Targeting hypoxia-induced HIF-1α/JMJD3/Notch axis in gastric cancer therapy.

IF 2.9 4区 生物学 Q2 BIOPHYSICS
Xin She, Lijun Geng, Qianwen Zhao, Haonan Guo, Guihong Rong, Yun Luo, Xia Li, Longkuan Xu, Fulin Ran, Shanshan Liu
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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.

靶向缺氧诱导的HIF-1α/JMJD3/Notch轴治疗胃癌。
据报道,缺氧可诱导多种癌症组织中HIF-1α的高表达,HIF-1α显著影响包括胃癌(GC)在内的癌症进展。然而,HIF-1α在GC过程中的作用机制尚不清楚。首先采用qRT-PCR和western blot检测GC组织中HIF-1α和JMJD3的表达。同时通过生物信息学分析HIF-1α的预后,以及HIF-1α与JMJD3的关系。然后,我们在缺氧条件下沉默GC细胞中的HIF-1α,敲低或过表达JMJD3,或处理γ -分泌酶抑制剂(DAPT)。在体内和体外均检测细胞增殖、凋亡和Notch激活。我们初步证实HIF-1α和JMJD3在胃癌组织中均高表达,HIF-1α高表达与预后不良相关。在功能上,我们观察到HIF-1α敲低可减弱缺氧条件下GC细胞的增殖并增强凋亡,而JMJD3敲低则在缺氧诱导的GC细胞中发挥相反的作用。此外,在缺氧条件下,JMJD3过表达通过上调Notch来促进GC细胞的增殖和减少凋亡。HIF-1α敲低抑制GC模型裸鼠肿瘤生长,改变肿瘤病理结构。在GC细胞中,HIF-1α下调通过影响JMJD3/Notch轴抑制细胞增殖,促进细胞凋亡。因此,我们证明HIF-1α/JMJD3/Notch轴可能是GC的一个新的治疗靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
6.00
自引率
0.00%
发文量
22
审稿时长
6-12 weeks
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.
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