CELF2 Is a Tumor Suppressor That Modulates SLC7A11 and Promotes Ferroptosis in Stomach Adenocarcinoma.

IF 5.8 2区医学 Q2 CELL BIOLOGY

Molecular Cancer Research Pub Date : 2026-10-02 DOI:10.1158/1541-7786.MCR-25-1017

Shoucai Zhang, Shichao Liu, Zeyu Zhang, Yingjie Liu, Maopeng Yin, Xueyan Geng, Helgi B Schioth, Yi Zhang

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引用次数: 0

Abstract

Stomach adenocarcinoma is among the most prevalent malignant gastrointestinal tumors worldwide. Ferroptosis, a relatively new form of programmed cell death, has garnered significant attention for its role in cancer molecular mechanisms and therapeutic strategies. Therefore, it is particularly important to explore the mechanism of key molecules in ferroptosis in stomach adenocarcinoma. In our study, CUGBP Elav-like family member 2 (CELF2) was identified as being lowly expressed in stomach adenocarcinoma tumor tissues at both the mRNA and protein levels. Next, CELF2 effectively inhibited the growth and migration of stomach adenocarcinoma cells both in vitro and in vivo. RNA sequencing (RNA-seq) analysis of AGSCELF2 and AGSNC cells showed that the functions of differentially expressed genes were enriched in the glutathione metabolism and ferroptosis pathways. CELF2 increased the levels of key ferroptosis markers, including reactive oxygen species, malondialdehyde, Fe2+, and 4-hydroxynonenal, while reducing glutathione levels. Furthermore, CELF2 enhanced the susceptibility of stomach adenocarcinoma tumor cells to ferroptosis. Interestingly, the expression levels of CELF2 and solute carrier family 7 member 11 (SLC7A11) were negatively correlated in RNA-seq data and The Cancer Genome Atlas database. RNA immunoprecipitation and RNA pull-down assays confirmed the interaction between CELF2 and SLC7A11. Overexpression (OE) of SLC7A11 reversed the effects of CELF2 on stomach adenocarcinoma growth and ferroptosis levels. Moreover, the ferroptosis inhibitor ferrostatin-1 effectively rescued the inhibitory effect of CELF2 OE on the proliferation of tumor cells. CELF2 is a tumor suppressor that promotes the level and susceptibility of ferroptosis in stomach adenocarcinoma cells by targeting SLC7A11.

Implications: This study offers valuable molecular insights for the development of ferroptosis-targeted therapies for stomach adenocarcinoma.

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CELF2是一种肿瘤抑制因子，可调节SLC7A11并促进胃腺癌中的铁下垂。

胃腺癌（STAD）是世界上最常见的恶性胃肠道肿瘤之一。铁下垂是一种相对较新的程序性细胞死亡形式，因其在癌症分子机制和治疗策略中的作用而引起了极大的关注。因此，探讨铁下垂关键分子对STAD的作用机制显得尤为重要。在我们的研究中，发现CUGBP Elav-like family member 1 （CELF2）在STAD肿瘤组织中mRNA和蛋白水平均低表达。其次，CELF2在体外和体内均能有效抑制STAD细胞的生长和迁移。AGSCELF2和AGSNC细胞的RNA-seq分析显示，差异表达基因在谷胱甘肽代谢和铁凋亡途径中功能丰富。CELF2增加了关键铁下垂标志物的水平，包括ROS、MDA、Fe +和4-HNE，同时降低了GSH水平。此外，CELF2增强了STAD肿瘤细胞对铁下垂的易感性。有趣的是，在RNA-seq数据和TCGA数据库中，CELF2和溶质载体家族7成员11 （SLC7A11）的表达水平呈负相关。RIP和RNA pull-down实验证实了CELF2和SLC7A11之间的相互作用。SLC7A11的过表达逆转了CELF2对STAD生长和铁下垂水平的影响。此外，Ferroptosis抑制剂Ferrostatin-1有效地恢复了CELF2过表达对肿瘤细胞增殖的抑制作用。CELF2是一种肿瘤抑制因子，通过靶向SLC7A11提高STAD细胞铁下垂水平和易感性。意义：本研究为开发针对STAD的铁中毒治疗方法提供了有价值的分子见解。

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

Molecular Cancer Research 医学-细胞生物学

CiteScore

9.90

自引率

0.00%

发文量

280

审稿时长

4-8 weeks

期刊介绍： Molecular Cancer Research publishes articles describing novel basic cancer research discoveries of broad interest to the field. Studies must be of demonstrated significance, and the journal prioritizes analyses performed at the molecular and cellular level that reveal novel mechanistic insight into pathways and processes linked to cancer risk, development, and/or progression. Areas of emphasis include all cancer-associated pathways (including cell-cycle regulation; cell death; chromatin regulation; DNA damage and repair; gene and RNA regulation; genomics; oncogenes and tumor suppressors; signal transduction; and tumor microenvironment), in addition to studies describing new molecular mechanisms and interactions that support cancer phenotypes. For full consideration, primary research submissions must provide significant novel insight into existing pathway functions or address new hypotheses associated with cancer-relevant biologic questions.