Abstract
Ether à go-go 1 (Eag1) channel is overexpressed in a variety of cancers but the therapeutic potential of Eag1 in osteosarcoma remains elusive. In this study, we constructed an Ad5-Eag1-shRNA vector and evaluated its efficiency for Eag1 knockdown and its effects on osteosarcoma. Our results showed that Ad5-Eag1-shRNA had high interference efficiency of Eag1 expression and suppressed osteosarcoma growth both in vitro and in vivo. To explore the molecular mechanism underlying tumor growth inhibition induced by Eag1 silencing, the intratumoral microvessel density (MVD) was assessed by CD31 staining and the expression of vascular endothelial growth factor (VEGF) was detected by Western blot analysis. We found that Eag1 silencing led to decreased angiogenesis and VEGF expression in the xenograft model of osteosarcoma. Finally, we detected a time-dependent decrease in VEGF expression and considerably reduced phosphoinositide 3-kinase (PI3K) and protein kinase B (AKT) activation in osteosarcoma cells treated by Eag1 shRNA. Taken together, our results suggest that Eag1 silencing inhibits tumor growth and angiogenesis in osteosarcoma via the down regulation of VEGF/PI3K/AKT signaling.
Highlights
Voltage-gated potassium channels (Kv) perform many vital functions in both electrically excitable and nonexcitable cells
The Ether à go-go 1 (Eag1 (Kv10.1, KCNH1)) channel is a member of Kv channels that has been implicated in tumor growth, progression and metastasis [2,3]
We demonstrated that Eag1 short hairpin RNA (shRNA) inhibited osteosarcoma angiogenesis and this is associated with the downregulation of the vascular endothelial growth factor (VEGF)/PI3K/AKT signaling
Summary
Voltage-gated potassium channels (Kv) perform many vital functions in both electrically excitable and nonexcitable cells. The importance of Kv channels in tumor biology has been an area of intense investigation [1]. The molecular mechanisms responsible for the oncogenic potential of Eag remain elusive [4,5]. Eag appears to induce tumor angiogenesis by the release of hypoxia inducible factor-1 (HIF-1) and vascular endothelial growth factor (VEGF) upon hypoxia [8]. Eag is overexpressed in a variety of cancers, the therapeutic potential of Eag in osteosarcoma remains elusive. We designed a short hairpin RNA (shRNA) targeting Eag and evaluated its effects on osteosarcoma growth and angiogenesis. We demonstrated that Eag shRNA inhibited osteosarcoma angiogenesis and this is associated with the downregulation of the VEGF/PI3K/AKT signaling
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