The microprotein HDSP promotes gastric cancer progression through activating the MECOM-SPINK1-EGFR signaling axis
Yuli Chen, Qiuhui Li, Xiang Yu, Lu Lu, Zihan Zhou, Mingjie Li, Rui Xia, Xiongkang Gan, Yanming Hu, Guoqing Guo, Jiahao Guo, Hanyang Li, Qiunuo Li, Yan-wen Liu, Xiang-hua Liu, Ming Sun
Abstract
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. Peptides encoded by noncanonical open reading frames play important roles in cancer. Here the authors identify that a microprotein HDSP derived from the long non-coding RNA HOXA10-HOXA9 is overexpressed in gastric cancer and forms a positive feedback loop with MECOM to drive EGFR signaling in gastric cancer progression.