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Cancer Cell International
Published in: Cancer Cell International 1/2021

01-12-2021 | Hepatocellular Carcinoma | Primary research

Gly-tRF enhances LCSC-like properties and promotes HCC cells migration by targeting NDFIP2

Authors: Yongqiang Zhou, Jinjing Hu, Lu Liu, Mengchao Yan, Qiyu Zhang, Xiaojing Song, Yan Lin, Dan Zhu, Yongjian Wei, Zongli Fu, Liming Hu, Yue Chen, Xun Li

Published in: Cancer Cell International | Issue 1/2021

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Abstract

Background

Accumulating evidence demonstrates that tRFs (tRNA-derived small RNA fragments) and tiRNAs (tRNA-derived stress-induced RNA), an emerging category of regulatory RNA molecules derived from transfer RNAs (tRNAs), are dysregulated in in various human cancer types and play crucial roles. However, their roles and mechanisms in hepatocellular carcinoma (HCC) and liver cancer stem cells (LCSCs) are still unknown.

Methods

The expression of glycine tRNA-derived fragment (Gly-tRF) was measured by qRT-PCR. Flow cytometric analysis and sphere formation assays were used to determine the properties of LCSCs. Transwell assays and scratch wound assays were performed to detect HCC cell migration. Western blotting was conducted to evaluate the abundance change of Epithelial-mesenchymal transition (EMT)-related proteins. Dual luciferase reporter assays and signalling pathway analysis were performed to explore the underlying mechanism of Gly-tRF functions.

Results

Gly-tRF was highly expressed in HCC cell lines and tumour tissues. Gly-tRF mimic increased the LCSC subpopulation proportion and LCSC-like cell properties. Gly-tRF mimic promoted HCC cell migration and EMT. Loss of Gly-tRF inhibited HCC cell migration and EMT. Mechanistically, Gly-tRF decreased the level of NDFIP2 mRNA by binding to the NDFIP2 mRNA 3′ UTR. Importantly, overexpression of NDFIP2 weakened the promotive effects of Gly-tRF on LCSC-like cell sphere formation and HCC cell migration. Signalling pathway analysis showed that Gly-tRF increased the abundance of phosphorylated AKT.

