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

Yarely M. Salinas-Vera, Laurence A. Marchat, Raúl García-Vázquez, Claudia Haydée González de la Rosa, Eduardo Castañeda-Saucedo, Napoleón Navarro Tito, Carlos Palma Flores, Carlos Pérez-Plasencia, José L. Cruz-Colin, Ángeles Carlos-Reyes, José Sullivan López-González, María Elizbeth Álvarez-Sánchez, César López-Camarillo

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Abstract

© 2018 Elsevier B.V. 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.
Original languageAmerican English
Pages (from-to)17-27
Number of pages14
JournalCancer Letters
DOIs
StatePublished - 28 Sep 2018

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Phosphatidylinositol 3-Kinases
Breast Neoplasms
Phosphorylation
Activation Analysis
Proto-Oncogenes
MCF-7 Cells
Survival Analysis
Transducers
Proteomics
Vascular Endothelial Growth Factor A
Pharmacology
RNA
Antibodies
Neoplasms
Proteins
Therapeutics

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Salinas-Vera, Y. M., Marchat, L. A., García-Vázquez, R., González de la Rosa, C. H., Castañeda-Saucedo, E., Tito, N. N., ... López-Camarillo, C. (2018). Cooperative multi-targeting of signaling networks by angiomiR-204 inhibits vasculogenic mimicry in breast cancer cells. Cancer Letters, 17-27. https://doi.org/10.1016/j.canlet.2018.06.003
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. / Cooperative multi-targeting of signaling networks by angiomiR-204 inhibits vasculogenic mimicry in breast cancer cells. In: Cancer Letters. 2018 ; pp. 17-27.
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abstract = "{\circledC} 2018 Elsevier B.V. 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.",
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Salinas-Vera, YM, Marchat, LA, García-Vázquez, R, González de la Rosa, CH, Castañeda-Saucedo, E, Tito, NN, Flores, CP, Pérez-Plasencia, C, Cruz-Colin, JL, Carlos-Reyes, Á, López-González, JS, Álvarez-Sánchez, ME & López-Camarillo, C 2018, 'Cooperative multi-targeting of signaling networks by angiomiR-204 inhibits vasculogenic mimicry in breast cancer cells', Cancer Letters, pp. 17-27. https://doi.org/10.1016/j.canlet.2018.06.003

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

In: Cancer Letters, 28.09.2018, p. 17-27.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Cooperative multi-targeting of signaling networks by angiomiR-204 inhibits vasculogenic mimicry in breast cancer cells

AU - Salinas-Vera, Yarely M.

AU - Marchat, Laurence A.

AU - García-Vázquez, Raúl

AU - González de la Rosa, Claudia Haydée

AU - Castañeda-Saucedo, Eduardo

AU - Tito, Napoleón Navarro

AU - Flores, Carlos Palma

AU - Pérez-Plasencia, Carlos

AU - Cruz-Colin, José L.

AU - Carlos-Reyes, Ángeles

AU - López-González, José Sullivan

AU - Álvarez-Sánchez, María Elizbeth

AU - López-Camarillo, César

PY - 2018/9/28

Y1 - 2018/9/28

N2 - © 2018 Elsevier B.V. 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.

AB - © 2018 Elsevier B.V. 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.

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