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

Abstract

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.

HE4 – not only an ovarian cancer biomarker – a brief review

“…Another aspect of HE4 in GC concerns sensitivity to radiotherapy. Peng et al (2019) [23] pointed out hypoxia-induced upregulation of HE4 as a reason for resistance to radiotherapy due to the fact that stable knockdown of HE4 sensitized cancer cells and xenograft tumors to radiotherapy. As a conclusion, radiotherapy connected with HE4 knockdown might become a potential therapeutic aim in GC.…”

Gene Expression Profile of Active HE4 Stimulation in Epithelial Ovarian Cancer Cells: Microarray Study and Comprehensive Bioinformatics Analysis

“…Human epididymis protein 4 (HE4) is a member of the WFDC domain family and encoded by the WFDC2 gene, features the characteristic WAP motif consisting of 8 cysteine-formed disul de bonds [1]. It was initially discovered in human distal epididymal epithelial cells by Kirchhoff et al in 1991[2].…”

“…In physiological conditions, HE4 is secreted into the blood to act as a protease inhibitor and is involved in the maturation of sperm cells [2]. Several types of cancers are associated with HE4 overexpression both in serum and tissues, and it is a relatively promising and useful biomarker for the diagnosis of ovarian cancer [3][4][5], primary fallopian tube carcinoma [6], endometrial cancer(combined with CA125) [7], lung cancer [8], breast cancer(combined with miR-127) [9], gastric cancer [1], colorectal cancer [10] and pancreatic adenocarcinomas [11]. In 2008, HE4 was cleared as a serum marker to monitor disease recurrence or progression in patients with epithelial ovarian cancer (EOC) by Food and Drug Administration of USA.…”

Gene expression profiles following active HE4 stimulation in epithelial ovarian cancer cells: microarray study and comprehensive bioinformatics analysis

“…Human epididymis protein 4 (HE4) is a member of the WFDC domain family and is encoded by the WFDC2 gene; it features the characteristic WAP motif consisting of eight disul de bonds formed by cysteines [1]. It was initially discovered in human distal epididymal epithelial cells by Kirchhoff et al in 1991 [2].…”

“…Several types of cancers are associated with HE4 overexpression in both the serum and tissues, and it is a relatively promising and useful biomarker for diagnosing ovarian cancer [3][4][5], primary fallopian tube carcinoma [6], endometrial cancer (combined with CA125) [7], lung cancer [8], breast cancer (combined with miR-127) [9], gastric cancer [1], colorectal cancer [10], and pancreatic adenocarcinomas [11]. In 2008, HE4 was approved for using as a serum marker to monitor disease recurrence or progression in patients with epithelial ovarian cancer (EOC) by the Food and Drug Administration of USA, and has been examined in many studies.…”