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

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

doi:10.1172/jci148130

Cited by 52 publications

(40 citation statements)

References 52 publications

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“…tRFs could also bind to mRNA 3′-UTR and induce its degradation, resulting in decreased protein production [ 12 ]. More recently, it was reported that certain tRFs could bind to proteins and alter the phosphorylation status and the function of the target protein [ 20 ]. The present study demonstrated, for the first time to our knowledge, that tRFs (i.e., AS-tDR-007333) interacted with binding protein to modify histone modifications and activate transcription factor to enhance promoter activity, resulting in gene expression alteration.…”

Section: Discussionmentioning

confidence: 99%

A novel tRNA-derived fragment AS-tDR-007333 promotes the malignancy of NSCLC via the HSPB1/MED29 and ELK4/MED29 axes

Yang

Gao

et al. 2022

J Hematol Oncol

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Background Transfer RNA-derived fragments (tRFs) are a new class of small non-coding RNAs. Recent studies suggest that tRFs participate in some pathological processes. However, the biological functions and mechanisms of tRFs in non-small cell lung cancer (NSCLC) are largely unknown. Methods Differentially expressed tRFs were identified by tRF and tiRNA sequencing using 9 pairs of pre- and post-operation plasma from patients with NSCLC. Quantitative real-time PCR (qRT-PCR) and fluorescence in situ hybridization (FISH) were used to determine the levels of tRF in tissues, plasma, and cells. Gain- and loss-of-function experiments were implemented to investigate the oncogenic effects of tRF on NSCLC cells in vitro and in vivo. Chromatin immunoprecipitation (ChIP), luciferase reporter, RNA pulldown, mass spectrum, RNA immunoprecipitation (RIP), Western blot, co-immunoprecipitation (Co-IP) assays, and rescue experiments were performed to explore the regulatory mechanisms of tRF in NSCLC. Results AS-tDR-007333 was an uncharacterized tRF and significantly up-regulated in NSCLC tissues, plasma, and cells. Clinically, AS-tDR-007333 overexpression could distinguish NSCLC patients from healthy controls and associated with poorer prognosis of NSCLC patients. Functionally, overexpression of AS-tDR-007333 enhanced proliferation and migration of NSCLC cells, whereas knockdown of AS-tDR-007333 resulted in opposite effects. Mechanistically, AS-tDR-007333 promoted the malignancy of NSCLC cells by activating MED29 through two distinct mechanisms. First, AS-tDR-007333 bound to and interacted with HSPB1, which activated MED29 expression by enhancing H3K4me1 and H3K27ac in MED29 promoter. Second, AS-tDR-007333 stimulated the expression of transcription factor ELK4, which bound to MED29 promoter and increased its transcription. Therapeutically, inhibition of AS-tDR-007333 suppressed NSCLC cell growth in vivo. Conclusions Our study identifies a new oncogenic tRF and uncovers a novel mechanism that AS-tDR-007333 promotes NSCLC malignancy through the HSPB1-MED29 and ELK4-MED29 axes. AS-tDR-007333 is a potential diagnostic or prognostic marker and therapeutic target for NSCLC.

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Section: Discussionmentioning

confidence: 99%

A novel tRNA-derived fragment AS-tDR-007333 promotes the malignancy of NSCLC via the HSPB1/MED29 and ELK4/MED29 axes

Yang

Gao

et al. 2022

J Hematol Oncol

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“…PXN-AS1-IR3 recruits Tex10 and p300 to the MYC enhancer region to promote MYC transcriptional activation, thereby promoting the migration and invasion of hepatocellular carcinoma ( 36 ). In addition, DDX5 and/or DDX17 are also involved in the alternative splicing of Caspase 9, mH2A1 ( 37 ), macroH2A1 ( 38 ), etc., which increased the malignancy of pancreatic ductal adenocarcinoma and breast cancer.…”

Section: Involvement Of Ddx5/ddx17 In Rna Metabolism and Cancer Devel...mentioning

confidence: 99%

DDX5 and DDX17—multifaceted proteins in the regulation of tumorigenesis and tumor progression

Sun

Yan

et al. 2022

Front. Oncol.

