Zhang Jia-Ning, Yi Zi-Lu, Zhou Xi-Rui, Liu Sha-Sha, Liu Hong
The Second Surgical Department of Breast Cancer, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin, 300060, China.
Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China.
Noncoding RNA Res. 2025 Jun 17;14:156-165. doi: 10.1016/j.ncrna.2025.06.002. eCollection 2025 Oct.
Long non-coding RNAs (lncRNAs) have emerged as pivotal regulators in tumorigenesis and therapeutic resistance. This study investigates the prognostic significance and dual biological functions of lncRNA OTUD6B-AS1 in breast cancer (BC), focusing on its roles in immune evasion and ferroptosis resistance.
Multi-omics data from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), and lncRNA databases (AnnoLnc2, LncACTdb 3.0) were integrated to analyze OTUD6B-AS1 expression, clinical relevance, and molecular networks. Experimental validations included co-culture assays with CD8 T cells, drug sensitivity tests, and ferroptosis marker analysis.
OTUD6B-AS1 exhibited significant overexpression across multiple cancers, particularly in breast cancer (BC), where elevated levels strongly correlated with poor prognosis. Its expression was closely associated with key clinical indicators (T/N/M stage, ER/PR/HER2 status), prompting the development of a nomogram prognostic model with high clinical applicability. Genomic analysis revealed frequent amplification of OTUD6B-AS1 and co-occurrence of PIK3CA mutations. Co-expression and ceRNA networks highlighted its interaction with RNA degradation pathways. Notably, OTUD6B-AS1 was associated with immune evasion by regulating PD-L1 and CD8 T cell activity. Concurrently, high OTUD6B-AS1 expression conferred ferroptosis resistance via GPX4/SLC7A11 modulation.
In conclusion, OTUD6B-AS1 serves as a biomarker in BC, driving immune evasion and ferroptosis resistance. Targeting OTUD6B-AS1 may enhance immunotherapy efficacy and overcome chemoresistance, offering novel therapeutic avenues.
长链非编码RNA（lncRNAs）已成为肿瘤发生和治疗耐药性的关键调节因子。本研究探讨lncRNA OTUD6B-AS1在乳腺癌（BC）中的预后意义和双重生物学功能，重点关注其在免疫逃逸和铁死亡抗性中的作用。
整合来自癌症基因组图谱（TCGA）、基因表达综合数据库（GEO）和lncRNA数据库（AnnoLnc2、LncACTdb 3.0）的多组学数据，以分析OTUD6B-AS1的表达、临床相关性和分子网络。实验验证包括与CD8 T细胞的共培养试验、药物敏感性测试和铁死亡标志物分析。
OTUD6B-AS1在多种癌症中均表现出显著过表达，尤其是在乳腺癌（BC）中，其水平升高与不良预后密切相关。其表达与关键临床指标（T/N/M分期、ER/PR/HER2状态）密切相关，促使开发出具有高临床适用性的列线图预后模型。基因组分析显示OTUD6B-AS1频繁扩增且PIK3CA突变共存。共表达和ceRNA网络突出了其与RNA降解途径的相互作用。值得注意的是，OTUD6B-AS1通过调节PD-L1和CD8 T细胞活性与免疫逃逸相关。同时，高OTUD6B-AS1表达通过GPX4/SLC7A11调节赋予铁死亡抗性。
总之，OTUD6B-AS1作为BC中的一种生物标志物，驱动免疫逃逸和铁死亡抗性。靶向OTUD6B-AS1可能增强免疫治疗效果并克服化疗耐药性，提供新的治疗途径。
