Abstract

Pancreatic cancer (PC) is a devastating disease with rising incidence and mortality rates, characterized by late-stage presentation and aggressive progression, underscoring the urgent need for effective therapies. Recent studies have highlighted tRNA-derived fragments (tRFs) as potential therapeutic targets and biomarkers in cancer. In this study, we identified the cancer-associated tRF, tRF-Gly-CCC-012, which was observed to be highly expressed in PC tissues and cell lines. FISH and Nuclear/cytoplasmic RNA isolation analyses showed that tRF-Gly-CCC-012 was predominantly localized in the cytoplasm. Knockdown of tRF-Gly-CCC-012 suppressed aggressive phenotypes in PC cells, whereas its overexpression conversely promoted malignancy in PC organoids. In vivo experiments further confirmed that inhibition of tRF-Gly-CCC-012 suppressed PC cell growth. Mechanistically, RNA sequencing analysis demonstrated that tRF-Gly-CCC-012 upregulated the expression of PHGDH, involved in serine synthesis. RNA pulldown assays combined with mass spectrometry (MS) showed that tRF-Gly-CCC-012 specifically bound to the 162–306 amino acid domain of HNRNPC. Furthermore, tRF-Gly-CCC-012 enhanced HNRNPC protein expression by inhibiting its ubiquitination and degradation, leading to an upregulation of PHGDH and promoting the malignant progression of PC. These findings highlight tRF-Gly-CCC-012 as a viable diagnostic biomarker for PC, providing insights for detection and innovative strategies for clinical intervention.