Conclusions

Gly-tRF enhances LCSC-like cell properties and promotes EMT by targeting NDFIP2 and activating the AKT signalling pathway. Gly-tRF plays tumor-promoting role in HCC and may lead to a potential therapeutic target for HCC.
Appendix
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Literature
1.
Llovet JM, Kelley RK, Villanueva A, Singal AG, Pikarsky E, Roayaie S, Lencioni R, Koike K, Zucman-Rossi J, Finn RS. Hepatocellular carcinoma. Nat Rev Dis Primers. 2021;7(1):6.PubMedCrossRef
2.
Kulik L, El-Serag HB. Epidemiology and management of hepatocellular carcinoma. Gastroenterology 2019;156(2):477–491 e471.
3.
Krishnan MS, Rajan KdA, Park J, Arjunan V, Garcia Marques FJ, Bermudez A, Girvan OA, Hoang NS, Yin J, Nguyen MH, et al. Genomic analysis of vascular invasion in hepatocellular carcinoma (HCC) reveals molecular drivers and predictive biomarkers. Hepatology. 2020;73(6):2342–60.CrossRef
4.
Sun C, Fu Z, Wang S, Li J, Li Y, Zhang Y, Yang F, Chu J, Wu H, Huang X, et al. Roles of tRNA-derived fragments in human cancers. Cancer Lett. 2018;414:16–25.PubMedCrossRef
5.
Park J, Ahn SH, Shin MG, Kim HK, Chang S. tRNA-derived small RNAs: novel epigenetic regulators. Cancers (Basel). 2020;12(10):2773.CrossRef
6.
Shen Y, Yu X, Zhu L, Li T, Yan Z, Guo J. Transfer RNA-derived fragments and tRNA halves: biogenesis, biological functions and their roles in diseases. J Mol Med (Berl). 2018;96(11):1167–76.CrossRef
7.
Godoy PM, Bhakta NR, Barczak AJ, Cakmak H, Fisher S, MacKenzie TC, Patel T, Price RW, Smith JF, Woodruff PG, et al. Large differences in small RNA composition between human biofluids. Cell Rep. 2018;25(5):1346–58.PubMedPubMedCentralCrossRef
8.
Chiou NT, Kageyama R, Ansel KM: Selective export into extracellular vesicles and function of tRNA fragments during T cell activation. Cell Rep 2018, 25(12):3356–3370 e3354.
9.
Li F, Kaczor-Urbanowicz KE, Sun J, Majem B, Lo HC, Kim Y, Koyano K, Rao SL, Kang SY, Kim SM, et al. Characterization of human salivary extracellular RNA by next-generation sequencing. Clin Chem. 2018;64(7):1085–95.PubMedPubMedCentralCrossRef
10.
Molla-Herman A, Angelova MT, Ginestet M, Carre C, Antoniewski C, Huynh JR. tRNA fragments populations analysis in mutants affecting tRNAs processing and tRNA methylation. Front Genet. 2020;11:518949.PubMedPubMedCentralCrossRef
11.
Jia Y, Tan W, Zhou Y. Transfer RNA-derived small RNAs: potential applications as novel biomarkers for disease diagnosis and prognosis. Ann Transl Med. 2020;8(17):1092.PubMedPubMedCentralCrossRef
12.
Goodarzi H, Liu X, Nguyen HC, Zhang S, Fish L, Tavazoie SF. Endogenous tRNA-derived fragments suppress breast cancer progression via YBX1 displacement. Cell. 2015;161(4):790–802.PubMedPubMedCentralCrossRef
13.
Cui Y, Huang Y, Wu X, Zheng M, Xia Y, Fu Z, Ge H, Wang S, Xie H. Hypoxia-induced tRNA-derived fragments, novel regulatory factor for doxorubicin resistance in triple-negative breast cancer. J Cell Physiol. 2019;234(6):8740–51.PubMedCrossRef
14.
Telonis AG, Rigoutsos I. Race disparities in the contribution of miRNA isoforms and tRNA-derived fragments to triple-negative breast cancer. Cancer Res. 2018;78(5):1140–54.PubMedCrossRef
15.
Sun C, Yang F, Zhang Y, Chu J, Wang J, Wang Y, Zhang Y, Li J, Li Y, Fan R, et al. tRNA-derived fragments as novel predictive biomarkers for trastuzumab-resistant breast cancer. Cell Physiol Biochem. 2018;49(2):419–31.PubMedCrossRef
16.
Martens-Uzunova E, Jalava S, Dits N. Leenders Gv: Diagnostic and prognostic signatures from the small non-coding RNA transcriptome in prostate cancer. Oncogene. 2012;31(8):978–91.CrossRefPubMed
17.
Olvedy M, Scaravilli M, Hoogstrate Y, Visakorpi T. A comprehensive repertoire of tRNA-derived fragments in prostate cancer. Oncotarget. 2016;7(17):24766–77.PubMedPubMedCentralCrossRef
18.
