{"title":"Targeting hypoxia-induced HIF-1α/JMJD3/Notch axis in gastric cancer therapy.","authors":"Xin She, Lijun Geng, Qianwen Zhao, Haonan Guo, Guihong Rong, Yun Luo, Xia Li, Longkuan Xu, Fulin Ran, Shanshan Liu","doi":"10.1007/s10863-025-10057-y","DOIUrl":null,"url":null,"abstract":"<p><p>Hypoxia has been reported to induce high expression of HIF-1α in multiple cancer tissues, and HIF-1α significantly influences cancer progression, including gastric cancer (GC). However, the mechanism of HIF-1α in the GC process is not clearly elucidated. HIF-1α and JMJD3 expressions in GC tissues were first determined by qRT-PCR and western blot. Meanwhile, the prognosis of HIF-1α, and the relationship between HIF-1α and JMJD3 were analyzed through bioinformatics. Then, we silenced HIF-1α, knocked down or overexpressed JMJD3, or treated gamma-secretase inhibitor (DAPT) in GC cells under hypoxic conditions. Cell proliferation, apoptosis, and Notch activation was determined both in vivo and vitro. We initially proved that both HIF-1α and JMJD3 were highly expressed in GC tissues, high expression of HIF-1α was associated with a poor prognosis. Functionally, we observed that HIF-1α knockdown attenuated GC cell proliferation and enhanced apoptosis under hypoxic conditions, while JMJD3 knockdown exerted the opposite effect in hypoxia-induced GC cells. Besides, JMJD3 overexpression promoted proliferation and reduced apoptosis by upregulating Notch in GC cells under hypoxia conditions. Furthermore, HIF-1α knockdown inhibited tumor growth and altered the pathological structure in the tumors of GC model nude mouse. In GC cells, HIF-1α knockdown inhibited cell proliferation and promoted apoptosis by affecting JMJD3/Notch axis. Therefore, we demonstrated that HIF-1α/JMJD3/Notch axis might be a new therapeutic target for GC.</p>","PeriodicalId":15080,"journal":{"name":"Journal of Bioenergetics and Biomembranes","volume":" ","pages":""},"PeriodicalIF":2.9000,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Bioenergetics and Biomembranes","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1007/s10863-025-10057-y","RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"BIOPHYSICS","Score":null,"Total":0}
引用次数: 0
Abstract
Hypoxia has been reported to induce high expression of HIF-1α in multiple cancer tissues, and HIF-1α significantly influences cancer progression, including gastric cancer (GC). However, the mechanism of HIF-1α in the GC process is not clearly elucidated. HIF-1α and JMJD3 expressions in GC tissues were first determined by qRT-PCR and western blot. Meanwhile, the prognosis of HIF-1α, and the relationship between HIF-1α and JMJD3 were analyzed through bioinformatics. Then, we silenced HIF-1α, knocked down or overexpressed JMJD3, or treated gamma-secretase inhibitor (DAPT) in GC cells under hypoxic conditions. Cell proliferation, apoptosis, and Notch activation was determined both in vivo and vitro. We initially proved that both HIF-1α and JMJD3 were highly expressed in GC tissues, high expression of HIF-1α was associated with a poor prognosis. Functionally, we observed that HIF-1α knockdown attenuated GC cell proliferation and enhanced apoptosis under hypoxic conditions, while JMJD3 knockdown exerted the opposite effect in hypoxia-induced GC cells. Besides, JMJD3 overexpression promoted proliferation and reduced apoptosis by upregulating Notch in GC cells under hypoxia conditions. Furthermore, HIF-1α knockdown inhibited tumor growth and altered the pathological structure in the tumors of GC model nude mouse. In GC cells, HIF-1α knockdown inhibited cell proliferation and promoted apoptosis by affecting JMJD3/Notch axis. Therefore, we demonstrated that HIF-1α/JMJD3/Notch axis might be a new therapeutic target for GC.
期刊介绍:
The Journal of Bioenergetics and Biomembranes is an international journal devoted to the publication of original research that contributes to fundamental knowledge in the areas of bioenergetics, biomembranes, and transport, including oxidative phosphorylation, photosynthesis, muscle contraction, as well as cellular and systemic metabolism. The timely research in this international journal benefits biophysicists, membrane biologists, cell biologists, biochemists, molecular biologists, physiologists, endocrinologists, and bio-organic chemists.