J Cancer 2021; 12(7):1967-1977. doi:10.7150/jca.52455

Research Paper

Reduced miR-16 levels are associated with VEGF upregulation in high-risk myelodysplastic syndromes

Bei Xiong1✉*, Yanbo Nie2*, Yalan Yu1, Shixuan Wang3, Xuelan Zuo1✉

1. Department of Hematology, Zhongnan Hospital of Wuhan University, Wuhan, China.
2. Sino-us-diagnostics, Tianjin, China.
3. Department of Hematology, The First Affiliated Hospital of Nanchang University, Nanchang, China.
* These authors contributed equally to this work.

This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.
Citation:
Xiong B, Nie Y, Yu Y, Wang S, Zuo X. Reduced miR-16 levels are associated with VEGF upregulation in high-risk myelodysplastic syndromes. J Cancer 2021; 12(7):1967-1977. doi:10.7150/jca.52455. Available from https://www.jcancer.org/v12p1967.htm

File import instruction

Abstract

Objective: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

Keywords: myelodysplastic syndromes, vascular endothelial growth factor, miR-16, angiogenesis, SKM-1 cells.