高分好文解读｜MEN1 调控 CD44 可变剪接，解锁肺癌铁死亡新机制

研究团队：贵州医科大学金帮明团队

核心亮点：首次揭示MEN1 通过调控 CD44 可变剪接促进铁死亡、抑制肺癌进展的全新机制，为 MEN1 缺陷型肺癌提供精准干预新靶点！

文献标题：MEN1 Promotes Ferroptosis by Disrupting CD44 Alternative Splicing to Suppress Lung Cancer

发表期刊：Cancer Res (IF=16.6)

DOI：https://doi.org/10.1158/0008-5472.can-25-0021

使用 Absin 产品：Mouse anti-Flag Tag Monoclonal Antibody（货号：abs137958）

一、研究背景：铁死亡与肺癌的 “生死博弈”

铁死亡（Ferroptosis）是铁依赖的脂质 ROS 过量累积引发的程序性细胞死亡，在肿瘤抑制中扮演关键角色。MEN1 作为经典抑癌基因，已知可调控细胞周期、凋亡等通路，但其在铁死亡中的作用尚未明确。

同时，CD44 基因可变剪接产生的 CD44 变异体（如 CD44v6）在肺癌中高表达，且与不良预后密切相关。但MEN1、CD44 剪接与铁死亡三者的调控轴，此前从未被破解！

二、研究思路：从 “表型” 到 “机制” 的层层深挖

团队采用 “临床样本→细胞实验→动物模型→机制验证” 的完整研究逻辑，环环相扣锁定核心通路：

1. 表型初探：对比 MEN1 野生型与缺失型肺癌细胞，检测铁死亡相关指标（脂质 ROS、GPX4），明确 MEN 与铁死亡的关联；

2. 靶点筛选：通过多组学分析，锁定 CD44 可变剪接为 MEN1 的关键下游靶点；

3. 机制拆解：探究 MEN1 如何调控 CD44 前体 mRNA 剪接，明确 RNA 聚合酶 II（Pol II）、PAF1 复合体的核心作用；

4. 功能验证：敲除 / 过表达 MEN1、干预 CD44v6，验证对铁死亡、肿瘤生长的影响；

5. 转化延伸：开发 CD44v6 干扰肽，在动物模型中验证抑癌效果。

三、重磅研究成果：解锁 MEN1 抑癌新机制

1. MEN1 是肺癌铁死亡的 “关键驱动因子”

? MEN1 缺失显著上调 GPX4（铁死亡抑制蛋白）表达，抑制脂质 ROS 生成，削弱肺癌细胞对 Erastin/RSL3 诱导铁死亡的敏感性；

? 反之，MEN1 过表达可促进脂质 ROS 累积，增强铁死亡，有效抑制肺癌细胞增殖（对应原文图 1）。

Figure 1.
MEN1 regulates lipid peroxidation and ferroptosis in lung cancer cells. A and B, ROS levels in shNC and shMEN1 A549 cells treated with erastin or RSL3 (24 hours) or RosUP (0.5 hours). C and D, Lipid peroxidation levels in shNC and shMEN1 A549 cells treated with erastin (C) or RSL3 (24 hours; D). E and F, Lipid peroxidation levels in WT, KO, and rMEN1 NCI-H460 cells treated with erastin (E) or RSL3 (24 hours; F). G, Cell viability of WT, KO, and rMEN1 NCI-H460 cells under different concentrations of erastin treatment for 48 hours. H, Relative viability of rMEN1 NCI-H460 cells treated with erastin or RSL3 (24 hours) with DMSO, deferoxamine (DFO), ferrostatin-1 (Fer-1), Z-VAD-FMK (Z-VAD), or necrostatin-1 (Nec-1). I, Transmission electron microscopy images of WT and KO NCI-H460 cells (±erastin, 24 hours). Scale bars, 5 μm or 500 nm. Green arrows, swelling mitochondria; yellow arrows, enlarged mitochondria; and purple arrows, mitochondria with disrupted cristae. J, Mitochondrial numbers and areas in WT and KO NCI-H460 cells (±erastin, 24 hours). K, Hierarchical clustering of significantly changed metabolites from WT and KO NCI-H460 cells. L, Altered metabolic pathways in KO cells compared with WT NCI-H460 cells summarized from metabolic pathway enrichment analysis (MPWEA). *, P < 0.05; **, P < 0.01; ***, P < 0.001; ns, not significant. Ctrl, control.

2. MEN1 通过抑制 CD44 可变剪接发挥抑癌作用

? MEN1 缺失会加速 RNA 聚合酶 II（Pol II）延伸速率，促进 CD44 前体 mRNA 可变剪接，导致 CD44 变异体（v3-v10）大量累积；

