Because fibrous remodeling of the subepithelium could limit delivery of nutrients and oxygen to the epithelium, we assessed expression of hypoxia-inducible factor-1alpha (HIF-1alpha) and carbonic anhydrase IX (CA IX) as markers of cellular hypoxia.
Taken together, our results suggest that besides the PI3K pathway, the MAPK cascade is involved in the regulation of CA9 gene expression under both hypoxia and high cell density.
In contrast, coexpression of HIF-1alpha and CAIX in the epithelium in phyllodes tumors points to epithelial hypoxia, most probably caused by relatively distant blood vessels.
Our findings suggest that hypoxia regulates both expression and activity of CA IX in order to enhance the extracellular acidification, which may have important implications for tumor progression.
The SP1/SP3 and hypoxia-response element in the CA9 promoter thus may represent a novel type of enhancer capable of mounting responses to a wider range of hypoxic conditions.