Competing endogenous RNA regulatory network of factor inhibiting HIF inhibitor as radioprotector for gastrointestinal toxicity via activating hypoxia-inducible factor-1 pathway

Abstract

Abstract Given the relentlessly renewal ability for intestinal crypt-base stem cells, small intestine in gastrointestinal (GI) tract is more vulnerable to radiation-induced disruption. Through promoting epithelial integrity and reducing intracellular reactive oxygen species (ROS) level, hypoxia-inducible factors (HIFs) have been proved to exhibit radioprotective effect in GI tract. Therefore, enhancing stability or transcriptional activity of HIFs might be a therapeutic strategy for developing radioprotectors. Factor inhibiting HIF (FIH or HIF-1AN) can hamper transcriptional capacity of HIF-1α via interacting with Asn803 in its C-terminal domain. Previously, we discovered promoting HIF-1α transcriptional activity in vitro by a FIH inhibitor-N-oxalyl-D-phenylalanine (NOFD) exert radioprotection on cells. However, the radioprotective effect of FIH inhibitor on GI tract and its competing endogenous RNA (ceRNA) regulatory network from FIH/HIF axis has never been addressed. Here we verified radioprotection of NOFD against GI tract by animal model and performed whole-transcriptome analysis to fully elucidate radioprotective mechanism from FIH/HIF axis against GI syndrome. We identified two novel circRNAs (circRNA_2909, circRNA_0323) and two lncRNAs (NONMMUT140549.1, NONMMUT148249.1) promote expression of HIF1A and NOS2 in HIF-1 pathway by sponging miRNAs especially mmu-miR-92a-1-5p. The de-repression of HIF-1α transcriptional capacity by inhibiting FIH proteomic activity suggests a new therapeutic strategy in alleviating radiation-induced GI syndrome.