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DEAD-box (DDX)5 and DDX17, which belong to the DEAD-box RNA helicase family, are nuclear and cytoplasmic shuttle proteins. These proteins are expressed in most tissues and cells and participate in the regulation of normal physiological functions; their abnormal expression is closely related to tumorigenesis and tumor progression. DDX5/DDX17 participate in almost all processes of RNA metabolism, such as the alternative splicing of mRNA, biogenesis of microRNAs (miRNAs) and ribosomes, degradation of mRNA, interaction with long noncoding RNAs (lncRNAs) and coregulation of transcriptional activity. Moreover, different posttranslational modifications, such as phosphorylation, acetylation, ubiquitination, and sumoylation, endow DDX5/DDX17 with different functions in tumorigenesis and tumor progression. Indeed, DDX5 and DDX17 also interact with multiple key tumor-promoting molecules and participate in tumorigenesis and tumor progression signaling pathways. When DDX5/DDX17 expression or their posttranslational modification is dysregulated, the normal cellular signaling network collapses, leading to many pathological states, including tumorigenesis and tumor development. This review mainly discusses the molecular structure features and biological functions of DDX5/DDX17 and their effects on tumorigenesis and tumor progression, as well as their potential clinical application for tumor treatment.

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“…Recently, more and more evidences have shown that a variety of ARSs are responsible for non-canonical functions other than enzymatic catalytic activity, such as translation regulation, transcription regulation, synthesis, signal transduction, angiogenesis, inflammation, apoptosis, and the development of cancer [25][26][27][28][29]. The nonclassical function of LARS was first reported in 2012.…”

Section: Discussionmentioning

confidence: 99%

Identification of LARS as an essential gene for osteosarcoma proliferation through large-Scale CRISPR-Cas9 screening database and experimental verification

et al. 2022

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Background Osteosarcoma is one of the most malignant tumors, and it occurs mostly in children and adolescents. Currently, surgery and chemotherapy are the main treatments. The recurrence rate is high and the prognosis is often poor. Finding an effective target gene therapy for osteosarcoma may effectively improve its prognosis. Method In this study, genes essential for the survival of osteosarcoma cells were identified by genome-wide screening of CRISPR-Cas9 based on the DepMap database. The expression of these essential genes in osteosarcoma patients’ tissues and normal tissues was identified in the GSE19276 database. Functional pathway enrichment analysis, protein interaction network construction, and LASSO were performed to construct a prognostic risk model based on these essential genes. CCK8 assay was used to detect the effect of essential gene-LARS (Leucyl-TRNA Synthetase 1) on the proliferation of osteosarcoma. Results In this study, 785 genes critical for osteosarcoma cell proliferation were identified from the DepMap. Among these 785 essential genes, 59 DEGs were identified in osteosarcoma tissues. In the functional enrichment analysis, these 59 essential genes were mainly enriched in cell cycle-related signaling pathways. Furthermore, we established a risk score module, including LARS and DNAJC17, screened from these 59 genes, and this module could divide osteosarcoma patients into the low-risk and high-risk groups. In addition, knockdown of LARS expression inhibited the proliferative ability of osteosarcoma cells. A significant correlation was found between LARS expression and Monocytic lineage, T cells, and Fibroblasts. Conclusion In conclusion, LARS was identified as an essential gene for survival in osteosarcoma based on the DepMap database. Knockdown of LARS expression significantly inhibited the proliferation of osteosarcoma cells, suggesting that it is involved in the formation and development of osteosarcoma. The results are useful as a foundation for further studies to elucidate a potential osteosarcoma diagnostic index and therapeutic targets.

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

Cited by 52 publications

References 52 publications

A novel tRNA-derived fragment AS-tDR-007333 promotes the malignancy of NSCLC via the HSPB1/MED29 and ELK4/MED29 axes

A novel tRNA-derived fragment AS-tDR-007333 promotes the malignancy of NSCLC via the HSPB1/MED29 and ELK4/MED29 axes

DDX5 and DDX17—multifaceted proteins in the regulation of tumorigenesis and tumor progression

Identification of LARS as an essential gene for osteosarcoma proliferation through large-Scale CRISPR-Cas9 screening database and experimental verification

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