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Abstract
Ovarian cancers often highly express inflammatory cytokines and form implants throughout
the peritoneal cavity. However, the mechanisms that drive inflammatory signaling and
peritoneal metastasis of ovarian cancer are poorly understood. We previously identified
that high expression of DLX4, a transcription factor encoded by a homeobox gene, is
associated with reduced survival of ovarian cancer patients. In this study, we identified
that DLX4 stimulates attachment of ovarian tumor cells to peritoneal mesothelial cells
in vitro and increases the numbers of peritoneal implants in xenograft models. DLX4
induced expression of the cell surface molecule CD44 in ovarian tumor cells, and inhibition
of CD44 abrogated the ability of DLX4 to stimulate tumor-mesothelial cell interactions.
The induction of CD44 by DLX4 was attributed to increased activity of NF-κB that was
stimulated by the inflammatory cytokine IL-1β, a transcriptional target of DLX4. The
stimulatory effects of DLX4 on CD44 levels and tumor-mesothelial cell interactions
were abrogated when IL-1β or NF-κB was inhibited in tumor cells. Furthermore, DLX4
expression levels strongly correlated with NF-κB activation and disease stage in clinical
specimens of ovarian cancer. Collectively, these findings indicate that DLX4 induces
CD44 by stimulating IL-1β-mediated NF-κB activity, thereby promoting peritoneal metastasis
of ovarian cancer.