1. Inflammatory cytokine-regulated tRNA-derived fragment tRF-21 suppresses pancreatic ductal adenocarcinoma progression
- Author
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Pan, Ling, Huang, Xudong, Liu, Ze-Xian, Ye, Ying, Li, Rui, Zhang, Jialiang, Wu, Guandi, Bai, Ruihong, Zhuang, Lisha, Wei, Lusheng, Li, Mei, Zheng, Yanfen, Su, Jiachun, Deng, Junge, Deng, Shuang, Zeng, Lingxing, Zhang, Shaoping, Wu, Chen, Che, Xu, Wang, Chengfeng, Chen, Rufu, Lin, Dongxin, and Zheng, Jian
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Cytokines -- Health aspects ,Transfer RNA -- Health aspects ,Pancreatic cancer -- Development and progression -- Genetic aspects -- Care and treatment ,Health care industry - Abstract
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-21VBY9PYKHD (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 Caspase9b 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., Introduction Pancreatic ductal adenocarcinoma (PDAC) is the most lethal malignancy, with a 5-year survival rate of less than 9% (1, 2). Most PDAC tumors are already in an advanced stage [...]
- Published
- 2021
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