Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, 211166, China.
Suzhou Cancer Center Core Laboratory, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, 215001, China.
Nat Commun. 2024 Sep 27;15(1):8381. doi: 10.1038/s41467-024-50986-7.
The presence of noncanonical open reading frames within lncRNAs (long non-coding RNAs) suggests their potential for translation, yielding various functional peptides or proteins. However, the existence and specific roles of these products in gastric cancer remain largely unclear. Here we identify the HOXA10-HOXA9-derived small protein (HDSP) in gastric cancer through comprehensive analysis and experimental validation, including mass spectrometry and western blotting. HDSP exhibits high expression and oncogenic roles in gastric cancer. Mechanistically, HDSP blocks TRIM25-mediated ubiquitination and degradation by interacting with MECOM, leading to MECOM accumulation and enhanced SPINK1 transcription-a gene promoting cancer via the EGFR signaling pathway. Furthermore, MECOM fosters HOXA10-HOXA9 transcription, establishing a feedback loop activating SPINK1-EGFR signaling. HDSP knockdown inhibits tumor growth in a PDX (patient-derived xenograft) model, and infusion of an artificially synthesized HDSP peptide as a neoantigen enhances immune cell-mediated anti-tumor efficacy against gastric cancer in vitro and in vivo. These findings propose HDSP as a potential therapeutic target or neoantigen candidate for gastric cancer treatment.
长链非编码 RNA（lncRNAs）中的非规范开放阅读框的存在表明它们具有翻译的潜力，能够产生各种功能性肽或蛋白质。然而，这些产物在胃癌中的存在和特定作用在很大程度上仍不清楚。在这里，我们通过全面的分析和实验验证，包括质谱分析和 Western blot，鉴定出胃癌中的 HOXA10-HOXA9 衍生的小蛋白（HDSP）。HDSP 在胃癌中表现出高表达和致癌作用。在机制上，HDSP 通过与 MECOM 相互作用，阻止 TRIM25 介导的泛素化和降解，导致 MECOM 积累和增强 SPINK1 转录——一种通过 EGFR 信号通路促进癌症的基因。此外，MECOM 促进 HOXA10-HOXA9 的转录，建立了一个反馈环，激活 SPINK1-EGFR 信号。HDSP 敲低抑制 PDX（患者来源的异种移植）模型中的肿瘤生长，而人工合成的 HDSP 肽作为新抗原注入可增强体外和体内免疫细胞介导的抗胃癌疗效。这些发现表明 HDSP 可能成为胃癌治疗的潜在治疗靶点或新抗原候选物。