? 临床样本验证：肺癌组织中CD44v6 高表达与 MEN1 低表达、不良预后显著相关（对应原文图 2、图 3）。

Figure 2.
MEN1-modulated ferroptosis is required for suppressing lung tumor growth and metastasis. A–D, Cell viability and representative invasion and migration images of WT and KO NCI-H460 cells; invaded cells and migration rate were quantified at the indicated time points. E, Schematic of experimental lung metastasis model in M-NSG mice. F, Representative IHC (Ki67 and HMGB1) and H&E staining images of lung tissue sections from M-NSG mice xenografted with WT/KO NCI-H460 cells. Scale bars, 1 mm or 50 μm. G and H, Tumor burden (G) and quantification of Ki67/HMGB1 IHC staining in lung tissues (H) from xenografted M-NSG mice. I, Schematic of the primary mouse lung cancer study (n = 7, 9, and 8 for WT, KS, and KMS cohorts). J–M, Representative lung pictures (J), H&E staining and Ki67/HMGB1 IHC images of lung tissues (K), tumor burden and tumor number (L), and quantification of Ki67/HMGB1 IHC staining (M). Scale bars, 1 mm or 50 μm. Black arrows, tumor nodules. N, Kaplan–Meier survival analysis of WT, KS, and KMS mice. O, Lipid peroxidation (LPO) levels in lungs from WT, KS, and KMS mice. a.u, arbitrary unit. P and Q, Representative RNA FISH images (P) and quantification of GPX4 probe numbers in WT lung tissues and KS/KMS lung tumor tissues (Q). Scale bars, 20 or 50 μm. *, P < 0.05; **, P < 0.01; ***, P < 0.001; ns, not significant.

Figure 3.
MEN1 regulation of ferroptosis in lung cancer cells depends on CD44 variant isoforms. A, Heatmap of the hyperactivated genes in KMS mice vs. KS mice. B, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of hyperactivated genes in KMS vs. KS mice. C, Gene set enrichment analysis of gene ontology terms comparing KS and KMS mice. ES, enrichment score; NES, normalized enrichment score. D, Kaplan–Meier survival curves of patients with LUAD (The Cancer Genome Atlas) with high/low CD44 PSI or mRNA expression. E and F, H&E staining and fluorescence images (E), and quantification (F) of CD44v3/CD44v6 in lung cancer tissues (metastatic, n = 41; nonmetastatic, n = 74). Scale bar, 50 μm. G and H, Representative fluorescence images (G) and quantification (H) for CD44v3/CD44v6 in M-NSG mice xenografted with WT/KO NCI-H460 cells. Scale bar, 50 μm. I, Flow cytometry analysis of CD44v6 expression in WT/KO NCI-H460 cells (40 ng/mL PMA, 12 hours). J, Representative transwell images and quantification of invaded cells in WT/KO NCI-H460 cells treated with anti-CD44v6 or control IgG antibody. K, Immunoblotting analysis of indicated proteins in WT/KO NCI-H460 cells transfected with siV6#1/#2 or siNC for 48 hours. L, Cell viability of WT/KO NCI-H460 cells transfected with siV6 or siNC, followed by 48-hour treatment with erastin. OD, optical density. M and N, Lipid peroxidation and ROS levels in WT/KO NCI-H460 cells transfected with siV6 or siNC, followed by 24-hour treatment with erastin. *, P < 0.05; **, P < 0.01; ***, P < 0.001. a.u, arbitrary unit.

3. 核心调控轴：MEN1-PAF1-CD44v6-GPX4

? 机制核心：MEN1 通过控制 PAF1 复合体从 CD44 前体 mRNA 上释放，维持 Pol II 慢速延伸，抑制 CD44 可变外显子（如 v6）的纳入；

? 下游效应：MEN1 缺失→CD44v6 上调→GPX4 激活→铁死亡抑制→肺癌进展（对应原文图 4、图 5）。

4. 靶向 CD44v6：MEN1 缺陷型肺癌的精准治疗新策略

? CD44v6 干扰肽可特异性阻断 CD44v6 功能，显著激活铁死亡，抑制 MEN1 缺陷型肿瘤生长与转移；

? 动物实验：CD44v6 干扰肽抑癌效果优于传统铁死亡诱导剂 Erastin，为临床转化提供新方向（对应原文图 6、图 7）。

四、Absin 产品硬核助力，护航关键实验！

本研究中，Absin 货号 abs137958（CD44 抗体） 作为核心工具，全程支撑 CD44 变异体的表达验证与机制研究，为数据可靠性提供关键保障！

abs137958 核心作用

? 精准识别 CD44 总蛋白及变异体：特异性识别 CD44 恒定区，高效检测肺癌细胞 / 组织中 CD44 及变异体（CD44v6）的表达差异；

? 多平台适配，数据稳定：适配 Western Blot、免疫荧光、免疫组化等多种实验技术；

? 助力关键结论验证：清晰证实 MEN1 缺失可显著上调 CD44 变异体表达，为 “MEN1-CD44 剪接 - 铁死亡” 调控轴提供直接蛋白水平证据（对应原文图 2、图 3）。

Absin 配套高分工具（同款文献常用）

? 铁死亡检测相关：abs42197174（DCFH-DA，ROS 检测探针）；

? 剪接调控相关：abs 系列 RNA 聚合酶 II、PAF1 抗体；

? 实验保障：一站式试剂解决方案，助力高分论文发表。

五、研究价值：从基础到临床的双重突破

学术价值

首次将抑癌基因、RNA 可变剪接、铁死亡三大热点领域串联，揭示 MEN1 全新抑癌机制，为肺癌表观遗传调控研究提供新视角。

临床价值

1. 生物标志物：CD44v6 可作为 MEN1 缺陷型肺癌的预后评估标志物；

2. 治疗新策略：靶向 CD44v 干扰肽为MEN1 缺陷型肺癌提供精准治疗新方案，克服传统治疗耐药难题。

六、总结

这项发表于 Cancer Research 的重磅研究，以 MEN1 为核心，破解了 CD44 可变剪接调控铁死亡的关键密码，为肺癌机制研究与精准治疗开辟新方向。

而Absin abs137958 抗体的精准赋能，为研究的关键结论提供了坚实可靠的实验证据，再次印证 Absin 产品在高分生命科学研究中的核心价值！