Hypoxia-inducible factor-1alpha mediates oral squamous cell carcinoma invasion via upregulation of alpha5 integrin and fibronectin.

ABSTRACT

With progressive and rapid growth of malignant tumors, cancer cells in an ischemic condition are expected to develop an increased potential for local invasive growth. To address this hypothesis, we first examined the effect of hypoxia on the invasiveness of oral squamous cell carcinoma (OSCC) cells using the Matrigel invasion assay. We then investigated the effect of hypoxia on the protein and mRNA expression of alpha5 integrin and fibronectin, which are major factors involved in tumor cell invasion. We showed that (i) hypoxia increased the invasiveness of OSCC cells, (ii) alpha5 integrin and fibronectin protein and mRNA expression levels were increased in OSCC cells under hypoxic conditions, (iii) hypoxia stimulated autocrine secretion of fibronectin in OSCC cells, (iv) administration of siRNA(HIF-1alpha) caused a significant decrease in alpha5 integrin and fibronectin protein, confirming that HIF-1alpha plays a role in their induction, and (v) siRNA(HIF-1alpha) abrogated hypoxia-induced cell invasion. Collectively, these data suggest that hypoxia promotes OSCC cell invasion that is elicited by HIF-1alpha-dependent alpha5 integrin and fibronectin induction.