Huang B, Yang H, Cheng X, Wang D, Fu S, Shen W, Zhang Q, Zhang L, Xue Z, Li Y, et al. tRF/miR-1280 suppresses stem cell–like cells and metastasis in colorectal cancer. Can Res. 2017;77(12):3194–206.CrossRef
19.
Li S, Shi X, Chen M, Xu N, Sun D, Bai R, Chen H, Ding K, Sheng J, Xu Z. Angiogenin promotes colorectal cancer metastasis via tiRNA production. Int J Cancer. 2019;145(5):1395–407.PubMedCrossRef
20.
Yu M, Lu B, Zhang J, Ding J, Liu P, Lu Y. tRNA-derived RNA fragments in cancer: current status and future perspectives. J Hematol Oncol. 2020;13(1):121.PubMedPubMedCentralCrossRef
21.
Zhong F, Hu Z, Jiang K, Lei B, Wu Z. Complement C3 activation regulates the production of tRNA-derived fragments Gly-tRFs and promotes alcohol-induced liver injury and steatosis. Cell Res. 2019;29(7):548–61.PubMedPubMedCentralCrossRef
22.
Lakshman R, Shah R, Reyes-Gordillo K, Varatharajalu R. Synergy between NAFLD and AFLD and potential biomarkers. Clin Res Hepatol Gastroenterol. 2015;39(Suppl 1):S29-34.PubMedCrossRef
23.
Da Z, Gao L, Su G, Yao J, Fu W, Zhang J, Zhang X, Pei Z, Yue P, Bai B, et al. Bioinformatics combined with quantitative proteomics analyses and identification of potential biomarkers in cholangiocarcinoma. Cancer Cell Int. 2020;20:130.PubMedPubMedCentralCrossRef
24.
Green JA, Ansari MY, Ball HC, Haqqi TM. tRNA-derived fragments (tRFs) regulate post-transcriptional gene expression via AGO-dependent mechanism in IL-1beta stimulated chondrocytes. Osteoarthritis Cartilage. 2020;28(8):1102–10.PubMedPubMedCentralCrossRef
25.
Zhuo Z, Hu J, Yang X, Chen M, Lei X, Deng L, Yao N, Peng Q, Chen Z, Ye W, et al. Ailanthone inhibits Huh7 cancer cell growth via cell cycle arrest and apoptosis in vitro and in vivo. Sci Rep. 2015;5:16185.PubMedPubMedCentralCrossRef
26.
Yao D, Sun X, Zhou L, Amanullah M, Pan X, Liu Y, Liang M, Liu P, Lu Y. OncotRF: an online resource for exploration of tRNA-derived fragments in human cancers. RNA Biol. 2020;17(8):1081–91.PubMedPubMedCentralCrossRef
27.
Chai S, Ng KY, Tong M, Lau EY, Lee TK, Chan KW, Yuan YF, Cheung TT, Cheung ST, Wang XQ, et al. Octamer 4/microRNA-1246 signaling axis drives Wnt/beta-catenin activation in liver cancer stem cells. Hepatology. 2016;64(6):2062–76.PubMedCrossRef
28.
Wu J, Zhu P, Lu T, Du Y, Wang Y, He L, Ye B, Liu B, Yang L, Wang J, et al. The long non-coding RNA LncHDAC2 drives the self-renewal of liver cancer stem cells via activation of Hedgehog signaling. J Hepatol. 2019;70(5):918–29.PubMedCrossRef
29.
Tian W, Li J, Wang Z, Zhang T, Han Y, Liu Y, Chu W, Liu Y, Yang B. HYD-PEP06 suppresses hepatocellular carcinoma metastasis, epithelial-mesenchymal transition and cancer stem cell-like properties by inhibiting PI3K/AKT and WNT/beta-catenin signaling activation. Acta Pharm Sin B. 2021;11(6):1592–606.PubMedPubMedCentralCrossRef
30.
Zhou Q, Jin P, Liu J, Li S, Liu W, Xi S. HER2 overexpression triggers the IL-8 to promote arsenic-induced EMT and stem cell-like phenotypes in human bladder epithelial cells. Ecotoxicol Environ Saf. 2021;208:111693.PubMedCrossRef
31.
Steinbichler TB, Savic D, Dudas J, Kvitsaridze I, Skvortsov S, Riechelmann H, Skvortsova II. Cancer stem cells and their unique role in metastatic spread. Semin Cancer Biol. 2020;60:148–56.PubMedCrossRef
32.
Yang J, Antin P, Berx G, Blanpain C, Brabletz T, Bronner M, Campbell K, Cano A, Casanova J, Christofori G, et al. Guidelines and definitions for research on epithelial-mesenchymal transition. Nat Rev Mol Cell Biol. 2020;21(6):341–52.PubMedPubMedCentralCrossRef
33.
Zhang S, Li H, Zheng L, Li H, Feng C. Identification of functional tRNA-derived fragments in senescenceaccelerated mouse prone 8 brain. Aging. 2019;11(22):10485–98.PubMedPubMedCentralCrossRef
34.
Shen L, Tan Z, Gan M, Li Q, Chen L, Niu L, Jiang D, Zhao Y, Wang J, Li X, et al. tRNA-derived small non-coding RNAs as novel epigenetic molecules regulating adipogenesis. Biomolecules. 2019;9(7):274.PubMedCentralCrossRef
