Downregulation of extracellular vesicle microRNA‑101 derived from bone marrow mesenchymal stromal cells in myelodysplastic syndrome with disease progression

Saitoh,Yuu; Umezu,Tomohiro; Imanishi,Satoshi; Asano,Michiyo; Yoshizawa,Seiichiro; Katagiri,Seiichiro; Suguro,Tamiko; Fujimoto,Hiroaki; Akahane,Daigo; Kobayashi‑Kawana,Chiaki; Ohyashiki,Junko  H.; Ohyashiki,Kazuma

doi:10.3892/ol.2020.11282

Downregulation of extracellular vesicle microRNA‑101 derived from bone marrow mesenchymal stromal cells in myelodysplastic syndrome with disease progression

Authors:
- Yuu Saitoh
- Tomohiro Umezu
- Satoshi Imanishi
- Michiyo Asano
- Seiichiro Yoshizawa
- Seiichiro Katagiri
- Tamiko Suguro
- Hiroaki Fujimoto
- Daigo Akahane
- Chiaki Kobayashi‑Kawana
- Junko H. Ohyashiki
- Kazuma Ohyashiki
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Affiliations: Department of Hematology, Tokyo Medical University, Tokyo 160‑8402, Japan, Institute of Medical Sciences, Tokyo Medical University, Tokyo 160‑0023, Japan
Published online on: January 9, 2020 https://doi.org/10.3892/ol.2020.11282
Pages: 2053-2061

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Abstract

To evaluate the mechanism underlying the communication between myeloid malignant and bone marrow (BM) microenvironment cells in disease progression, the current study established BM mesenchymal stromal cells (MSCs) and assessed extracellular vesicle (EV) microRNA (miR) expression in 22 patients with myelodysplastic syndrome (MDS) and 7 patients with acute myeloid leukemia and myelodysplasia‑related changes (AML/MRC). Patients with MDS were separated into two categories based on the revised International Prognostic Scoring System (IPSS‑R), and EV‑miR expression in BM‑MSCs was evaluated using a TaqMan low‑density array. The selected miRs were evaluated using reverse transcription‑quantitative PCR. The current study demonstrated that the expression of BM‑MSC‑derived EV‑miR was heterogenous and based on MDS severity, the expression of EV‑miR‑101 was lower in high‑risk group and patients with AML/MRC compared with the control and low‑risk groups. This reversibly correlated with BM blast percentage, with which the cellular miR‑101 from BM‑MSCs or serum EV‑miR‑101 expression exhibited no association. Database analyses indicated that miR‑101 negatively regulated cell proliferation and epigenetic gene expression. The downregulation of BM‑MSC‑derived EV‑miR‑101 may be associated with cell‑to‑cell communication and may accelerate the malignant process in MDS cells.

