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Downregulation of miR-221–3p promotes the ferroptosis in gastric cancer cells via upregulation of ATF3 to mediate the transcription inhibition of GPX4 and HRD1
BACKGROUND: Gastric cancer (GC) is an aggressive gastrointestinal tumor. MiRNAs participate in the tumorigenesis of GC. Nevertheless, the function of miR-221–3p in GC remains largely unknown. METHODS: RNA levels were assessed by RT-qPCR. Western blot was performed to test the protein levels. The rel...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Neoplasia Press
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10040875/ https://www.ncbi.nlm.nih.gov/pubmed/36947996 http://dx.doi.org/10.1016/j.tranon.2023.101649 |
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author | Shao, Chang-Jiang Zhou, Hai-Lang Gao, Xu-Zhu Xu, Chun-Fang |
author_facet | Shao, Chang-Jiang Zhou, Hai-Lang Gao, Xu-Zhu Xu, Chun-Fang |
author_sort | Shao, Chang-Jiang |
collection | PubMed |
description | BACKGROUND: Gastric cancer (GC) is an aggressive gastrointestinal tumor. MiRNAs participate in the tumorigenesis of GC. Nevertheless, the function of miR-221–3p in GC remains largely unknown. METHODS: RNA levels were assessed by RT-qPCR. Western blot was performed to test the protein levels. The relation between miR-221–3p and ATF3 was investigated by dual-luciferase reporter assay. ChIP and dual-luciferase reporter assay were applied to assess the interaction between ATF3 and HRD1 or GPX4. Meanwhile, cell proliferation was investigated by CCK8 and colony formation assay. The content of erastin-induced Fe(2+) was investigated by iron assay kit. Erastin-induced lipid ROS level was assessed by C11-BODIPY 581/591. Co-immunoprecipitation was used to detect the interaction between HRD1 and ACSL4. In addition, xenograft mice model was established to detect the effect of miR-221–3p in GC. RESULTS: Depletion of miR-221–3p greatly attenuated GC cell proliferation through promoting ferroptosis. Meanwhile, ATF3 was downregulated in GC, and it was identified to be the downstream mRNA of miR-221–3p. MiR-221–3p downregulation could promoted the ferroptosis in GC cells through upregulation of ATF3. HRD1 mediates ubiquitination and degradation of ACSL4 to inhibit ferroptosis. ATF3 upregulation could reduce GC cell proliferation via downregulating the transcription of GPX4 and HRD1. Furthermore, downregulation of miR-221–3p markedly attenuated the growth of GC in mice. CONCLUSION: HRD1 mediates ubiquitination and degradation of ACSL4 to inhibit ferroptosis. MiR-221–3p depletion upregulates the ferroptosis in GC cells via upregulation of ATF3 to mediate the transcription inhibition of GPX4 and HRD1. Our study might provide a novel target for GC treatment. |
format | Online Article Text |
id | pubmed-10040875 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Neoplasia Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-100408752023-03-28 Downregulation of miR-221–3p promotes the ferroptosis in gastric cancer cells via upregulation of ATF3 to mediate the transcription inhibition of GPX4 and HRD1 Shao, Chang-Jiang Zhou, Hai-Lang Gao, Xu-Zhu Xu, Chun-Fang Transl Oncol Original Research BACKGROUND: Gastric cancer (GC) is an aggressive gastrointestinal tumor. MiRNAs participate in the tumorigenesis of GC. Nevertheless, the function of miR-221–3p in GC remains largely unknown. METHODS: RNA levels were assessed by RT-qPCR. Western blot was performed to test the protein levels. The relation between miR-221–3p and ATF3 was investigated by dual-luciferase reporter assay. ChIP and dual-luciferase reporter assay were applied to assess the interaction between ATF3 and HRD1 or GPX4. Meanwhile, cell proliferation was investigated by CCK8 and colony formation assay. The content of erastin-induced Fe(2+) was investigated by iron assay kit. Erastin-induced lipid ROS level was assessed by C11-BODIPY 581/591. Co-immunoprecipitation was used to detect the interaction between HRD1 and ACSL4. In addition, xenograft mice model was established to detect the effect of miR-221–3p in GC. RESULTS: Depletion of miR-221–3p greatly attenuated GC cell proliferation through promoting ferroptosis. Meanwhile, ATF3 was downregulated in GC, and it was identified to be the downstream mRNA of miR-221–3p. MiR-221–3p downregulation could promoted the ferroptosis in GC cells through upregulation of ATF3. HRD1 mediates ubiquitination and degradation of ACSL4 to inhibit ferroptosis. ATF3 upregulation could reduce GC cell proliferation via downregulating the transcription of GPX4 and HRD1. Furthermore, downregulation of miR-221–3p markedly attenuated the growth of GC in mice. CONCLUSION: HRD1 mediates ubiquitination and degradation of ACSL4 to inhibit ferroptosis. MiR-221–3p depletion upregulates the ferroptosis in GC cells via upregulation of ATF3 to mediate the transcription inhibition of GPX4 and HRD1. Our study might provide a novel target for GC treatment. Neoplasia Press 2023-03-21 /pmc/articles/PMC10040875/ /pubmed/36947996 http://dx.doi.org/10.1016/j.tranon.2023.101649 Text en © 2023 The Authors. Published by Elsevier Inc. 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 Research Shao, Chang-Jiang Zhou, Hai-Lang Gao, Xu-Zhu Xu, Chun-Fang Downregulation of miR-221–3p promotes the ferroptosis in gastric cancer cells via upregulation of ATF3 to mediate the transcription inhibition of GPX4 and HRD1 |
title | Downregulation of miR-221–3p promotes the ferroptosis in gastric cancer cells via upregulation of ATF3 to mediate the transcription inhibition of GPX4 and HRD1 |
title_full | Downregulation of miR-221–3p promotes the ferroptosis in gastric cancer cells via upregulation of ATF3 to mediate the transcription inhibition of GPX4 and HRD1 |
title_fullStr | Downregulation of miR-221–3p promotes the ferroptosis in gastric cancer cells via upregulation of ATF3 to mediate the transcription inhibition of GPX4 and HRD1 |
title_full_unstemmed | Downregulation of miR-221–3p promotes the ferroptosis in gastric cancer cells via upregulation of ATF3 to mediate the transcription inhibition of GPX4 and HRD1 |
title_short | Downregulation of miR-221–3p promotes the ferroptosis in gastric cancer cells via upregulation of ATF3 to mediate the transcription inhibition of GPX4 and HRD1 |
title_sort | downregulation of mir-221–3p promotes the ferroptosis in gastric cancer cells via upregulation of atf3 to mediate the transcription inhibition of gpx4 and hrd1 |
topic | Original Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10040875/ https://www.ncbi.nlm.nih.gov/pubmed/36947996 http://dx.doi.org/10.1016/j.tranon.2023.101649 |
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