Hypoxia-Induced Upregulation of HE4 Is Responsible for Resistance to Radiation Therapy of Gastric Cancer

Upregulation of human epididymis protein 4 (HE4) is often observed in different types of cancers, including gastric cancer (GC), but the association of elevated HE4 level with radiation resistance in GC remains unclear. The expression of HE4 and hypoxia-inducible factor 1α subunit (HIF1α) was assessed in GC patient samples and cell lines. Chromatin immunoprecipitation (ChIP) and luciferase reporter assays were performed to reveal the regulation between HE4 and HIF1α. Stable HE4 knockdown and HIF1α overexpression were introduced into GC cell lines to study the role of HE4 in the resistance of GC to radiation therapy. Colony formation assay and the xenograft mouse model were used to investigate the effects of radiation on GC cells. HE4 and HIF1α were upregulated in both GC patient tissues and GC cells. Hypoxia and HIF1α upregulated HE4 by directly targeting the hypoxia response element in its promoter region. Stable HE4 knockdown significantly sensitized GC cells and xenograft tumors to radiation. HIF1α overexpression markedly elevated the radiation resistance of GC cells, which was almost completely abolished by HE4 knockdown. Hypoxia-induced upregulation of HE4 is responsible for resistance to radiation therapy of GC, suggesting that HE4 knockdown or inhibition, combined with radiation therapy, holds great potential in the clinical treatment of GC.