Inflammatory cytokine–regulated tRNA-derived fragment tRF-21 suppresses pancreatic ductal adenocarcinoma progression
Ling Pan, Xudong Huang, Ze-Xian Liu, Ying Ye, Rui Li, Jialiang Zhang, Guandi Wu, Ruihong Bai, Lisha Zhuang, Lusheng Wei, Mei Li, Yanfen Zheng, Jiachun Su, Junge Deng, Shuang Deng, Lingxing Zeng, Shaoping Zhang, Chen Wu, Xu Che, Chengfeng Wang, Rufu Chen, Dongxin Lin, Jian Zheng
Ling Pan, Xudong Huang, Ze-Xian Liu, Ying Ye, Rui Li, Jialiang Zhang, Guandi Wu, Ruihong Bai, Lisha Zhuang, Lusheng Wei, Mei Li, Yanfen Zheng, Jiachun Su, Junge Deng, Shuang Deng, Lingxing Zeng, Shaoping Zhang, Chen Wu, Xu Che, Chengfeng Wang, Rufu Chen, Dongxin Lin, Jian Zheng
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Research Article Oncology

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

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-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.

Authors

Ling Pan, Xudong Huang, Ze-Xian Liu, Ying Ye, Rui Li, Jialiang Zhang, Guandi Wu, Ruihong Bai, Lisha Zhuang, Lusheng Wei, Mei Li, Yanfen Zheng, Jiachun Su, Junge Deng, Shuang Deng, Lingxing Zeng, Shaoping Zhang, Chen Wu, Xu Che, Chengfeng Wang, Rufu Chen, Dongxin Lin, Jian Zheng

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Figure 8

LIF or IL-6 enhances KLF4 binding to the SRSF5 promoter region.

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LIF or IL-6 enhances KLF4 binding to the SRSF5 promoter region. (A) Asso...
(A) Association of SRSF5 with tRNAGlyGCC determined by RIP assays in cells cultured with LIF or IL-6 at different concentrations. (B) SRSF5 mRNA levels in cells treated with LIF or IL-6 at different concentrations. (C) Venn diagram of silico analysis of potential transcription factors in the SRSF5 promoter region in cells (left panel). Schematic shows the putative KLF4 binding site in the promoter of the SRSF5 gene and the primers used for ChIP analysis. The consensus and mutant sequences for KLF4 binding are highlighted. (D) ChIP assays using anti-KLF4 antibody or IgG control coupled with qPCR analysis. qPCR results are shown in the left panel, and agarose gel electrophoresis of the qPCR products is shown in the right panel. (E and F) KLF4 bound to the SRSF5 promoter, as measured by ChIP assays in cells cultured with LIF or IL-6 at different concentrations in Capan-2 (E) and SW1990 (F) cell lines. Data in A, B, and D–F indicate the mean ± SEM of at least 3 independent experiments. *P < 0.05, **P < 0.01, and ***P < 0.001, by 1-way ANOVA with Dunnett’s T3 multiple-comparison test (A, B, E, and F) and Student’s t test (D).