Inflammatory cytokine-regulated tRNA-derived fragment tRF-21 suppresses pancreatic ductal adenocarcinoma progression

J Clin Invest. 2021 Nov 15;131(22):e148130. doi: 10.1172/JCI148130.


The tumorigenic mechanism for pancreatic ductal adenocarcinoma (PDAC) is not clear, although chronic inflammation is implicated. Here, we identified an inflammatory cytokine-regulated transfer RNA-derived (tRNA-derived) fragment, tRF-21-VBY9PYKHD (tRF-21), as a tumor suppressor in PDAC progression. We found that the biogenesis of tRF-21 could be inhibited by leukemia inhibitory factor and IL-6 via the splicing factor SRSF5. Reduced tRF-21 promoted AKT2/1-mediated heterogeneous nuclear ribonucleoprotein L (hnRNP L) phosphorylation, enhancing hnRNP L to interact with dead-box helicase 17 (DDX17) to form an alternative splicing complex. The provoked hnRNP L-DDX17 activity preferentially spliced Caspase 9 and mH2A1 pre-mRNAs to form Caspase 9b and mH2A1.2, promoting PDAC cell malignant phenotypes. The tRF-21 levels were significantly lower in PDACs than in normal tissues, and patients with low tRF-21 levels had a poor prognosis. Treatment of mouse PDAC xenografts or patient-derived xenografts (PDXs) with tRF-21 mimics repressed tumor growth and metastasis. These results demonstrate that tRF-21 has a tumor-suppressive effect and is a potential therapeutic agent for PDAC.

Keywords: Apoptosis; Cancer; Oncology; Therapeutics.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alternative Splicing
  • Carcinoma, Pancreatic Ductal / genetics
  • Carcinoma, Pancreatic Ductal / prevention & control*
  • Cell Line, Tumor
  • Cytokines / physiology*
  • DEAD-box RNA Helicases / metabolism
  • Disease Progression
  • Humans
  • Pancreatic Neoplasms / genetics
  • Pancreatic Neoplasms / prevention & control*
  • Proto-Oncogene Proteins c-akt / physiology
  • RNA, Transfer / physiology*
  • Ribonucleoproteins / metabolism
  • Serine-Arginine Splicing Factors / physiology
  • Tumor Suppressor Proteins
  • Xenograft Model Antitumor Assays


  • Cytokines
  • HNRNPL protein, human
  • Ribonucleoproteins
  • SRSF5 protein, human
  • Tumor Suppressor Proteins
  • Serine-Arginine Splicing Factors
  • RNA, Transfer
  • Proto-Oncogene Proteins c-akt
  • DDX17 protein, human
  • DEAD-box RNA Helicases