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1	Morrison SJ and Scadden DT: The bone marrow niche for haematopoietic stem cells. Nature. 505:327–334. 2014. View Article : Google Scholar : PubMed/NCBI
2	Anthony BA and Link DC: Regulation of hematopoietic stem cells by bone marrow stromal cells. Trends Immunol. 35:32–37. 2014. View Article : Google Scholar : PubMed/NCBI
3	Wang J, Hendrix A, Hernot S, Lemaire M, De Bruyne E, Van Valckenborgh E, Lahoutte T, De Wever O, Vandenrkerken K and Menu E: Bone marrow stroma cell-derived exosomes as communications in drug resistance in multiple myeloma cells. Blood. 124:555–566. 2014. View Article : Google Scholar : PubMed/NCBI
4	Bernardo ME and Fibbe WE: Mesenchymal stromal cells: Sensors and switches of inflammation. Cell Stem Cell. 13:392–402. 2013. View Article : Google Scholar : PubMed/NCBI
5	Nauta AJ and Fibbe WE: Immunomodulatory properties of mesenchymal stromal cells. Blood. 110:3499–3506. 2007. View Article : Google Scholar : PubMed/NCBI
6	Whiteside TL: Exosome and mesenchymal stem cell cross-talk in the tumor microenvironment. Semin Immunol. 35:69–79. 2018. View Article : Google Scholar : PubMed/NCBI
7	Lin LY, Du LM, Cao K, Huang Y, Yu PF, Zhang LY, Li FY, Wang Y and Shi YF: Tumor cell-derived exosomes endow mesenchymal stromal cells with tumour-promotion capabilities. Oncogene. 35:6038–6042. 2016. View Article : Google Scholar : PubMed/NCBI
8	Gebert LFR and MacRae IJ: Regulation of microRNA function in animals. Nat Rev Mol Cell Biol. 20:21–37. 2019. View Article : Google Scholar : PubMed/NCBI
9	Makarova JA, Shkumikov MU, Wicklein D, Lange T, Samatov TR, Turchinovich AA and Tonevitsky AG: Intracellular and extracellular microRNA: An update on localization and biological role. Prog Histochem Cytochem. 51:33–49. 2016. View Article : Google Scholar : PubMed/NCBI
10	Ohyashiki JH, Umezu T and Ohyashiki K: Extracellular vesicle-mediated cell-cell communication in haematological neoplasms. Philos Trans R Soc Lond B Biol Sci. 373(pii): 201604842018. View Article : Google Scholar : PubMed/NCBI
11	Azmi AS, Bao B and Sarkar FH: Exosomes in cancer development, metastasis and drug resistance: A comprehensive review. Cancer Metastasis Rev. 32:623–642. 2013. View Article : Google Scholar : PubMed/NCBI
12	Yang X, Li Y, Zou L and Zhu Z: Role of exosomes in crosstalk between cancer-associated fibroblasts and cancer cells. Front Oncol. 9:3562019. View Article : Google Scholar : PubMed/NCBI
13	Greenberg PL, Tuechler H, Schanz J, Sanz G, Garcia-Manero G, Solé F, Bennett JM, Bowen D, Fenaux P, Dreyfus F, et al: Revised international prognostic scoring system for myelodysplastic syndromes. Blood. 120:2454–2465. 2012. View Article : Google Scholar : PubMed/NCBI
14	Greenberg PL, Stone RM, Al-Kli A, Barta SK, Bejar R, Bennett JM, Carraway H, De Castro CM, Deeg HJ, DeZern AE, et al: Myelodysplastic syndrome, version 2. 2017, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw. 15:60–87. 2017. View Article : Google Scholar : PubMed/NCBI
15	Azuma K, Umezu T, Imanishi S, Asano M, Yoshizawa S, Katagiri S, Ohyashiki K and Ohyashiki JH: Genetic variations of bone marrow mesenchymal stromal cells derive from acute leukemia and myelodysplastic syndrome by targeted deep sequencing. Leuk Res. 62:23–28. 2017. View Article : Google Scholar : PubMed/NCBI
16	Umezu T, Ohyashiki K, Kuroda M and Ohyashiki JH: Leukemia cell to endothelial cell communication via exosomal miRNAs. Oncogene. 32:2747–2755. 2013. View Article : Google Scholar : PubMed/NCBI
17	Yoshizawa S, Umezu T, Saitoh Y, Gotoh M, Akahane D, Kobayashi C, Ohyashiki JH and Ohyashiki K: Exosomal miRNA signatures for late-onset acute graft-versus host disease in allogeneic hematopoietic stem cell transplantation. Int J Mol Sci. 19(pii): E24932018. View Article : Google Scholar : PubMed/NCBI
18	Umezu T, Tadokoro H, Azuma K, Yoshizawa S, Ohyashiki K and Ohyashiki JH: Exosomal miR-135b shed from hypoxic multiple myeloma cells enhances angiogenesis by targeting factor-inhibiting HIF-1. Blood. 124:3748–3757. 2014. View Article : Google Scholar : PubMed/NCBI
19	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
20	Paggetti J, Haderk F, Seiffert M, Janji B, Distler U, Ammerlaan W, Kim YJ, Adam J, Lichter P, Solary E, et al: Exosomes released by chronic lymphocytic leukemia cells induce the transition of stromal cells into cancer-associated fibroblasts. Blood. 126:1106–1117. 2015. View Article : Google Scholar : PubMed/NCBI
21	Orimo A and Weinberg RA: Stromal fibroblasts in cancer: A novel tumor-promoting cell type. Cell Cycle. 5:1597–1601. 2006. View Article : Google Scholar : PubMed/NCBI
