Cooperative multi-targeting of signaling networks by angiomiR-204 inhibits vasculogenic mimicry in breast cancer cells. (28th September 2018)

• Record Type: Journal Article
• Authors: Salinas-Vera, Yarely M.; Marchat, Laurence A.; García-Vázquez, Raúl; González de la Rosa, Claudia Haydée; Castañeda-Saucedo, Eduardo; Tito, Napoleón Navarro; Flores, Carlos Palma; Pérez-Plasencia, Carlos; Cruz-Colin, José L.; Carlos-Reyes, Ángeles; López-González, José Sullivan; Álvarez-Sánchez, María Elizbeth; López-Camarillo, César
• Is Part Of: Cancer letters. Volume 432(2018)
• Page Start: 17
• Page End: 27
• Publication Date: 2018-09-28
• Subjects: Breast cancer -- Vasculogenic mimicry -- miR-204 -- Signaling pathways -- Phospho-proteomics; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2018.06.003
• Languages: English
• ISSNs: 0304-3835

Abstract

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. Highlights: Mir-204 inhibits vascular mimicry in triple negative breast cancer cells. Mir-204 downregulates the expression/phosphorylation of multiple signaling proteins. Pharmacological inhibition of PI3K and SRC impairs vascular mimicry. MiR-204 targets the 3′UTR of PI3K-α and c-SRC tyrosine kinases. Low levels of miR-204 and high levels of c-SRC and FAK proto-oncogenes in clinical samples correlate with worst outcomes.