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A novel microprotein HDSP encoded by HOXA10-HOXA9 triggers progression of gastric cancer through maintaining the stability of MECOM and activating SPINK1-EGFR signaling

ABSTRACT: The abundance of noncanonical open reading frames present in long noncoding RNAs (lncRNAs) indicates the potential for translational capacity, thereby enabling the generation of multiple functional peptides or proteins. Nevertheless, the existence of peptide or protein products derived from lncRNAs and their specific roles in gastric cancer remain largely unexplored. In this study, we identified HOXA10-HOXA9-derived small protein (HDSP) in gastric cancer by conducting a comprehensive analysis and experimental validation with mass spectrometry and western blotting. HDSP is highly expressed and has oncogenic roles in gastric cancer. Mechanistically, HDSP blocked TRIM25-mediated ubiquitination and degradation by interacting with MECOM. This led to the accumulation of MECOM, which further enhanced the transcription of SPINK1, a gene that promotes cancer through the EGFR signaling pathway. In addition, MECOM promoted the transcription of HOXA10-HOXA9, creating a feedback regulatory loop that activated downstream SPINK1-EGFR signaling. Finally, we found that HDSP knockdown inhibited tumor growth in a patient-derived xenograft (PDX) model, and the infusion of an artificially synthesized HDSP peptide as a neoantigen improved the anti-tumor efficacy of immune cells against gastric cancer in vitro and in vivo. Our findings provide a potential therapeutic target or neoantigen candidate for the treatment of gastric cancer.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Permanent Cell Line Cell, Cell Culture

DISEASE(S): Diffuse Gastric Cancer

SUBMITTER: Ming Sun

LAB HEAD: Sun Ming

PROVIDER: PXD043737 | Pride | 2024-05-07

REPOSITORIES: Pride

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