Carbonic Anhydrase IX Shedding Through Exosomes in Renal Carcinoma Cells

Abstract

Carbonic anhydrase IX (CA IX) is a transmembrane glycoprotein highly expressed in clear cell carcinoma of the kidney and in a wide variety of other human cancers. Its expression is largely under the control of intratumoral hypoxia and in some subtypes of renal cell carcinoma (RCC), by the presence of a defective version of the von Hippel Lindau (VHL) gene by which the HIF-1α factor is stabilized. Several notable studies have shown that CA IX is involved in the control of acidity intracellularly. Thus, this enzyme could be involved in the regulation of pH within the tumor and may modulate the tumor microenvironment. Recent studies have also shown that this enzyme could be involved in the control of cell adhesion processes between the cancer cells, contributing to their invasive potential. Here, we have analyzed the effect of increasing the level of CA IX expression in the CA IX negative SKRC-17 renal cancer cells. Our results showed that CA IX is recruited to the lipid rafts of these cancer cells. Our results also highly suggest that the lipid raft component gangliosides are shed in the form of exosomes in this model system as a result of forced CA IX expression. The level of ganglioside shedding positively correlated with the increased level of CA IX expression in these cells. Finally, from a glycobiological perspective, our results indicate that elevated levels of CA IX expression contributes to increased ganglioside shedding in the form of exosomes which in turn may contribute to increased invasiveness and immunological escape in this malignancy.