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, Yanwen Liu, Xianghua Liu () and Ming Sun ()
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Yuli Chen: Nanjing Medical University
Qiuhui Li: Nanjing Medical University
Xiang Yu: The Affiliated Yantai Yuhuangding Hospital of Qingdao University
Lu Lu: Nanjing Medical University
Zihan Zhou: The First Clinical Medical College of Nanjing Medical University
Mingjie Li: Nanjing Medical University
Rui Xia: Nanjing Chest Hospital
Xiongkang Gan: The First Affiliated Hospital of Nanjing Medical University
Yanming Hu: Nanjing Medical University
Guoqing Guo: Nanjing Medical University
Jiahao Guo: Nanjing Medical University
Hanyang Li: Nanjing Medical University
Qiunuo Li: The First Clinical Medical College of Nanjing Medical University
Yanwen Liu: Zhongda Hospital, Medical School of Southeast University
Xianghua Liu: Nanjing Medical University
Ming Sun: Nanjing Medical University

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-50986-7

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