Send to

Choose Destination
Front Oncol. 2019 May 14;9:381. doi: 10.3389/fonc.2019.00381. eCollection 2019.

HypoxamiRs Profiling Identify miR-745 as a Regulator of the Early Stages of Vasculogenic Mimicry in SKOV3 Ovarian Cancer Cells.

Author information

Posgrado en Ciencias Genómicas, Universidad Autónoma de la Ciudad de Mexico, Mexico City, Mexico.
Laboratorio de Medicina Translacional y Departamento de Tumores Gastro-Intestinales, Instituto Nacional de Cancerología, Mexico City, Mexico.
Programa en Biomedicina Molecular y Red de Biotecnología, Instituto Politécnico Nacional, Mexico City, Mexico.
Laboratorio de Medicina Genómica, Hospital Regional 1 de Octubre ISSSTE, Mexico City, Mexico.
Departamento de Infectómica y Patogénesis Molecular, CINVESTAV-IPN, Mexico City, Mexico.
Laboratorio de Investigación Translacional en Cáncer y Terapia Celular, Hospital de Oncología, Centro Médico Nacional Siglo XXI, Mexico City, Mexico.
Subdirección de Investigación Básica, Instituto Nacional de Medicina Genómica, Mexico City, Mexico.
Laboratorio de Genómica, Instituto Nacional de Cancerología, Mexico City, Mexico.


Vasculogenic mimicry (VM) is a novel cancer hallmark in which malignant cells develop matrix-associated 3D tubular networks with a lumen under hypoxia to supply nutrients needed for tumor growth. Recent studies showed that microRNAs (miRNAs) may have a role in VM regulation. In this study, we examined the relevance of hypoxia-regulated miRNAs (hypoxamiRs) in the early stages of VM formation. Data showed that after 48 h hypoxia and 12 h incubation on matrigel SKOV3 ovarian cancer cells undergo the formation of matrix-associated intercellular connections referred hereafter as 3D channels-like structures, which arose previous to the apparition of canonical tubular structures representative of VM. Comprehensive profiling of 754 mature miRNAs at the onset of hypoxia-induced 3D channels-like structures showed that 11 hypoxamiRs were modulated (FC>1.5; p < 0.05) in SKOV3 cells (9 downregulated and 2 upregulated). Bioinformatic analysis of the set of regulated miRNAs showed that they might impact cellular pathways related with tumorigenesis. Moreover, overall survival analysis in a cohort of ovarian cancer patients (n = 485) indicated that low miR-765, miR-193b, miR-148a and high miR-138 levels were associated with worst patients outcome. In particular, miR-765 was severely downregulated after hypoxia (FC < 32.02; p < 0.05), and predicted to target a number of protein-encoding genes involved in angiogenesis and VM. Functional assays showed that ectopic restoration of miR-765 in SKOV3 cells resulted in a significant inhibition of hypoxia-induced 3D channels-like formation that was associated with a reduced number of branch points and patterned tubular-like structures. Mechanistic studies confirmed that miR-765 decreased the levels of VEGFA, AKT1 and SRC-α transducers and exerted a negative regulation of VEGFA by specific binding to its 3'UTR. Finally, overall survival analysis of a cohort of ovarian cancer patients (n = 1435) indicates that high levels of VEGFA, AKT1 and SRC-α and low miR-765 expression were associated with worst patients outcome. In conclusion, here we reported a novel hypoxamiRs signature which constitutes a molecular guide for further clinical and functional studies on the early stages of VM. Our data also suggested that miR-765 coordinates the formation of 3D channels-like structures through modulation of VEGFA/AKT1/SRC-α axis in SKOV3 ovarian cancer cells.


VEGFA; hypoxia; miR-765; ovarian cancer; vasculogenic mimicry

Supplemental Content

Full text links

Icon for Frontiers Media SA Icon for PubMed Central
Loading ...
Support Center