Reduced MiR-16 Levels Are Associated with VEGF Upregulation in High-risk Myelodysplastic Syndromes

Overview

Journal J Cancer

Specialty Oncology

Date 2021 Mar 23

PMID 33753995

Citations 1

Authors

Bei Xiong

Yanbo Nie

Yalan Yu

Shixuan Wang

Xuelan Zuo

Affiliations

Soon will be listed here.

Abstract

Overexpression of vascular endothelial growth factor (VEGF), a major angiogenic factor, was found in myelodysplastic syndromes (MDS) and showed different expression statuses in different risk groups of MDS. We aimed to investigate the possible role of microRNA (miR)-15a and miR-16 on the regulation of VEGF expression and their effect on angiogenesis in lower- and higher-risk MDS. We studied peripheral blood and bone marrow samples of MDS patients or several leukaemia and MDS cell lines by enzyme-linked immunosorbent assay, immunohistochemical staining, immunofluorescence and quantitative PCR for expression levels of VEGF, miR-15a and miR-16. MiRNA transfection and Luciferase reporter assays were conducted to investigate whether VEGF is a target of miR-16. Migration and tube formation assays were performed in cells exposed to medium from cells with overexpressed or knockdown miR-16. It showed a significantly lower level of miR-16 in higher-risk MDS patients, while the VEGF levels were upregulated. Inverse correlation between VEGF and miR-16 were determined in cells lines including SKM-1, THP-1, and K562 cells. Overexpression of miR-16 in SKM-1 cells resulted in reduced VEGF secretion and cell protein levels. Direct binding of miR-16 to the 3' untranslated region (3'-UTR) of VEGF was confirmed by luciferase reporter assays. The migration and tube formation of human umbilical vein endothelial cells decreased in the presence of medium from SKM-1 cells with overexpressed miR-16. These data suggest that miR-16 may play a role in angiogenesis in higher-risk MDS by targeting VEGF and therefore modulating MDS progression. MiR-16 might be a novel therapeutic target in higher-risk MDS.

Citing Articles

MicroRNA dysregulation in myelodysplastic syndromes: implications for diagnosis, prognosis, and therapeutic response.

Micheva I, Atanasova S Front Oncol. 2024; 14:1410656.

PMID: 39156702 PMC: 11327013. DOI: 10.3389/fonc.2024.1410656.

References

Pourgholami M, Khachigian L, Fahmy R, Badar S, Wang L, Chu S . Albendazole inhibits endothelial cell migration, tube formation, vasopermeability, VEGF receptor-2 expression and suppresses retinal neovascularization in ROP model of angiogenesis. Biochem Biophys Res Commun. 2010; 397(4):729-34. DOI: 10.1016/j.bbrc.2010.06.019. View

Verstovsek S, Estey E, Manshouri T, Giles F, Cortes J, Beran M . Clinical relevance of vascular endothelial growth factor receptors 1 and 2 in acute myeloid leukaemia and myelodysplastic syndrome. Br J Haematol. 2002; 118(1):151-6. DOI: 10.1046/j.1365-2141.2002.03551.x. View

Ye E, Liu L, Jiang Y, Jan J, Gaddipati S, Suvas S . miR-15a/16 reduces retinal leukostasis through decreased pro-inflammatory signaling. J Neuroinflammation. 2016; 13(1):305. PMC: 5146897. DOI: 10.1186/s12974-016-0771-8. View

Gerber H, Ferrara N . The role of VEGF in normal and neoplastic hematopoiesis. J Mol Med (Berl). 2003; 81(1):20-31. DOI: 10.1007/s00109-002-0397-4. View

Guo Y, Strickland S, Mohan S, Li S, Bosompem A, Vickers K . MicroRNAs and tRNA-derived fragments predict the transformation of myelodysplastic syndromes to acute myeloid leukemia. Leuk Lymphoma. 2017; 58(9):1-15. PMC: 5505168. DOI: 10.1080/10428194.2016.1272680. View

Raza A, Galili N . The genetic basis of phenotypic heterogeneity in myelodysplastic syndromes. Nat Rev Cancer. 2012; 12(12):849-59. DOI: 10.1038/nrc3321. View