35.
Chen Y, Wang X. miRDB: an online database for prediction of functional microRNA targets. Nucleic Acids Res. 2020;48(D1):D127–31.PubMedCrossRef
36.
O’Leary CE, Riling CR, Spruce LA, Ding H, Kumar S, Deng G, Liu Y, Seeholzer SH, Oliver PM. Ndfip-mediated degradation of Jak1 tunes cytokine signalling to limit expansion of CD4+ effector T cells. Nat Commun. 2016;7:11226.PubMedPubMedCentralCrossRef
37.
Mund T, Pelham HR. Regulation of PTEN/Akt and MAP kinase signaling pathways by the ubiquitin ligase activators Ndfip1 and Ndfip2. Proc Natl Acad Sci U S A. 2010;107(25):11429–34.PubMedPubMedCentralCrossRef
38.
Cho H, Lee W, Kim GW, Lee SH, Moon JS, Kim M, Kim HS, Oh JW. Regulation of La/SSB-dependent viral gene expression by pre-tRNA 3’ trailer-derived tRNA fragments. Nucleic Acids Res. 2019;47(18):9888–901.PubMedPubMedCentralCrossRef
39.
Selitsky SR, Baran-Gale J, Honda M, Yamane D, Masaki T, Fannin EE, Guerra B, Shirasaki T, Shimakami T, Kaneko S, et al. Small tRNA-derived RNAs are increased and more abundant than microRNAs in chronic hepatitis B and C. Sci Rep. 2015;5:7675.PubMedPubMedCentralCrossRef
40.
Honda S, Loher P, Shigematsu M, Palazzo JP, Suzuki R, Imoto I, Rigoutsos I, Kirino Y. Sex hormone-dependent tRNA halves enhance cell proliferation in breast and prostate cancers. Proc Natl Acad Sci U S A. 2015;112(29):E3816-3825.PubMedPubMedCentralCrossRef
41.
Zhang F, Shi J, Wu Z, Gao P, Zhang W, Qu B, Wang X, Song Y, Wang Z. A 3’-tRNA-derived fragment enhances cell proliferation, migration and invasion in gastric cancer by targeting FBXO47. Arch Biochem Biophys. 2020;690:108467.PubMedCrossRef
42.
Farina NH, Scalia S, Adams CE, Hong D, Fritz AJ, Messier TL, Balatti V, Veneziano D, Lian JB, Croce CM, et al. Identification of tRNA-derived small RNA (tsRNA) responsive to the tumor suppressor, RUNX1, in breast cancer. J Cell Physiol. 2020;235(6):5318–27.PubMedPubMedCentralCrossRef
43.
44.
Boskovic A, Bing XY, Kaymak E, Rando OJ. Control of noncoding RNA production and histone levels by a 5’ tRNA fragment. Genes Dev. 2020;34(1–2):118–31.PubMedPubMedCentralCrossRef
45.
Mo D, He F, Zheng J, Chen H, Tang L, Yan F. tRNA-derived fragment tRF-17-79MP9PP attenuates cell invasion and migration via THBS1/TGF-beta1/Smad3 axis in breast cancer. Front Oncol. 2021;11:656078.PubMedPubMedCentralCrossRef
46.
Blanco S, Bandiera R, Popis M, Hussain S, Lombard P, Aleksic J, Sajini A, Tanna H, Cortes-Garrido R, Gkatza N, et al. Stem cell function and stress response are controlled by protein synthesis. Nature. 2016;534(7607):335–40.PubMedPubMedCentralCrossRef
47.
Guzzi N, Ciesla M, Ngoc PCT, Lang S, Arora S, Dimitriou M, Pimkova K, Sommarin MNE, Munita R, Lubas M et al. Pseudouridylation of tRNA-derived fragments steers translational control in stem cells. Cell 2018;173(5):1204–1216 e1226.
48.
Dimri M, Humphries A, Laknaur A, Elattar S, Lee TJ, Sharma A, Kolhe R, Satyanarayana A. NAD(P)H quinone dehydrogenase 1 ablation inhibits activation of the phosphoinositide 3-kinase/Akt serine/threonine kinase and mitogen-activated protein kinase/extracellular signal-regulated kinase pathways and blocks metabolic adaptation in hepatocellular carcinoma. Hepatology. 2020;71(2):549–68.PubMedCrossRef
49.
Rebouissou S, Nault JC. Advances in molecular classification and precision oncology in hepatocellular carcinoma. J Hepatol. 2020;72(2):215–29.PubMedCrossRef
Metadata
Title
Gly-tRF enhances LCSC-like properties and promotes HCC cells migration by targeting NDFIP2
Authors
Yongqiang Zhou
Jinjing Hu
Lu Liu
Mengchao Yan
Qiyu Zhang
Xiaojing Song
Yan Lin
Dan Zhu
Yongjian Wei
Zongli Fu
Liming Hu
Yue Chen
Xun Li
Publication date
01-12-2021
Publisher
BioMed Central
Published in
Cancer Cell International / Issue 1/2021
Electronic ISSN: 1475-2867
DOI
https://doi.org/10.1186/s12935-021-02102-8

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