5-tRF-His, tRNA-derived fragments, regulate CKAP2 to inhibit the proliferation of breast cancer
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Author(s)
Abstract
tRNA derived fragments are differentiated expressed in human breast cancer( BC) tissues. Among of them, 5-tRF-His attracted our attention due to its potential role in breast cancer progression. PCR and in situ hybridization were used to measure the expression and location of 5-tRF-His. The role of 5-tRF-His in vitro was explored by cell proliferation assays and flow cytometery. The effect of 5-tRF-His in vivo was performed by Xenograft experiments and immunohistochemistry. We determined the derivation of 5-tRF-His by northern blot and clarified the mechanism of 5-tRF-His by immunoprecipitation and western blot. We observed that strong downregulation of 5-tRF-His in clinical BC samples. Reduced 5-tRF-His can lead to lymph node metastasis. 5-tRF-His, a tRNA-derived fragment linked to pan-ago, regulates the proliferation and apoptosis of BC cells and inhibits BC tumor growth explant tumor in vivo. The increase in proliferation and the decrease in apoptosis induced by the 5-tRF-His inhibitor were reversed by si-CKAP2. 5-tRF-His inhibits BC development in vivo and vitro. The 5-tRF-His/CKAP2/erk2 axis affects the proliferation and apoptosis of BC cells, imply that 5-tRF-His may be a promising tumor marker of BC patients serum and treatment target for BC therapy.
Keywords
breast cancer; serum; tRNA-derived fragments; CKAP2; proliferation; ERK2 signaling pathway
Cite this paper
Xun Tang, Pan Jiang, Huanhuan Chen, Jun Wu, Xiaodong Xie, Xuelian Mao, Dongping Mo, Li Tang, Feng Yan,
5-tRF-His, tRNA-derived fragments, regulate CKAP2 to inhibit the proliferation of breast cancer
, SCIREA Journal of Clinical Medicine.
Volume 5, Issue 2, April 2020 | PP. 8-29.
References
[ 1 ] | Bray F; Ferlay J; Soerjomataram I; Siegel RL; Torre LA; Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018, 68, 394-424. DOI: 10.3322/caac.21492 |
[ 2 ] | DeSantis CE; Ma J; Goding Sauer A; Newman LA; Jemal A. Breast cancer statistics, 2017, racial disparity in mortality by state. CA Cancer J Clin. 2017, 67, 439-48. DOI: 10.3322/caac.21412 |
[ 3 ] | Benoit Bouvrette LP; Cody NAL; Bergalet J; Lefebvre; FA; Diot C; Wang X et al. CeFra-seq reveals broad asymmetric mRNA and noncoding RNA distribution profiles in Drosophila and human cells. RNA 2018, 24, 98-113. DOI: 10.1261/rna.063172.117 |
[ 4 ] | Ta HQ; Whitworth H; Yin Y; Conaway M; Frierson HFJ; Campbell MJ et al. Discovery of a novel long noncoding RNA overlapping the LCK gene that regulates prostate cancer cell growth. Mol Cancer. 2019, 18, 113. DOI: 10.1186/s12943-019-1039-6 |
[ 5 ] | Martinez G; Choudury SG; Slotkin RK. tRNA-derived small RNAs target transposable element transcripts. Nucleic Acids Res. 2017, 45, 5142-52. DOI: 10.1093/nar/gkx103 |
[ 6 ] | Lyons SM; Fay MM; Akiyama Y; Anderson PJ; Ivanov P. RNA biology of angiogenin: Current state and perspectives. RNA Biol. 2017, 14, 171-8. DOI: 10.1080/15476286.2016.1272746 |
[ 7 ] | Kumar P; Kuscu C; Dutta A. Biogenesis and Function of Transfer RNA-Related Fragments (tRFs). Trends Biochem Sci. 2016, 41, 679-89. DOI: 10.1016/j.tibs.2016.05.004 |
[ 8 ] | Chen Z; Qi M; Shen B; Luo G; Wu Y; Li J et al. Transfer RNA demethylase ALKBH3 promotes cancer progression via induction of tRNA-derived small RNAs. Nucleic Acids Res. 2019, 47, 2533-45. DOI: 10.1093/nar/gky1250 |
[ 9 ] | Wang X; Yang Y; Tan X; Mao X; Wei D; Yao Y et al. Identification of tRNA-Derived Fragments Expression Profile in Breast Cancer Tissues. Curr Genomics. 2019, 20, 199-213. DOI: 10.2174/1389202920666190326145459 |
[ 10 ] | Case CM; Sackett DL; Wangsa D; Karpova T; McNally JG; Ried T et al. CKAP2 ensures chromosomal stability by maintaining the integrity of microtubule nucleation sites. PLoS One. 2013, 8, e64575. DOI: 10.1371/journal.pone.0064575 |
[ 11 ] | Yoo BH; Kang DS; Park CH; Kang K; Bae CD. CKAP2 phosphorylation by CDK1/cyclinB1 is crucial for maintaining centrosome integrity. Exp Mol Med. 2017, 49, e354. DOI: 10.1038/emm.2017.92 |
[ 12 ] | Guo QS; Song Y; Hua KQ; Gao SJ. Involvement of FAK-ERK2 signaling pathway in CKAP2-induced proliferation and motility in cervical carcinoma cell lines. Sci Rep. 2017, 7, 2117. DOI: 10.1038/s41598-017-01832-y |