McWhirter E, Quirt I, Gajewski T, Pond G, Wang L, Hui J . A phase II study of cediranib, an oral VEGF inhibitor, in previously untreated patients with metastatic or recurrent malignant melanoma. Invest New Drugs. 2016; 34(2):231-5. DOI: 10.1007/s10637-016-0324-0. View

Garzon R, Fabbri M, Cimmino A, Calin G, Croce C . MicroRNA expression and function in cancer. Trends Mol Med. 2006; 12(12):580-7. DOI: 10.1016/j.molmed.2006.10.006. View

Shetty V, Hussaini S, Allampallam K, Mundle S, BOROK R, Broderick E . Intramedullary apoptosis of hematopoietic cells in myelodysplastic syndrome patients can be massive: apoptotic cells recovered from high-density fraction of bone marrow aspirates. Blood. 2000; 96(4):1388-92. View

10.

Ma X, Does M, Raza A, Mayne S . Myelodysplastic syndromes: incidence and survival in the United States. Cancer. 2007; 109(8):1536-42. DOI: 10.1002/cncr.22570. View

11.

Bartel D . MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 2004; 116(2):281-97. DOI: 10.1016/s0092-8674(04)00045-5. View

12.

Garzon R, Garofalo M, Martelli M, Briesewitz R, Wang L, Fernandez-Cymering C . Distinctive microRNA signature of acute myeloid leukemia bearing cytoplasmic mutated nucleophosmin. Proc Natl Acad Sci U S A. 2008; 105(10):3945-50. PMC: 2268779. DOI: 10.1073/pnas.0800135105. View

13.

Bhagat T, Zhou L, Sokol L, Kessel R, Caceres G, Gundabolu K . miR-21 mediates hematopoietic suppression in MDS by activating TGF-β signaling. Blood. 2013; 121(15):2875-81. PMC: 3624935. DOI: 10.1182/blood-2011-12-397067. View

14.

Dejean E, Renalier M, Foisseau M, Agirre X, Joseph N, de Paiva G . Hypoxia-microRNA-16 downregulation induces VEGF expression in anaplastic lymphoma kinase (ALK)-positive anaplastic large-cell lymphomas. Leukemia. 2011; 25(12):1882-90. DOI: 10.1038/leu.2011.168. View

15.

Corey S, Minden M, Barber D, Kantarjian H, Wang J, Schimmer A . Myelodysplastic syndromes: the complexity of stem-cell diseases. Nat Rev Cancer. 2007; 7(2):118-29. DOI: 10.1038/nrc2047. View

16.

He R, Liu B, Yang C, Yang R, Tobelem G, Han Z . Inhibition of K562 leukemia angiogenesis and growth by expression of antisense vascular endothelial growth factor (VEGF) sequence. Cancer Gene Ther. 2004; 10(12):879-86. DOI: 10.1038/sj.cgt.7700645. View

17.

Pons A, Nomdedeu B, Navarro A, Gaya A, Gel B, Diaz T . Hematopoiesis-related microRNA expression in myelodysplastic syndromes. Leuk Lymphoma. 2009; 50(11):1854-9. DOI: 10.3109/10428190903147645. View

18.

Bandi N, Zbinden S, Gugger M, Arnold M, Kocher V, Hasan L . miR-15a and miR-16 are implicated in cell cycle regulation in a Rb-dependent manner and are frequently deleted or down-regulated in non-small cell lung cancer. Cancer Res. 2009; 69(13):5553-9. DOI: 10.1158/0008-5472.CAN-08-4277. View

19.

Cimmino A, Calin G, Fabbri M, Iorio M, Ferracin M, Shimizu M . miR-15 and miR-16 induce apoptosis by targeting BCL2. Proc Natl Acad Sci U S A. 2005; 102(39):13944-9. PMC: 1236577. DOI: 10.1073/pnas.0506654102. View

20.

Gerber H, Malik A, Solar G, Sherman D, Liang X, Meng G . VEGF regulates haematopoietic stem cell survival by an internal autocrine loop mechanism. Nature. 2002; 417(6892):954-8. DOI: 10.1038/nature00821. View