Hypoxia inducible factor-1α/vascular endothelial growth factor signaling activation correlates with response to radiotherapy and its inhibition reduces hypoxia-induced angiogenesis in lung cancer

Abstract

Like other tumors, lung cancer must induce angiogenesis as it grows. Hypoxia-inducible factor 1α (HIF-1α) is the inducible subunit of the HIF-1 transcription factor that regulates genes involved in the response to hypoxia, some of which contributes to angiogenesis. Vascular endothelial growth factor (VEGF) is one of the genes upregulated by HIF-1 and is the primary cytokine in relation to angiogenesis. In this study we tested whether aberrant activation of hypoxia inducible factor-1α/vascular endothelial growth factor (HIF-1α/VEGF) pathway correlates with response to radiotherapy and examined the response of lung cancer cells to hypoxia in vitro. We determined increased expressions of HIF-1α and VEGF-A in 76 cancerous tissues of responders (complete remission and partial remission). HIF-1α and VEGF-A were shown to be upregulated in lung cancer cells in response to hypoxia. The treatment with anti-HIF-1α siRNA prior to hypoxia exposure was shown to decrease HIF-1α and VEGF-A expressions and reduce hypoxia-induced angiogenesis, suggesting that HIF-1α expression resulted in increased VEGF-A expression and activation of HIF-1α/VEGF pathway was responsible for hypoxia-induced angiogenesis. In conclusion, we identified the relationship between HIF-1α/VEGF pathway and response to radiotherapy and its role in angiogenesis in lung cancer in vitro. HIF-1α/VEGF pathway as a target for antiangiogenic treatment strategies for this tumor requires further investigation.

Keywords: angiogenesis; hypoxia; hypoxia-inducible factor 1α/vascular endothelial growth factor (HIF-1α/VEGF) pathway; lung cancer; resistance to radiotherapy.