22	De Veirman K, Rao L, De Bruyne E, Menu E, Van Valckenborgh E, Van Riet I, Frassanito MA, Di Marzo L, Vacca A and Vanderkerken K: Cancer associated fibroblasts and tumor growth: Focus on multiple myeloma. Cancers (Basel). 6:1363–1381. 2014. View Article : Google Scholar : PubMed/NCBI
23	Ozdogan H, Gur Dedeoglu B, Oztemur Islakoglu Y, Aydos A, Kose S, Ataly A, Yegin ZA, Avcu F, Uckan Cetinkaya D and Ihan O: DICER1 gene and miRNA dysregulation in mesenchymal stem cells of patients with myelodysplastic syndrome and acute myeloblastic leukemia. Leuk Res. 63:62–71. 2017. View Article : Google Scholar : PubMed/NCBI
24	Zhao Y, Wu D, Fei C, Guo J, Gu S, Xu F, Zhang Z, Wu L, Li X and Chang C: Down-regulation of Dicer1 promotes cellular senescence and decreases the differentiation and stem cell-supporting capacities of mesenchymal stromal cells in patient with myelodysplastic syndrome. Haematologica. 100:194–204. 2015. View Article : Google Scholar : PubMed/NCBI
25	Umezu T, Imanishi S, Azuma K, Kobayashi C, Yoshizawa S, Ohyashiki K and Ohyashiki JH: Replenishing exosomes from older bone marrow stromal cells with miR-340 inhibits myeloma-related angiogenesis. Blood Adv. 1:812–823. 2017. View Article : Google Scholar : PubMed/NCBI
26	Su H, Yang JR, Xu T, Huang J, Xu L, Yuan Y and Zhuang SM: MicroRNA-101, down-regulated in hepatocellular carcinoma, promotes apoptosis and suppresses tumorigenicity. Cancer Res. 69:1135–1142. 2009. View Article : Google Scholar : PubMed/NCBI
27	Long Y, Wu Z, Yang X, Chen L, Han Z, Zhang Y, Liu L, Liu W and Liu X: MicroRNA-101 inhibits the proliferation and invasion of bladder cancer cells via targeting c-FOS. Mol Med Rep. 14:2651–2656. 2016. View Article : Google Scholar : PubMed/NCBI
28	Peng Z and Zhang Y: Methyl jasmonate induces the apoptosis of human colorectal cancer cells via down regulation of EZH2 expression by microRNA-101. Mol Med Rep. 15:957–962. 2017. View Article : Google Scholar : PubMed/NCBI
29	Guan H, Dai Z, Ma Y, Wang Z, Liu X and Whang X: MicroRNA-101 inhibits cell proliferation and induces apoptosis by targeting EYA1 in breast cancer. Int J Mol Med. 37:1643–1651. 2016. View Article : Google Scholar : PubMed/NCBI
30	Deng G, Teng Y, Huang F, Nie W, Zhu I, Huang W and Xu H: MicroRNA-101 inhibits the migration and invasion of intrahepatic cholangiocarcinoma cells via direct suppression of vascular endothelial growth factor-C. Mol Med Rep. 12:7079–7085. 2015. View Article : Google Scholar : PubMed/NCBI
31	Li G, Yang F, Gu S, Li Z and Xue M: MicroRNA-101 induces apoptosis in cisplatin-resistant gastric cancer cells by targeting VEGF-C. Mol Med Rep. 13:572–578. 2016. View Article : Google Scholar : PubMed/NCBI
32	Gonzales-Aloy E, Connerty P, Salik B, Liu B, Woo AW, Haber M, Norris MD, Wand J and Wand JY: MiR-101 suppresses the development of MLL-rearranged acute myeloid leukemia. Haematologica. 104:e296–e300. 2019. View Article : Google Scholar : PubMed/NCBI
33	Qian L, Zhang W, Lei B, He A, Ye L, Li X and Don X: MicroRNA-101 regulates T-cell acute lymphoblastic leukemia progression and chemotherapeutic sensitivity by targeting Notch1. Oncol Rep. 36:2511–2526. 2015. View Article : Google Scholar
34	Ghobrial IM, Detappe A, Anderson KC and Steensma SP: The bone-marrow niche in MDS and MGUS: Implications for AML and MM. Nat Rev Clin Oncol. 15:219–233. 2018. View Article : Google Scholar : PubMed/NCBI
35	Flores-Figueroa E, Arana-Trejo RM, Gutierrez-Espindola G, Perez-Cabrera A and Mayani H: Mesenchymal stem cells in myelodysplastic syndromes: Phenotypic and cytogenetic characterization. Leuk Res. 29:215–224. 2005. View Article : Google Scholar : PubMed/NCBI
36	Blau O, Hofmann WK, Baldus CD, Thiel G, Serbent GV, Schumann E, Thiel E and Blau IW: Chromosomal aberrations in bone marrow mesenchymal stroma cells from patients with myelodysplastic syndrome and acute myeloblastic leukemia. Exp Hematol. 35:221–229. 2007. View Article : Google Scholar : PubMed/NCBI
37	Poon Z, Dighe N, Venkatesan SS, Cheung AMS, Fan X, Bari S, Hota M, Ghosh S and Hwang WYK: Bone marrow MSCs in MDS: Contribution towards dysfunctional hematopoiesis and potential targets for disease response to hypomethylating therapy. Leukemia. 33:1487–1500. 2019. View Article : Google Scholar : PubMed/NCBI
38	WMA declaration of Helsinki: Ethical principles for medical research involving human subjects. Retrieved from. https://www.wma.net/policies-post/wma-declaration-of-helsinki-ethical-principles-for-medical-research-involving-human-subjects/World Medical Association; 2013