Cargando…
ceRNA regulatory network of FIH inhibitor as a radioprotector for gastrointestinal toxicity by activating the HIF-1 pathway
Given the relentless renewal ability of intestinal crypt-base stem cells, small intestine in the gastrointestinal (GI) tract is more vulnerable to radiation-induced disruption. Through promoting epithelial integrity and reducing intracellular reactive oxygen species (ROS) levels, hypoxia-inducible f...
Autores principales: | , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society of Gene & Cell Therapy
2021
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8368776/ https://www.ncbi.nlm.nih.gov/pubmed/34458003 http://dx.doi.org/10.1016/j.omtn.2021.05.008 |
_version_ | 1783739185915494400 |
---|---|
author | Yang, Yu-wei Meng, Xin Meng, Yuan-yuan Tang, Hai-kang Cheng, Ming-hui Zhang, Zi-qi Xu, Wen-qing Long, Wei |
author_facet | Yang, Yu-wei Meng, Xin Meng, Yuan-yuan Tang, Hai-kang Cheng, Ming-hui Zhang, Zi-qi Xu, Wen-qing Long, Wei |
author_sort | Yang, Yu-wei |
collection | PubMed |
description | Given the relentless renewal ability of intestinal crypt-base stem cells, small intestine in the gastrointestinal (GI) tract is more vulnerable to radiation-induced disruption. Through promoting epithelial integrity and reducing intracellular reactive oxygen species (ROS) levels, hypoxia-inducible factors (HIFs) have been proved to exhibit radioprotective effects in the 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 FIH inhibitor-N-oxalyl-D-phenylalanine (NOFD) exerts radioprotection on cells. However, the radioprotective effect of FIH inhibitor on the GI tract and its competing endogenous RNA (ceRNA) regulatory network from the FIH/HIF axis has never been addressed. Here we verified radioprotection of NOFD for the GI tract by an animal model and performed whole-transcriptome analysis to fully elucidate the radioprotective mechanism from the FIH/HIF axis against GI syndrome. We identified two novel circular RNAs (circRNAs) (circRNA_2909 and circRNA_0323) and two long non-coding RNAs (lncRNAs) (NONMMUT140549.1 and NONMMUT148249.1) that promote expression of HIF1A and NOS2 in the HIF-1 pathway by sponging microRNAs (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. |
format | Online Article Text |
id | pubmed-8368776 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | American Society of Gene & Cell Therapy |
record_format | MEDLINE/PubMed |
spelling | pubmed-83687762021-08-27 ceRNA regulatory network of FIH inhibitor as a radioprotector for gastrointestinal toxicity by activating the HIF-1 pathway Yang, Yu-wei Meng, Xin Meng, Yuan-yuan Tang, Hai-kang Cheng, Ming-hui Zhang, Zi-qi Xu, Wen-qing Long, Wei Mol Ther Nucleic Acids Original Article Given the relentless renewal ability of intestinal crypt-base stem cells, small intestine in the gastrointestinal (GI) tract is more vulnerable to radiation-induced disruption. Through promoting epithelial integrity and reducing intracellular reactive oxygen species (ROS) levels, hypoxia-inducible factors (HIFs) have been proved to exhibit radioprotective effects in the 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 FIH inhibitor-N-oxalyl-D-phenylalanine (NOFD) exerts radioprotection on cells. However, the radioprotective effect of FIH inhibitor on the GI tract and its competing endogenous RNA (ceRNA) regulatory network from the FIH/HIF axis has never been addressed. Here we verified radioprotection of NOFD for the GI tract by an animal model and performed whole-transcriptome analysis to fully elucidate the radioprotective mechanism from the FIH/HIF axis against GI syndrome. We identified two novel circular RNAs (circRNAs) (circRNA_2909 and circRNA_0323) and two long non-coding RNAs (lncRNAs) (NONMMUT140549.1 and NONMMUT148249.1) that promote expression of HIF1A and NOS2 in the HIF-1 pathway by sponging microRNAs (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. American Society of Gene & Cell Therapy 2021-05-19 /pmc/articles/PMC8368776/ /pubmed/34458003 http://dx.doi.org/10.1016/j.omtn.2021.05.008 Text en © 2021 The Author(s) https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Original Article Yang, Yu-wei Meng, Xin Meng, Yuan-yuan Tang, Hai-kang Cheng, Ming-hui Zhang, Zi-qi Xu, Wen-qing Long, Wei ceRNA regulatory network of FIH inhibitor as a radioprotector for gastrointestinal toxicity by activating the HIF-1 pathway |
title | ceRNA regulatory network of FIH inhibitor as a radioprotector for gastrointestinal toxicity by activating the HIF-1 pathway |
title_full | ceRNA regulatory network of FIH inhibitor as a radioprotector for gastrointestinal toxicity by activating the HIF-1 pathway |
title_fullStr | ceRNA regulatory network of FIH inhibitor as a radioprotector for gastrointestinal toxicity by activating the HIF-1 pathway |
title_full_unstemmed | ceRNA regulatory network of FIH inhibitor as a radioprotector for gastrointestinal toxicity by activating the HIF-1 pathway |
title_short | ceRNA regulatory network of FIH inhibitor as a radioprotector for gastrointestinal toxicity by activating the HIF-1 pathway |
title_sort | cerna regulatory network of fih inhibitor as a radioprotector for gastrointestinal toxicity by activating the hif-1 pathway |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8368776/ https://www.ncbi.nlm.nih.gov/pubmed/34458003 http://dx.doi.org/10.1016/j.omtn.2021.05.008 |
work_keys_str_mv | AT yangyuwei cernaregulatorynetworkoffihinhibitorasaradioprotectorforgastrointestinaltoxicitybyactivatingthehif1pathway AT mengxin cernaregulatorynetworkoffihinhibitorasaradioprotectorforgastrointestinaltoxicitybyactivatingthehif1pathway AT mengyuanyuan cernaregulatorynetworkoffihinhibitorasaradioprotectorforgastrointestinaltoxicitybyactivatingthehif1pathway AT tanghaikang cernaregulatorynetworkoffihinhibitorasaradioprotectorforgastrointestinaltoxicitybyactivatingthehif1pathway AT chengminghui cernaregulatorynetworkoffihinhibitorasaradioprotectorforgastrointestinaltoxicitybyactivatingthehif1pathway AT zhangziqi cernaregulatorynetworkoffihinhibitorasaradioprotectorforgastrointestinaltoxicitybyactivatingthehif1pathway AT xuwenqing cernaregulatorynetworkoffihinhibitorasaradioprotectorforgastrointestinaltoxicitybyactivatingthehif1pathway AT longwei cernaregulatorynetworkoffihinhibitorasaradioprotectorforgastrointestinaltoxicitybyactivatingthehif1pathway |