Wang Huiping, Wang Cong, Wei Jia, Zhao Xuan'er, Yang Xuemei, Li Renren, Li Mengmeng, Zhu Zhansheng
Jiangsu Engineering Center for Precision Diagnosis and Treatment Research of Polygenic Diseases, Key Laboratory of Genetic Foundation and Clinical Application, Department of Genetics, Xuzhou Medical University, Xuzhou, Jiangsu 221004, PR China.
Laboratory of Experimental and Clinical Pathology, Departments of Pathology, School of Basic Medical Sciences, Xuzhou Medical University, Xuzhou, Jiangsu 221004, PR China.
Transl Oncol. 2025 Jul;57:102409. doi: 10.1016/j.tranon.2025.102409. Epub 2025 May 10.
Emerging evidence highlights LIM-domain only 2 (LMO2) as both a potential biomarker and therapeutic target in diverse cancers. However, its functional characterization and clinical significance remain insufficiently explored in cancers such as Clear Cell Renal Cell Carcinoma (ccRCC). Therefore, comprehensive pan-cancer analysis and mechanistic investigation are necessary for optimizing LMO2-targeted immunotherapy strategies.
We conducted comprehensive multi-omics analyses and clinicopathological correlation studies across all cancers using TCGA data and specialized bioinformatics tools. Immune microenvironment associations were evaluated through Pearson correlation coefficients and TIMER algorithm validation. Subsequent functional enrichment analyses and predictive regulator identification were performed to delineate signaling pathways in ccRCC. Mechanistic insights were validated through in vitro models and xenograft experiments.
LMO2 demonstrates significant deregulation across multiple malignancies, with its mRNA expression exhibiting distinct correlations with clinical staging, survival outcomes, and tumor immune microenvironment characteristics. Systematic analysis further confirmed it as a potentially novel immunotherapeutic target. Mechanistic investigations revealed that ZC3H13 depletion mediates LMO2 downregulation through N6-methyladenosine (m6A)-dependent epigenetic modifications. Through comprehensive functional validation in ccRCC, we established LMO2's tumor-suppressive properties using both in vitro models and xenograft assays. Subsequent pathway investigation demonstrated that LMO2 exerts its anti-tumor effects through direct modulation of the NF-κB signaling cascade via the GATA2-BEX1 regulatory axis.
Our findings establish substantial evidence for LMO2 as both a potential therapeutic candidate in cancer immunotherapy and a significant prognostic modulator in ccRCC pathogenesis. The mechanistic characterization of LMO2's tumor-suppressive functions warrants heightened translational consideration in both clinical management strategies and molecular etiology research.
新出现的证据表明，仅含LIM结构域2（LMO2）在多种癌症中既是潜在的生物标志物又是治疗靶点。然而，在透明细胞肾细胞癌（ccRCC）等癌症中，其功能特征和临床意义仍未得到充分探索。因此，进行全面的泛癌分析和机制研究对于优化针对LMO2的免疫治疗策略是必要的。
我们使用TCGA数据和专门的生物信息学工具，对所有癌症进行了全面的多组学分析和临床病理相关性研究。通过Pearson相关系数和TIMER算法验证评估免疫微环境关联。随后进行功能富集分析和预测调节因子鉴定，以描绘ccRCC中的信号通路。通过体外模型和异种移植实验验证机制见解。
LMO2在多种恶性肿瘤中表现出明显的失调，其mRNA表达与临床分期、生存结果和肿瘤免疫微环境特征呈现出不同的相关性。系统分析进一步证实它是一个潜在的新型免疫治疗靶点。机制研究表明，ZC3H13的缺失通过N6-甲基腺苷（m6A）依赖性表观遗传修饰介导LMO2下调。通过在ccRCC中进行全面的功能验证，我们使用体外模型和异种移植试验确定了LMO2的肿瘤抑制特性。随后的通路研究表明，LMO2通过GATA2-BEX1调节轴直接调节NF-κB信号级联反应来发挥其抗肿瘤作用。
我们的研究结果为LMO2作为癌症免疫治疗的潜在候选药物以及ccRCC发病机制中的重要预后调节因子提供了大量证据。LMO2肿瘤抑制功能的机制特征在临床管理策略和分子病因学研究中都值得进一步的转化考虑。
