MYCN‑amplified neuroblastoma cell‑derived exosomal miR‑17‑5p promotes proliferation and migration of non‑MYCN amplified cells

Chen,Weiming; Hao,Xiwei; Yang,Binyi; Zhang,Yuezhen; Sun,Lingyun; Hua,Yanan; Yang,Li; Yu,Jiabin; Zhao,Jing; Hou,Lin; Lu,Hongting

doi:10.3892/mmr.2021.11884

MYCN‑amplified neuroblastoma cell‑derived exosomal miR‑17‑5p promotes proliferation and migration of non‑MYCN amplified cells

Authors:
- Weiming Chen
- Xiwei Hao
- Binyi Yang
- Yuezhen Zhang
- Lingyun Sun
- Yanan Hua
- Li Yang
- Jiabin Yu
- Jing Zhao
- Lin Hou
- Hongting Lu
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Affiliations: Department of Pediatric Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, P.R. China, Department of Biochemistry and Molecular Biology of Basic Medical College, Qingdao University, Qingdao, Shandong 266071, P.R. China
Published online on: February 1, 2021 https://doi.org/10.3892/mmr.2021.11884
Article Number: 245
Copyright: © Chen et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Neuroblastoma (NB) is considered a highly prevalent extracranial solid tumor in young children, and the upregulation of N‑myc proto‑oncogene (MYCN) is closely associated with the late stages of NB and poor prognostic outcomes. The current study was designed to evaluate the effects of exosomal microRNA (miRNA/miR)‑17‑5p from MYCN‑amplified NB cells on the proliferative and migratory potential of non‑MYCN amplified NB cells. miR‑17‑5p was found to activate the PI3K/Akt signaling cascade by targeting PTEN, and the overexpression of miR‑17‑5p was found to promote cellular migration and proliferation in vitro. Further experimentation revealed that the elevated expression of miR‑17‑5p in SK‑N‑BE(2) cell‑derived exosomes significantly promoted the proliferative and migratory capacities of SH‑SY5Y cells by inhibiting PTEN. Collectively, these findings demonstrated that miR‑17‑5p derived from MYCN‑amplified NB cell exosomes promoted the migration and proliferation of non‑MYCN amplified cells, highlighting an exosome‑associated malignant role for miR‑17‑5p.

