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
N1 - Publisher Copyright:
© 2018 Elsevier B.V.
PY - 2018/9/28
Y1 - 2018/9/28
N2 - 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 - 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.
KW - Breast cancer
KW - Phospho-proteomics
KW - Signaling pathways
KW - Vasculogenic mimicry
KW - miR-204
UR - http://www.scopus.com/inward/record.url?scp=85048587771&partnerID=8YFLogxK
U2 - 10.1016/j.canlet.2018.06.003
DO - 10.1016/j.canlet.2018.06.003
M3 - Artículo
C2 - 29885516
SN - 0304-3835
VL - 432
SP - 17
EP - 27
JO - Cancer Letters
JF - Cancer Letters
ER -