肿瘤细胞治疗研究
英文原题：A novel microprotein L3EMP triggers lung adenocarcinoma progression by catalysing the deubiquitination of SIRT1.
肺腺癌（LUAD）的治疗靶点有限，生存率低。长链非编码RNA（lncRNA）中的非经典开放阅读框（ORF）可能编码功能性微蛋白，但其在LUAD中的作用仍不清楚。本研究旨在表征LINC00973编码的微蛋白L3EMP，并探讨其促肿瘤机制及治疗潜力。
肺腺癌（LUAD）的治疗靶点有限，生存率低。长链非编码RNA（lncRNA）中的非经典开放阅读框（ORF）可能编码功能性微蛋白，但其在LUAD中的作用仍不清楚。本研究旨在表征LINC00973编码的微蛋白L3EMP，并探讨其促肿瘤机制及治疗潜力。
通过核糖体图谱分析和RNA测序鉴定出L3EMP，并通过质谱（MS）和Western blotting确认其表达。利用CRISPR/Cas9介导的基因操作进一步验证了其功能相关性。在LUAD细胞和CAR-T（CAR-T）细胞模型中进行了功能实验，以阐明潜在的分子机制。通过泛素化实验和信号通路分析研究了USP22与SIRT1之间的相互作用。最后，利用合成的L3EMP肽和靶向B7-H3的CAR-T细胞评估了免疫治疗潜力。关键结果：（1）L3EMP是一种由LINC00973编码的微蛋白，在LUAD中过表达，其表达水平与不良预后相关。（2）L3EMP通过促进USP22介导的去泛素化来稳定SIRT1。这形成了一个涉及YY1的正反馈环路，激活AKT/ERK信号通路，从而促进增殖和侵袭。（3）L3EMP敲除抑制PDX模型中的肿瘤生长。（4）合成的L3EMP肽作为新抗原增强抗肿瘤免疫。（5）L3EMP缺失通过IFN-通路激活与B7-H3 CAR-T疗法产生协同作用。结论与意义：L3EMP通过USP22/SIRT1信号轴促进LUAD进展，既是治疗靶点也是免疫原性新抗原。靶向L3EMP或其通路可抑制肿瘤生长，而合成的L3EMP肽可增强免疫治疗。L3EMP缺失与B7-H3 CAR-T疗法的联合增强了抗肿瘤疗效，提示了一种有前景的LUAD治疗联合策略。
BACKGROUND AND PURPOSE: Lung adenocarcinoma (LUAD) has limited therapeutic targets and poor survival. Noncanonical open reading frames (ORFs) in long noncoding RNAs (lncRNAs) may encode functional microproteins, but their roles in LUAD remain unclear. This study aims to characterise the LINC00973-encoded microprotein L3EMP and to investigate its tumour-promoting mechanisms and therapeutic potential. METHODS: L3EMP was identified through ribosome profiling and RNA sequencing, with its expression confirmed by mass spectrometry (MS) and Western blotting. Its functional relevance was further validated using CRISPR/Cas9-mediated gene manipulation. Functional experiments were performed in LUAD cells and chimeric antigen receptor T (CAR-T) cell models to elucidate the underlying molecular mechanisms. The interaction between USP22 and SIRT1 was investigated via ubiquitination assays and signalling pathway profiling. Finally, immunotherapeutic potential was evaluated using synthetic L3EMP peptides and B7-H3-targeted CAR-T cells. KEY RESULTS: (1) L3EMP, a microprotein encoded by LINC00973, is overexpressed in LUAD and its expression level is correlated with poor prognosis. (2) L3EMP stabilises SIRT1 by promoting USP22-mediated deubiquitination. This forms a positive feedback loop involving YY1 that activates AKT/ERK signalling, thereby promoting proliferation and invasion. (3) L3EMP knockout suppresses tumour growth in PDX models. (4) Synthetic L3EMP peptide enhances antitumor immunity as a neoantigen. (5) L3EMP deletion synergises with B7-H3 CAR-T therapy via IFN- pathway activation. CONCLUSIONS AND IMPLICATIONS: L3EMP contributes to LUAD progression through the USP22/SIRT1 signalling axis and represents both a therapeutic target and an immunogenic neoantigen. Targeting L3EMP or its pathway inhibits tumour growth, while the synthetic L3EMP peptide can potentiate immunotherapy. The combination of L3EMP depletion and B7-H3 CAR-T therapy enhances antitumor efficacy, suggesting a promising combinatorial strategy for LUAD treatment.
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