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1	Maris JM, Hogarty MD, Bagatell R and Cohn SL: Neuroblastoma. Lancet. 369:2106–2120. 2007. View Article : Google Scholar : PubMed/NCBI
2	Pastor ER and Mousa SA: Current management of neuroblastoma and future direction. Crit Rev Oncol Hematol. 138:38–43. 2019. View Article : Google Scholar : PubMed/NCBI
3	Johnsen JI, Dyberg C and Wickstrom M: Neuroblastoma-A neural crest derived embryonal malignancy. Front Mol Neurosci. 12:92019. View Article : Google Scholar : PubMed/NCBI
4	Huang M and Weiss WA: Neuroblastoma and MYCN. Cold Spring Harb Perspect Med. 3:a0144152013. View Article : Google Scholar : PubMed/NCBI
5	Buechner J and Einvik C: N-myc and noncoding RNAs in neuroblastoma. Mol Cancer Res. 10:1243–1253. 2012. View Article : Google Scholar : PubMed/NCBI
6	Schulte JH, Horn S, Otto T, Samans B, Heukamp LC, Eilers UC, Krause M, Astrahantseff K, Klein-Hitpass L, Buettner R, et al: MYCN regulates oncogenic MicroRNAs in neuroblastoma. Int J Cancer. 122:699–704. 2008. View Article : Google Scholar : PubMed/NCBI
7	Bray I, Bryan K, Prenter S, Buckley PG, Foley NH, Murphy DM, Alcock L, Mestdagh P, Vandesompele J, Speleman F, et al: Widespread dysregulation of miRNAs by MYCN amplification and chromosomal imbalances in neuroblastoma: Association of miRNA expression with survival. PLoS One. 4:e78502009. View Article : Google Scholar : PubMed/NCBI
8	Mestdagh P, Fredlund E, Pattyn F, Schulte JH, Muth D, Vermeulen J, Kumps C, Schlierf S, De Preter K, Van Roy N, et al: MYCN/c-MYC-induced microRNAs repress coding gene networks associated with poor outcome in MYCN/c-MYC-activated tumors. Oncogene. 29:1394–1404. 2010. View Article : Google Scholar : PubMed/NCBI
9	Babaei K, Shams S, Keymoradzadeh A, Vahidi S, Hamami P, Khaksar R, Norollahi SE and Samadani AA: An insight of microRNAs performance in carcinogenesis and tumorigenesis; an overview of cancer therapy. Life Sci. 240:1170772020. View Article : Google Scholar : PubMed/NCBI
10	Zhou X, Lu H, Li F, Hao X, Han L, Dong Q and Chen X: MicroRNA-429 inhibits neuroblastoma cell proliferation, migration and invasion via the NF-κB pathway. Cell Mol Biol Lett. 25:52020. View Article : Google Scholar : PubMed/NCBI
11	Zhao X, Gu H, Wang L, Zhang P, Du J, Shen L, Jiang D, Wang J, Li X, Zhang S, et al: MicroRNA-23a-5p mediates the proliferation and differentiation of C2C12 myoblasts. Mol Med Rep. 22:3705–3714. 2020.PubMed/NCBI
12	Tang D, Gao W, Yang J, Liu J, Zhao J, Ge J, Chen Q and Liu B: miR181d promotes cell proliferation via the IGF1/PI3K/AKT axis in glioma. Mol Med Rep. 22:3804–3812. 2020.PubMed/NCBI
13	Galardi A, Colletti M, Businaro P, Quintarelli C, Locatelli F and Di Giannatale A: MicroRNAs in neuroblastoma: Biomarkers with therapeutic potential. Curr Med Chem. 25:584–600. 2018. View Article : Google Scholar : PubMed/NCBI
14	Pegtel DM and Gould SJ: Exosomes. Annu Rev Biochem. 88:487–514. 2019. View Article : Google Scholar : PubMed/NCBI
15	McAndrews KM and Kalluri R: Mechanisms associated with biogenesis of exosomes in cancer. Mol Cancer. 18:522019. View Article : Google Scholar : PubMed/NCBI
16	Sun Z, Shi K, Yang S, Liu J, Zhou Q, Wang G, Song J, Li Z, Zhang Z and Yuan W: Effect of exosomal miRNA on cancer biology and clinical applications. Mol Cancer. 17:1472018. View Article : Google Scholar : PubMed/NCBI
17	Morini M, Cangelosi D, Segalerba D, Marimpietri D, Raggi F, Castellano A, Fruci D, de Mora JF, Canete A, Yanez Y, et al: Exosomal microRNAs from longitudinal liquid biopsies for the prediction of response to induction chemotherapy in high-risk neuroblastoma patients: A proof of concept SIOPEN Study. Cancers (Basel). 11:14762019. View Article : Google Scholar
18	Ma J, Xu M, Yin M, Hong J, Chen H, Gao Y, Xie C, Shen N, Gu S and Mo X: Exosomal hsa-miR199a-3p promotes proliferation and migration in neuroblastoma. Front Oncol. 9:4592019. View Article : Google Scholar : PubMed/NCBI
19	Fonseka P, Liem M, Ozcitti C, Adda CG, Ang CS and Mathivanan S: Exosomes from N-Myc amplified neuroblastoma cells induce migration and confer chemoresistance to non-N-Myc amplified cells: Implications of intra-tumour heterogeneity. J Extracell Vesicles. 8:15976142019. View Article : Google Scholar : PubMed/NCBI
