miR-138-5p Inhibits Vascular Mimicry by Targeting the HIF-1 alpha/VEGFA Pathway in Hepatocellular Carcinoma

Tumour vascular mimicry (VM) is the process by which new blood vessels are formed by tumour cells rather than endothelial cells. An increasing number of studies have revealed that the VM process is associated with cancer progression and metastasis. MiR-138-5p has been reported to act as a tumour suppressor in many cancers. However, the role and underlying mechanism of miR-138-5p in hepatocellular carcinoma (HCC) VM remain unclear. In this study, VM density was detected by CD31/periodic acid-Schiff double staining in HCC clinical specimens. We found that miR-138-5p expression correlated strongly and negatively with microvessel density. Additionally, the miR-138-5p mimic or inhibitor decreased or increased, respectively, tube formation capacity in HepG2 and Hep3B cells. Consistent with this finding, miR-138-5p repressed vessel density in vivo. Moreover, miR-138-5p targeted hypoxia-inducible factor 1 alpha (HIF-1 alpha) and regulated the expression of HIF-1 alpha and vascular endothelial growth factor A (VEGFA), which are established classical master regulators for angiogenesis. Consistent with these findings, the HIF-1 alpha inhibitor CAY10585 effectively blocked HCC cell VM and VEGFA expression. In conclusion, miR-138-5p inhibits HepG2 and Hep3B cell VM by blocking the HIF-1 alpha/VEGFA pathway. Therefore, miR-138-5p may serve as a useful therapeutic target for miRNA-based HCC therapy.