5-tRF-His, tRNA-derived fragments, regulate CKAP2 to inhibit the proliferation of breast cancer

Volume 5, Issue 2, April 2020     |     PP. 8-29      |     PDF (4467 K)    |     Pub. Date: May 10, 2020
DOI:    206 Downloads     2768 Views  

Author(s)

Xun Tang, Department of Clinical Laboratory, the Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Baiziting Road 42, Nanjing 210009, P. R. China.
Pan Jiang, Department of Clinical Laboratory, the Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Baiziting Road 42, Nanjing 210009, P. R. China.
Huanhuan Chen, Department of Clinical Laboratory, the Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Baiziting Road 42, Nanjing 210009, P. R. China.
Jun Wu, Department of Clinical Laboratory, the Affiliated Brain Hospital of Nanjing Medical University, Guangzhou Road 264, Nanjing 210009, P. R. China.
Xiaodong Xie, Department of Radiology, the Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Baiziting Road 42, Nanjing 210009, P. R. China.
Xuelian Mao, Department of Clinical Laboratory, the Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Baiziting Road 42, Nanjing 210009, P. R. China.
Dongping Mo, Department of Clinical Laboratory, the Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Baiziting Road 42, Nanjing 210009, P. R. China.
Li Tang, Department of Clinical Laboratory, the Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Baiziting Road 42, Nanjing 210009, P. R. China.
Feng Yan, Department of Clinical Laboratory, the Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Baiziting Road 42, Nanjing 210009, P. R. China.

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