Induction of erythropoietin increases the cell proliferation rate in a hypoxia-inducible factor-1-dependent and -independent manner in renal cell carcinoma cell lines

Erythropoietin (Epo) is a potent inducer of erythro-poiesis that is mainly produced in the kidney. Epo is expressed not only in the normal kidney, but also in renal cell carcinomas (RCCs). The aim of the present study was to gain insights into the roles of Epo and its receptor (EpoR) in RCC cells. The study used two RCC cell lines, Caki-1 and SKRC44, in which Epo and EpoR are known to be highly expressed. The proliferation rate and expression level of hypoxia-inducible factor-1α (HIF-1α) were measured prior to and following Epo treatment and under normoxic and hypoxic conditions. To examine whether HIF-1α or Epo were involved in cellular proliferation during hypoxia, these proteins were knocked down using small interfering RNA (siRNA) in Caki-1 and SKRC44 cells. The results demonstrated that Epo enhanced the proliferation of the Caki-1 and SKRC44 cells. HIF-1α expression was increased upon the induction of hypoxia in the Caki-1 cells, but remained unaffected in the SKRC44 cells. The proliferation rate was increased under hypoxic conditions in the Caki-1 cells, but was decreased in the SKRC44 cells. Under hypoxic conditions, the proliferation of the Caki-1 cells was significantly reduced by the knock-down of HIF-1α or Epo, while the proliferation of the SKRC44 cells was significantly suppressed by the knock-down of Epo, but not HIF-1α. In conclusion, these data suggest that the induction of Epo may accelerate the proliferation of the RCC cell lines in either a HIF-1α-dependent or -independent manner.