2-Methoxyestradiol promotes radiosensitivity of esophageal squamous cell carcinoma by suppressing hypoxia-inducible...

Acquired radioresistance remains the primary obstacle to improving the survival of esophageal cancer (EC). Related hypoxia factors play crucial roles in radioresistance such as hypoxia-inducible factor 1α (HIF-1α), vascular endothelial growth factor (VEGF), and angiogenic factor with G-patch and FHA domains 1 (AGGF1). The aim of this study was to investigate the effect of 2-methoxyestradiol (2ME2) on the radiosensitivity of EC.

The expression of HIF-1α, VEGF, and AGGF1 in 70 EC patients was detected using immunohistochemistry. The relation between the expression levels of the above genes with clinicopathologic characteristics was explored as well. Human ECA-109 cells were subjected to hypoxia and/or radiation in the presence or absence of 2ME2. Subsequently, cell growth, colony formation, and apoptosis were evaluated. Moreover, the mRNA and protein expression levels were determined using quantitative Real Time-Polymerase Chain Reaction (qRT-PCR) and Western blotting, respectively.

HIF-1α, VEGF, and AGGF1 were significantly in EC tissues and were associated with cancer aggressiveness. 2ME2 treatment significantly increased the radiosensitivity of ESCC cells in a dose-dependent manner, which was related to the inhibited expression of HIF-1α. Subsequent immunohistochemical staining results showed that the VEGF expression was positively correlated with the HIF-1α expression in EC.

High levels of HIF-1α, VEGF, and AGGF1 in EC are indicators of poor prognosis in patients treated with radiotherapy, which can offer new ideas and methods for the treatment of ESCC. In addition, 2ME2 inhibits the expression of HIF-1α and confers radiosensitivity in ECA-109 cells. Our findings suggest that 2ME2 has the potential to be applied as an adjuvant treatment with radiotherapy for EC.