Focal Adhesion Kinase (FAK)-Hippo/YAP transduction signaling mediates the stimulatory effects exerted by S100A8/A9-RAGE system in triple-negative breast cancer (TNBC).

Autor: Rigiracciolo DC; Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036, Rende, Italy.; Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA., Nohata N; MSD K.K., Tokyo, 102-8667, Japan., Lappano R; Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036, Rende, Italy., Cirillo F; Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036, Rende, Italy., Talia M; Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036, Rende, Italy., Adame-Garcia SR; Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA., Arang N; Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA., Lubrano S; Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA., De Francesco EM; Department of Clinical and Experimental Medicine, University of Catania, Garibaldi-Nesima Hospital, Catania, Italy., Belfiore A; Department of Clinical and Experimental Medicine, University of Catania, Garibaldi-Nesima Hospital, Catania, Italy., Gutkind JS; Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA. sgutkind@ucsd.edu.; Department of Pharmacology, University of California, San Diego, La Jolla, CA, USA. sgutkind@ucsd.edu., Maggiolini M; Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036, Rende, Italy. marcello.maggiolini@unical.it.
Jazyk: angličtina
Zdroj: Journal of experimental & clinical cancer research : CR [J Exp Clin Cancer Res] 2022 Jun 03; Vol. 41 (1), pp. 193. Date of Electronic Publication: 2022 Jun 03.
DOI: 10.1186/s13046-022-02396-0
Abstrakt: Background: Understanding the intricate signaling network involved in triple-negative breast cancer (TNBC) represents a challenge for developing novel therapeutic approaches. Here, we aim to provide novel mechanistic insights on the function of the S100A8/A9-RAGE system in TNBC.
Methods: TNM plot analyzer, Kaplan-Meier plotter, Meta-analysis, GEPIA2 and GOBO publicly available datasets were used to evaluate the clinical significance of S100A8/A9 and expression levels of S100A8/A9, RAGE and Filamin family members in breast cancer (BC) subtypes. METABRIC database and Cox proportional hazard model defined the clinical impact of high RAGE expression in BC patients. Multiple bioinformatics programs identified the main enriched pathways within high RAGE expression BC cohorts. By lentiviral system, TNBC cells were engineered to overexpress RAGE. Western blotting, immunofluorescence, nucleus/cytoplasm fractionation, qRT-PCR, gene silencing and luciferase experiments were performed to identify signal transduction mediators engaged by RAGE upon stimulation with S100A8/A9 in TNBC cells. Proliferation, colony formation and transwell migration assays were carried out to evaluate the growth and migratory capacity of TNBC cells. Statistical analysis was performed by ANOVA and independent t-tests.
Results: We found a remarkable high expression of S100A8 and S100A9 in BC, particularly in HER2-positive and TNBC, with the latter associated to worst clinical outcomes. In addition, high RAGE expression correlated with a poor overall survival in BC. Next, we determined that the S100A8/A9-RAGE system triggers FAK activation by engaging a cytoskeleton mechanosensing complex in TNBC cells. Through bioinformatics analysis, we identified the Hippo pathway as the most enriched in BC patients expressing high RAGE levels. In accordance with these data, we demonstrated the involvement of S100A8/A9-RAGE-FAK signaling in the control of Hippo/YAP activities, and we established the crucial contribution of RAGE-FAK-YAP circuitry in the growth and migratory effects initiated by S100A8/A9 in TNBC cells.
Conclusions: The present study provides novel mechanistic insights on RAGE actions in TNBC. Moreover, our findings suggest that RAGE-FAK-YAP transduction pathway could be exploited as a druggable system halting the aggressive TNBC subtype.
(© 2022. The Author(s).)
Databáze: MEDLINE
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