EIF2S2 transcriptionally upregulates HIF1α to promote gastric cancer progression via activating PI3K/AKT/mTOR pathway.

IF 3.3 3区医学 Q2 ONCOLOGY Carcinogenesis Pub Date : 2024-07-24 DOI:10.1093/carcin/bgae043

Zhiyong Wang, Yingyi Zhang, Yingwei Xue, Wei Huang, Hongfeng Zhang

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引用次数: 0

Abstract

Eukaryotic translation initiation factor 2 subunit beta (EIF2S2) is a protein that controls protein synthesis under various stress conditions and is abnormally expressed in several cancers. However, there is limited insight regarding the expression and molecular role of EIF2S2 in gastric cancer. In this study, we identified the overexpression of EIF2S2 in gastric cancer by immunohistochemical (IHC) staining and found a positive correlation between EIF2S2 expression and shorter overall survival and disease-free survival. Functionally, we revealed that EIF2S2 knockdown suppressed gastric cancer cell proliferation and migration, induced cell apoptosis, and caused G2 phase cell arrest. Additionally, EIF2S2 is essential for in vivo tumor formation. Mechanistically, we demonstrated that EIF2S2 transcriptionally regulated hypoxia induicible factor-1 alpha (HIF1α) expression by NRF1. The promoting role of EIF2S2 in malignant behaviors of gastric cancer cells depended on HIF1α expression. Furthermore, the PI3K/AKT/mTOR signaling was activated upon EIF2S2 overexpression in gastric cancer. Collectively, EIF2S2 exacerbates gastric cancer progression via targeting HIF1α, providing a fundamental basis for considering EIF2S2 as a potential therapeutic target for gastric cancer patients.

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EIF2S2 通过激活 PI3K/AKT/mTOR 通路，转录上调 HIF1α 以促进胃癌进展。

真核翻译起始因子 2 亚基 beta（EIF2S2）是一种在各种应激条件下控制蛋白质合成的蛋白质，在多种癌症中表达异常。然而，人们对 EIF2S2 在胃癌中的表达和分子作用了解有限。在这项研究中，我们通过免疫组化（IHC）染色确定了 EIF2S2 在胃癌中的过表达，并发现 EIF2S2 的表达与较短的总生存期和无病生存期呈正相关。在功能上，我们发现敲除 EIF2S2 可抑制胃癌细胞的增殖和迁移，诱导细胞凋亡，并导致 G2 期细胞停滞。此外，EIF2S2 对体内肿瘤的形成至关重要。从机理上讲，我们证实 EIF2S2 通过 NRF1 转录调控缺氧诱导因子-1 α（HIF1α）的表达。EIF2S2 对胃癌细胞恶性行为的促进作用取决于 HIF1α 的表达。此外，EIF2S2在胃癌中的过表达激活了PI3K/AKT/mTOR信号转导。总之，EIF2S2 通过靶向 HIF1α 使胃癌恶化，这为将 EIF2S2 作为胃癌患者的潜在治疗靶点提供了基本依据。

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

Carcinogenesis 医学-肿瘤学

CiteScore

9.20

自引率

2.10%

发文量

审稿时长

1 months

期刊介绍： Carcinogenesis: Integrative Cancer Research is a multi-disciplinary journal that brings together all the varied aspects of research that will ultimately lead to the prevention of cancer in man. The journal publishes papers that warrant prompt publication in the areas of Biology, Genetics and Epigenetics (including the processes of promotion, progression, signal transduction, apoptosis, genomic instability, growth factors, cell and molecular biology, mutation, DNA repair, genetics, etc.), Cancer Biomarkers and Molecular Epidemiology (including genetic predisposition to cancer, and epidemiology), Inflammation, Microenvironment and Prevention (including molecular dosimetry, chemoprevention, nutrition and cancer, etc.), and Carcinogenesis (including oncogenes and tumor suppressor genes in carcinogenesis, therapy resistance of solid tumors, cancer mouse models, apoptosis and senescence, novel therapeutic targets and cancer drugs).