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

Abstract

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 1α (HIF-1α) and regulated the expression of HIF-1α and vascular endothelial growth factor A (VEGFA), which are established classical master regulators for 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.

JAM3 promotes cervical cancer metastasis by activating the HIF-1α/VEGFA pathway

“…HIF-1α is a hypoxia-responsive factor that responds to hypoxia by activating the master regulator of the transcription of many genes and participates in cell energy metabolism, angiogenesis, proliferation, and apoptosis [29]. HIF-1α is upregulated in many tumors.…”

“…Studies have shown that HIF-1α acts as an oncogene and participates in tumor growth and metastasis [30]. Increasing evidence has demonstrated that VEGFA is an important downstream factor of HIF-1 [29]. Accumulating evidence has shown that VEGFA plays a key role in tumor angiogenesis and vascular mimicry [31,32].…”

Differential Impact of Intermittent vs. Sustained Hypoxia on HIF-1, VEGF and Proliferation of HepG2 Cells

“…Finally, a large body of literature investigated HIF-1 impact on tumorigenesis through other target genes and various biological pathways [ 41 ], including through a crosstalk with NF-kB [ 42 , 48 ], the regulation of pro-oncogenic miRNAs [ 49 , 50 ] known as targets of HIF-1, and key regulators of extracellular matrix degradation by tumor cells, leading to increased invasiveness [ 43 ]. It could thus be of interest to investigate the differential impact of IH vs. SH on these HIF-1 targets.…”

Little things with significant impact: miRNAs in hepatocellular carcinoma

“…As research progresses, this vascular mimetic system has been shown to exist in a variety of tumors, including HCC (40), breast cancer (41), and gastric cancer (42), posing a significant threat to patient survival. To date, researchers have identified several proteins that may affect VM in aggressive HCC, including HIF-1a, MMP2, and Twist-1 (43,44), and miRNAs play a crucial part in the VM process by regulating their expression. It has been revealed that miR-138-5p functions as a tumor suppressor in HCC and suppresses VM by binding to the 3′UTR of HIF-1a mRNA and further downregulating the expression of HIF-1a and VEGFA (43).…”

“…To date, researchers have identified several proteins that may affect VM in aggressive HCC, including HIF-1a, MMP2, and Twist-1 (43,44), and miRNAs play a crucial part in the VM process by regulating their expression. It has been revealed that miR-138-5p functions as a tumor suppressor in HCC and suppresses VM by binding to the 3′UTR of HIF-1a mRNA and further downregulating the expression of HIF-1a and VEGFA (43). Twist-1 is a transcription factor having the structure of a helix-loop-helix.…”