Osteopontin enhances the expression of HOTAIR in cancer cells via IRF1.

Osteopontin (OPN), a secreted phosphoglycoprotein, plays important roles in tumor growth, invasion, and metastasis for many types of cancers. The long, noncoding RNA HOTAIR has been strongly associated with the invasion and metastasis of cancer cells. In this study, we found that recombinant human OPN could induce HOTAIR expression in a time- and dose-dependent manner, and our data also showed that OPN transcriptionally activated the expression of HOTAIR in cancer cells. Furthermore, through chromatin immunoprecipitation and luciferase activity assays, we found that IRF1 could bind to the HOTAIR promoter region and decrease its transcriptional activity, and cellular overexpression of IRF1 downregulated the level of HOTAIR. The receptor CD44 has also been verified as a regulator of OPN-induced HOTAIR expression. Interestingly, our data demonstrated that OPN could regulate PI3K/AKT and IRF1 expression and signaling, thereby influencing the expression of HOTAIR. In hepatocellular carcinoma samples, levels of HOTAIR correlated with the expression of OPN and IRF1. We therefore conclude that OPN, as an extracellular matrix protein, can stimulate the expression of HOTAIR by attenuating the inhibitory effect of IRF1, and this results in promotion of the invasion and metastasis of cancer cells.