SOX17-mediated MALAT1-miR-199a-HIF1α axis confers sensitivity in esophageal squamous cell carcinoma cells to radiotherapy.

ABSTRACT

Radiotherapy is a main modality of esophageal squamous cell carcinoma (ESCC) treatment, while radioresistance largely limits the effect of this therapy. Evidence exists reporting that SOX17 may sensitize ESCC cells to irradiation, but the downstream mechanism remains poorly understood. Therefore, we attempt to explore the molecular basis of SOX17 effect on radioresistance in ESCC. The SOX17 expression was measured in ESCC tissues and cells, followed by evaluation of its relationship with patient survival. The fractionated irradiation-induced irradiation-resistant cell line KYSE150R was subjected to gain- and loss-of function studies to explore the effect of SOX17 and downstream effectors MALAT1, miR-199a, and HIF1α on the malignant phenotypes of ESCC. The interaction among these factors was explained using ChIP, dual luciferase reporter, RNA pull-down and RIP assays. Further, the in vivo effect of SOX17 on ESCC irradiation tolerance was assessed in nude mice. SOX17 was underexpressed in ESCC tissues and cells, which was negatively correlated with the prognosis of patients with ESCC. Besides, SOX17 inhibited irradiation tolerance of ESCC cells by suppressing MALAT1 transcription. Notably, MALAT1 acted as miR-199a sponge and thereby enhanced HIF1α expression. Moreover, SOX17 reduced the irradiation tolerance of ESCC cells by reducing HIF1α expression via the MALAT1-miR-199a axis, and attenuated tumor formation in nude mice. Our results indicate that SOX17 can impede the radioresistance of ESCC cells through the MALAT1-miR-199a-HIF1α axis, in support of further research for ESCC radiotherapy.