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

Abstract

Tumor vascular mimicry (VM) is the process of new blood vessels formed by tumor cells rather than endothelial cells. An increasing number of researches have revealed that VM process is associated with cancer progression and metastasis. miR-138-5p has been reported to act as a tumor 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 negatively with microvessel density. Additionally, miR-138-5p mimic or inhibitor decreased or increased, respectively, tube formation capacity in HepG2 and Hep3B cells. Consistent with this, miR-138-5p repressed vessel density in vivo. Moreover, miR-138-5p targeted hypoxia-inducible factor 1α (HIF-1α) and regulated expression of HIF-1α and vascular endothelial growth factor A (VEGFA), which are established classical markers of angiogenesis. Consistent with these findings, the HIF-1α 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-1α/VEGFA pathway. Therefore, miR-138-5p may serve as a useful therapeutic target for miRNA-based HCC therapy.

Involvement of microRNAs and their potential diagnostic, therapeutic, and prognostic role in hepatocellular carcinoma

“…31 MiR-138-5p inhibited VM by targeting the HIF-1α/VEGFA pathway in HCC. 32 A complex miRNAs-target RNAs interaction network inhibited VM formation in HCC by downregulating the circRNA7/ miR7-5p/VE-Cadherin/Notch4 signaling pathway. 33…”

“…To regulate angiogenesis in HCC [25,28] miR-130b-3p To promote tumor angiogenesis and progression of HCC [26] miR-3064-5p, miR-126, miR-138-5p, miR-7-5p, miR-375 To suppress angiogenesis in HCC [27,29,30,32,33,47] miR-20a, miR-193a-3p…”