20	Paul P, Qiao J, Kim KW, Romain C, Lee S, Volny N, Mobley B, Correa H and Chung DH: Targeting gastrin-releasing peptide suppresses neuroblastoma progression via upregulation of PTEN signaling. PLoS One. 8:e725702013. View Article : Google Scholar : PubMed/NCBI
21	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
22	Purushothaman A: Exosomes from cell Culture-Conditioned medium: Isolation by ultracentrifugation and characterization. Methods Mol Biol. 1952:233–244. 2019. View Article : Google Scholar : PubMed/NCBI
23	Zafar A, Wang W, Liu G, Wang X, Xian W, McKeon F, Foster J, Zhou J and Zhang R: Molecular targeting therapies for neuroblastoma: Progress and challenges. Med Res Rev. Nov 6–2020.(Epub ahead of print). doi: 10.1002/med.21750. View Article : Google Scholar : PubMed/NCBI
24	Haug BH, Hald ØH, Utnes P, Roth SA, LØkke C, FlÆgstad T and Einvik C: Exosome-like extracellular vesicles from MYCN-amplified neuroblastoma cells contain oncogenic miRNAs. Anticancer Res. 35:2521–2530. 2015.PubMed/NCBI
25	Su T, Xiao Y, Xiao Y, Guo Q, Li C, Huang Y, Deng Q, Wen J, Zhou F and Luo XH: Bone marrow mesenchymal stem Cells-Derived Exosomal miR-29b-3p Regulates Aging-Associated insulin resistance. ACS Nano. 13:2450–2462. 2019.PubMed/NCBI
26	Babuta M, Furi I, Bala S, Bukong TN, Lowe P, Catalano D, Calenda C, Kodys K and Szabo G: Dysregulated autophagy and lysosome function are linked to exosome production by Micro-RNA 155 in alcoholic liver disease. Hepatology. 70:2123–2141. 2019. View Article : Google Scholar : PubMed/NCBI
27	Loven J, Zinin N, Wahlstrom T, Muller I, Brodin P, Fredlund E, Ribacke U, Pivarcsi A, Pahlman S and Henriksson M: MYCN-regulated microRNAs repress estrogen receptor-alpha (ESR1) expression and neuronal differentiation in human neuroblastoma. Proc Natl Acad Sci USA. 107:1553–1558. 2010. View Article : Google Scholar : PubMed/NCBI
28	Khuu C, Utheim TP and Sehic A: The three paralogous MicroRNA clusters in development and disease, miR-17-92, miR-106a-363, and miR-106b-25. Scientifica (Cairo). 2016:13796432016.PubMed/NCBI
29	Opel D, Poremba C, Simon T, Debatin KM and Fulda S: Activation of Akt predicts poor outcome in neuroblastoma. Cancer Res. 67:735–745. 2007. View Article : Google Scholar : PubMed/NCBI
30	Hogarty MD and Maris JM: PI3King on MYCN to improve neuroblastoma therapeutics. Cancer Cell. 21:145–147. 2012. View Article : Google Scholar : PubMed/NCBI
31	Li Z, Xie J, Fei Y, Gao P, Xie Q, Gao W and Xu Z: GDNF family receptor alpha 2 promotes neuroblastoma cell proliferation by interacting with PTEN. Biochem Biophys Res Commun. 510:339–344. 2019. View Article : Google Scholar : PubMed/NCBI
32	Lee YR, Chen M and Pandolfi PP: The functions and regulation of the PTEN tumour suppressor: New modes and prospects. Nat Rev Mol Cell Biol. 19:547–562. 2018. View Article : Google Scholar : PubMed/NCBI
33	Wu Q, Shang Y, Shen T, Liu F, Xu Y and Wang H: Neuroprotection of miR-214 against isoflurane-induced neurotoxicity involves the PTEN/PI3K/Akt pathway in human neuroblastoma cell line SH-SY5Y. Arch Biochem Biophys. 678:1081812019. View Article : Google Scholar : PubMed/NCBI
34	Gerlinger M, Rowan AJ, Horswell S, Math M, Larkin J, Endesfelder D, Gronroos E, Martinez P, Matthews N, Stewart A, et al: Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med. 366:883–892. 2012. View Article : Google Scholar : PubMed/NCBI
35	Barranha R, Costa JL, Carneiro F and Machado JC: Genetic heterogeneity in colorectal cancer and its clinical implications. Acta Med Port. 28:370–375. 2015. View Article : Google Scholar : PubMed/NCBI
36	Lu R, Zhao G, Yang Y, Jiang Z, Cai J, Zhang Z and Hu H: Long noncoding RNA HOTAIRM1 inhibits cell progression by regulating miR-17-5p/ PTEN axis in gastric cancer. J Cell Biochem. 120:4952–4965. 2019. View Article : Google Scholar : PubMed/NCBI
37	Liang W and Yue Z: Lycium barbarum polysaccharides promote osteoblasts viability by regulating microRNA-17/PTEN. Life Sci. 225:72–78. 2019. View Article : Google Scholar : PubMed/NCBI
38	Wang X, Li Z, Bai J, Song W and Zhang F: miR-17-5p regulates the proliferation and apoptosis of human trabecular meshwork cells by targeting phosphatase and tensin homolog. Mol Med Rep. 19:3132–3138. 2019.PubMed/NCBI