via RT-PCR analysis. A negative correlation between DDR1 index (defined by the logarithmic value of DDR1 divided by ZEB1, based on the mRNA data from the RT-PCR analysis) and an invasive phenotype was observed in cancer cell lines in a sex-specific manner. Analysis of the CCLE database demonstrated that DDR1 and ZEB1, which are already known to be sex-biased, were negatively correlated in female-derived liver cancer cell lines, but not in male-derived liver cancer cell lines. In contrast, cell lines of colon and lung cancer did not reveal any sex-dependent difference in the correlation between DDR1 and ZEB1. Kaplan-Meier survival curves using the transcriptomic datasets such as Gene Expression Omnibus, European Genome-phenome Archiva and The Cancer Genome Atlas databases suggested a sex-biased difference in the correlation between DDR1 expression pattern and overall survival in patients with liver cancer. The results of the present study indicate that sex factors may affect the regulation of gene expression, contributing to the sex-biased progression of the different types of cancer, particularly liver cancer. Overall, these findings suggest that analyses of the correlation between DDR1 and ZEB1 may prove useful when investigating sex-biased cancers.