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The microprotein HDSP promotes gastric cancer progression through activating the MECOM-SPINK1-EGFR signaling axis

Author

Listed:
  • Yuli Chen

    (Nanjing Medical University
    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)

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.

Suggested Citation

  • 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 & Ming Sun, 2024. "The microprotein HDSP promotes gastric cancer progression through activating the MECOM-SPINK1-EGFR signaling axis," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-50986-7
    DOI: 10.1038/s41467-024-50986-7
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    References listed on IDEAS

    as
    1. Fei Chen & Qilai Long & Da Fu & Dexiang Zhu & Yan Ji & Liu Han & Boyi Zhang & Qixia Xu & Bingjie Liu & Yan Li & Shanshan Wu & Chen Yang & Min Qian & Jianmin Xu & Suling Liu & Liu Cao & Y. Eugene Chin , 2018. "Targeting SPINK1 in the damaged tumour microenvironment alleviates therapeutic resistance," Nature Communications, Nature, vol. 9(1), pages 1-19, December.
    2. Wojciech Barczak & Simon M. Carr & Geng Liu & Shonagh Munro & Annalisa Nicastri & Lian Ni Lee & Claire Hutchings & Nicola Ternette & Paul Klenerman & Alexander Kanapin & Anastasia Samsonova & Nicholas, 2023. "Long non-coding RNA-derived peptides are immunogenic and drive a potent anti-tumour response," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    3. Melusine Bleu & Fanny Mermet-Meillon & Verena Apfel & Louise Barys & Laura Holzer & Marianne Bachmann Salvy & Rui Lopes & Inês Amorim Monteiro Barbosa & Cecile Delmas & Alexandra Hinniger & Suzanne Ch, 2021. "PAX8 and MECOM are interaction partners driving ovarian cancer," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
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