<p>Interfering Human Papillomavirus E6/E7 Oncogenes in Cervical Cancer Cells Inhibits the Angiogenesis of Vascular Endothelial Cells via Increasing miR-377 in Cervical Cancer Cell-Derived Microvesicles</p>

Abstract

Background: The dysregulation of the human papillomavirus 18 E6 and E7 oncogenes plays a critical role in the angiogenesis of cervical cancer (CC), including the proliferation, migration, and tube formation of vascular endothelial cells. Interfering E6/E7 increases the number of CC cell-derived microvesicles (CC-MVs). Additionally, microRNAs (miRNAs) can modulate CC angiogenesis and can be encapsulated in MVs. Objective: We aim to investigate whether E6/E7 affects CC angiogenesis via regulating miRNAs in CC-MVs. Methods: CC-MVs were isolated from a CC cell line (HeLa) which were transfected with small interfering RNAs (siRNAs) against E6/E7 or co-transfected with miR-377 mimics/ inhibitors. The expression of several miRNAs in CC-MVs was detected using quantitative real-time PCR. After co-incubating CC-MVs with human umbilical vein endothelial cells (HUVECs), cell proliferation, migration, and tube formation of HUVECs were determined using cell counting kit-8, transwell, and tube formation assays, respectively. Results: MiR-377 was increased in E6/E7-interfering CC-MVs. Overexpressing miR-377 in CC-MVs suppressed HUVEC proliferation, migration, and tube formation. LPAR2, the cell surface G protein-coupled receptor, was the downstream target of miR-377 in HUVECs. The co-transfection of E6/E7 siRNAs and miR-377 inhibitors in CCs negated the effect of E6/E7 siRNAs on the elevation of miR-377 in CC-MVs. In HUVECs, the co-transfection of E6/E7 siRNAs and miR-377 inhibitors restored the LPAR2 expression which was reduced by the E6/E7 siRNA transfection. Meanwhile, miR-377 mimic reduced LPAR2 expression and inhibited HUVEC proliferation, migration, and tube formation, while such response was negated by LPAR2 overexpression. Conclusion: Interfering E6/E7 increased miR-377 in CC-MVs, and overexpressing miR-377 in CC-MVs inhibited angiogenesis of HUVECs via reducing LPAR2.

IRF-1 Inhibits Angiogenic Activity of HPV16 E6 Oncoprotein in Cervical Cancer

“…Besides, it was also confirmed in Figure 2 that E6 siRNA inhibits the VEGF-induced proliferation and migration, tube formation of HUVECs and tube formation. These results were consistent with those of Zhang et al, although the conditions of experiments were partially different [ 67 ]. These results suggested that HPV16 E6 is involved in VEGF-induced endothelial cell migration, proliferation and capillary-like tubular network formation.…”

Learning Cell-Type-Specific Gene Regulation Mechanisms by Multi-Attention Based Deep Learning With Regulatory Latent Space

“…Using a biomedical literature search platform, BEST (Lee et al, 2016 ), 14 genes were related to miRNA in the context of the HeLa cell line, cervical cancer, or ovarian cancer ( Supplementary Table 3 ). For example, the expression of LPAR2 was repressed by miR-377, and oncogenic processes such as cell proliferation or migration are known to be repressed by that inhibition mechanism (Zhang et al, 2020 ). As another example, ITGB1 was targeted by miR-183.…”

Exosomes from cervical cancer cells facilitate pro-angiogenic endothelial reconditioning through transfer of Hedgehog–GLI signaling components

“…MicroRNA miR-221-3p present in cervical cancer exosomes promoted angiogenic response [ 21 , 45 ]. Further, HPV oncogenes were shown to influence exosomal microRNA cargo by reducing level of anti-angiogenic miR-377 in microvesicles thereby promoting endothelial cell proliferation, migration, and tube formation [ 51 ]. In contrast, a recent study carried on HeLa exosomes showed breakdown of vascular integrity and endothelial cell permeability, essential for neo-angiogenic response, by triggering endoplasmic reticulum stress leading to metastasis.…”