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miR-503-5p inhibits colon cancer tumorigenesis, angiogenesis, and lymphangiogenesis by directly downregulating VEGF-A

Abstract

MicroRNAs (miRNAs) are considered important in the pathogenesis of colon cancer. But the mechanism of their role in colon cancer is still largely unknown. Here, we aimed to explore the function of miR-503-5p in the pathogenesis of colon cancer. This study analyzed miRNA microarray of colon cancer. Then, we performed EdU, CCK-8, flow cytometry, Transwell invasion assays and in vivo assays to explore the exact role of miR-503-5p in colon cancer. We observed considerable downregulation of miR-503-5p expression in colon cancer cells and tissues and significant correlation with the TNM stage, differentiation grade and lymph node metastasis of colon cancer. Overexpression of miR-503-5p promoted the apoptosis and G1 arrest of colon cancer cells, and inhibited migration, proliferation, invasion and colony formation. Interestingly, ectopic miR-503-5p overexpression could significantly inhibit vascular endothelial growth factor (VEGF)-A expression and reduce the activity of a luciferase reporter containing the VEGF-A 3′-untranslated region. Furthermore, overexpressed miR-503-5p in human umbilical vein endothelial cells (HUVECs) and colon cancer cells resulted in lower expression levels of VEGFR-2, and subsequently inhibited AKT signaling pathway. Additionally, overexpression of miR-503-5p suppressed both lymphangiogenesis and angiogenesis in vivo and significantly inhibited the tumorigenicity of HT-29 cells in nude mice. In summary, our study shows downregulation of miR-503-5p at least partially contributes to the tumorigenesis of colon cancer through modulating the angiogenesis and lymphangiogenesis by targeting VEGF-A while stimulating AKT signaling pathways. Therapeutic strategies to restore miR-503-5p in colon cancer could be useful to inhibit tumor progression.

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Fig. 1: miR-503-5p expression in colon cancer tissues and its clinical value.
Fig. 2: Effects of miR-503-5p overexpression on proliferation and apoptosis of colon cancer cells in vitro.
Fig. 3: Ectopic miR-503-5p expression inhibited migration and invasion of colon cancer cells.
Fig. 4: miR-503-5p directly targeted VEGF-A.
Fig. 5: miR-503-5p inhibited tumor growth, lymphangiogenesis and angiogenesis in vivo.
Fig. 6: Overexpression of miR-503-5p inhibited tube formation of HUVECs.
Fig. 7: Hypothetical model of miR-503-5p suppressive roles in colon cancer cells and endothelial cells.

Data availability

Upon reasonable request, the datasets used and analyzed during the present study are available from the corresponding author.

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Acknowledgements

I extend my sincere gratitude to my administrator Na Zhang, for her instructive advice and useful suggestion on my thesis. Specially thanks to Shenglong Li, for his valuable suggestions, guidance, and help in the completion of this article. Without his consistent and illuminating instructions, this thesis could not have reached its present form.

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LW designed the study. CS and SS performed the experiments. YZ analyzed the data. NH drafted this manuscript. LW reviewed and revised the manuscript. All authors read and approved the final manuscript.

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Correspondence to Linlin Wei.

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Wei, L., Sun, C., Zhang, Y. et al. miR-503-5p inhibits colon cancer tumorigenesis, angiogenesis, and lymphangiogenesis by directly downregulating VEGF-A. Gene Ther (2020). https://doi.org/10.1038/s41434-020-0167-3

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