[ 13 ] | Wang K; Huang R; Li G; Zeng F; Zhao Z; Liu Y et al. CKAP2 expression is associated with glioma tumor growth and acts as a prognostic factor in highgrade glioma. Oncol Rep. 2018, 40, 2036-46. DOI: 10.3892/or.2018.6611 |
[ 14 ] | Sim SH; Bae CD; Kwon Y; Hwang HL; Poojan S; Hong HI et al. CKAP2 (cytoskeleton-associated protein2) is a new prognostic marker in HER2-negative luminal type breast cancer. PLoS One. 2017, 12, e0182107. DOI: 10.1371/journal.pone.0182107 |
[ 15 ] | Tang X; Chen X; Xu Y; Qiao Y; Zhang X; Wang Y et al. CD166 positively regulates MCAM via inhibition to ubiquitin E3 ligases Smurf1 and betaTrCP through PI3K/AKT and c-Raf/MEK/ERK signaling in Bel-7402 hepatocellular carcinoma cells. Cell Signal. 2015, 27, 1694-702. DOI: 10.1016/j.cellsig.2015.05.006 |
[ 16 ] | Wang J; Tang X; Weng W; Qiao Y; Lin J; Liu W et al. The membrane protein melanoma cell adhesion molecule (MCAM) is a novel tumor marker that stimulates tumorigenesis in hepatocellular carcinoma. Oncogene 2015, 34, 5781-95. DOI: 10.1038/onc.2015.36 |
[ 17 ] | Loher P; Telonis AG; Rigoutsos I. MINTmap: fast and exhaustive profiling of nuclear and mitochondrial tRNA fragments from short RNA-seq data. Sci Rep. 2017, 7, 41184. DOI: 10.1038/srep41184 |
[ 18 ] | Maute RL; Schneider C; Sumazin P; Holmes A; Califano A; Basso K et al. tRNA-derived microRNA modulates proliferation and the DNA damage response and is down-regulated in B cell lymphoma. Proc Natl Acad Sci U S A. 2013,110, 1404-9. DOI: 10.1073/pnas.1206761110 |
[ 19 ] | Huang B; Yang H; Cheng X; Wang D; Fu S; Shen W et al. tRF/miR-1280 Suppresses Stem Cell-like Cells and Metastasis in Colorectal Cancer. Cancer Res. 2017, 77, 3194-206. DOI: 10.1158/0008-5472.CAN-16-3146 |
[ 20 ] | Mo D; Jiang P; Yang Y; Mao X; Tan X; Tang X et al. A tRNA fragment, 5'-tiRNA(Val), suppresses the Wnt/beta-catenin signaling pathway by targeting FZD3 in breast cancer. Cancer Lett. 2019, 457,60-73. DOI: 10.1016/j.canlet.2019.05.007 |
[ 21 ] | Hydbring P; Wang Y; Fassl A; Li X; Matia V; Otto T et al. Cell-Cycle-Targeting MicroRNAs as Therapeutic Tools against Refractory Cancers. Cancer Cell. 2017, 31, 576-90 e8. 10.1016/j.ccell.2017.03.004 |
[ 22 ] | Yang Y; Chen L; Gu J; Zhang H; Yuan J; Lian Q et al. Recurrently deregulated lncRNAs in hepatocellular carcinoma. Nat Commun. 2017, 8, 14421. DOI: 10.1038/ncomms14421 |
[ 23 ] | Vo JN; Cieslik M; Zhang Y; Shukla S; Xiao L; Zhang Y et al. The Landscape of Circular RNA in Cancer. Cell 2019, 176, 869-81 e13. DOI: 10.1016/j.cell.2018.12.021 |
[ 24 ] | Telonis AG; Loher P; Magee R; Pliatsika V; Londin E; Kirino Y et al. tRNA Fragments Show Intertwining with mRNAs of Specific Repeat Content and Have Links to Disparities. Cancer Res. 2019, 79, 034-49. DOI: 10.1158/0008-5472.CAN-19-0789 |
[ 25 ] | Roura Frigole H; Camacho N; Castellvi Coma M; Fernandez-Lozano C; Garcia-Lema J; Rafels-Ybern A et al. tRNA deamination by ADAT requires substrate-specific recognition mechanisms and can be inhibited by tRFs. RNA 2019, 25, 607-19. DOI: 10.1261/rna.068189.118 |
[ 26 ] | 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, 790-802. DOI: 10.1016/j.cell.2015.02.053 |
[ 27 ] | Schorn AJ; Gutbrod MJ; LeBlanc C; Martienssen R. LTR-Retrotransposon Control by tRNA-Derived Small RNAs. Cell 2017, 170, 61-71. DOI: 10.1016/j.cell.2017.06.013 |
[ 28 ] | Chiou NT; Kageyama R; Ansel KM. Selective Export into Extracellular Vesicles and Function of tRNA Fragments during T Cell Activation. Cell Rep. 2018,25,3356-70 e4. DOI: 10.1016/j.celrep.2018.11.073 |
[ 29 ] | Kuscu C; Kumar P; Kiran M; Su Z; Malik A; Dutta A. tRNA fragments (tRFs) guide Ago to regulate gene expression post-transcriptionally in a Dicer-independent manner. RNA 2018, 24, 1093-105. DOI: 10.1261/rna.066126.118 |
[ 30 ] | Vedanayagam J; Chatila WK; Aksoy BA; Majumdar S; Skanderup AJ; Demir E et al. Cancer-associated mutations in DICER1 RNase IIIa and IIIb domains exert similar effects on miRNA biogenesis. Nat Commun. 2019, 10, 3682. DOI: 10.1038/s41467-019-11610-1 |
[ 31 ] | Zhang M; Zhao L. CKAP2 Promotes Ovarian Cancer Proliferation and Tumorigenesis Through the FAK-ERK Pathway. DNA Cell Biol. 2017, 36, 983-90. DOI: 10.1089/dna.2017.3876 |