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Cancer Lett. 2018 Sep 28;432:17-27. doi: 10.1016/j.canlet.2018.06.003. Epub 2018 Jun 6.

Cooperative multi-targeting of signaling networks by angiomiR-204 inhibits vasculogenic mimicry in breast cancer cells.

Author information

1
Posgrado en Ciencias Genómicas, Universidad Autónoma de La Ciudad de México, CDMX, Mexico.
2
Programa en Biomedicina Molecular y Red de Biotecnología, Instituto Politécnico Nacional, CDMX, Mexico.
3
Departamento de Ciencias Naturales, Universidad Autónoma Metropolitana, CDMX, Mexico.
4
Laboratorio de Biología Celular Del Cáncer. Facultad de Ciencias Químico-Biológicas, Universidad Autónoma de Guerrero, Guerrero, Mexico.
5
Escuela Superior de Medicina, Instituto Politécnico Nacional, CDMX, Mexico.
6
Grupo de Genómica Del Cáncer, Instituto Nacional de Cancerología, CDMX, Mexico.
7
Subdirección de Investigación Básica, Instituto Nacional de Medicina Genómica, CDMX, Mexico.
8
Laboratorio de Cáncer de Pulmón. Instituto Nacional de Enfermedades Respiratorias "Ismael Cosio Villegas", CDMX, Mexico.
9
Posgrado en Ciencias Genómicas, Universidad Autónoma de La Ciudad de México, CDMX, Mexico. Electronic address: genomicas@yahoo.com.mx.

Abstract

RNA-based multi-target therapies focused in the blocking of signaling pathways represent an attractive approach in cancer. Here, we uncovered a miR-204 cooperative targeting of multiple signaling transducers involved in vasculogenic mimicry (VM). Our data showed that invasive triple negative MDA-MB-231 and Hs-578T breast cancer cells, but not poorly invasive MCF-7 cells, efficiently undergoes matrix-associated VM under hypoxia. Ectopic restoration of miR-204 in MDA-MB-231 cells leads to a potent inhibition of VM and reduction of number of branch points and patterned 3D channels. Further analysis of activation state of multiple signaling pathways using Phosphorylation Antibody Arrays revealed that miR-204 reduced the expression and phosphorylation levels of 13 proteins involved in PI3K/AKT, RAF1/MAPK, VEGF, and FAK/SRC signaling. In agreement with phospho-proteomic profiling, VM was impaired following pharmacological administration of PI3K and SRC inhibitors. Mechanistic studies confirmed that miR-204 exerts a negative post-transcriptional regulation of PI3K-α and c-SRC proto-oncogenes. Moreover, overall survival analysis of a large cohort of breast cancer patients indicates that low miR-204 and high FAK/SRC levels were associated with worst outcomes. In conclusion, our study provides novel lines of evidence indicating that miR-204 may exerts a fine-tuning regulation of the synergistic transduction of PI3K/AKT/FAK mediators critical in VM formation.

KEYWORDS:

Breast cancer; Phospho-proteomics; Signaling pathways; Vasculogenic mimicry; miR-204

PMID:
29885516
DOI:
10.1016/j.canlet.2018.06.003
[Indexed for MEDLINE]

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