Francesca Orso, Lorena Quirico, Federico Virga, Elisa Penna, Daniela Dettori, Daniela Cimino, Roberto Coppo, Elena Grassi, Angela Rita Elia, Davide Brusa, Silvia Deaglio,Maria Felice Brizzi, Michael B. Stadler, Paolo Provero, Michele Caselle, Daniela Taverna DOI: 10.1158/0008-5472.CAN-15-1322 Published June 2016
miR-214 and miR-148b have been proposed to antagonize the effects of each other in enabling or blocking metastasis, respectively. In this study, we provide evidence deepening their role and interrelationship in the process of metastatic dissemination. Depleting miR-214 or elevating miR-148b blocked the dissemination of melanoma or breast cancer cells, an effect that could be accentuated by dual alteration. Mechanistic investigations indicated that dual alteration suppressed passage of malignant cells through the blood vessel endothelium by reducing expression of the cell adhesion molecules ITGA5 and ALCAM. Notably, transendothelial migration in vitro and extravasation in vivo impaired by singly alterating miR-214 or miR-148b could be overriden by overexpression of ITGA5 or ALCAM in the same tumor cells. In clinical specimens of primary breast cancer or metastatic melanoma, we found a positive correlation between miR-214 and ITGA5 or ALCAM along with an inverse correlation of miR-214 and miR-148b in the same specimens. Our findings define an antagonistic relationship of miR-214 and miR-148b in determining the dissemination of cancer cells via tumor-endothelial cell interactions, with possible implications for microRNA-mediated therapeutic interventions aimed at blocking cancer extravasation.
miR-214 and miR-148b targeting inhibits dissemination of melanoma and breast cancer
Monica Raimo, Francesca Orso, Elena Grassi, Daniela Cimino, Elisa Penna, Cristiano De Pitta, Michael B. Stadler, Luca Primo, Enzo Calautti, Pietro Quaglino, Paolo Provero, and Daniela Taverna
Malignant melanoma is the most aggressive form of skin cancer; therefore, it is crucial to disclose its underlying molecular mechanisms. MicroRNAs (miRNAs) are small endogenous noncoding RNAs able to posttranscriptionally downregulate the expression of direct target genes. Using a melanoma progression model, miR-146a was identified as a key double-acting player in melanoma malignancy. In fact, miR-146a is able to enhance tumor growth, while it suppresses dissemination. It was determined that miR-146a coordinated melanoma cell growth by its direct targets lunatic fringe (LFNG) and NUMB, which operate on the NOTCH/PTEN/Akt pathway; while inhibition of metastasis formation was linked to decreased expression of ITGAV and ROCK1. Relevantly, miR-146a expression correlated with melanoma recurrence and was enriched in both patient-derived melanoma and cutaneous metastasis specimens, while its direct targets were depleted. However, miR-146a levels drop in circulating tumor cells (CTCs), suggesting the necessity for miR-146a expression to fluctuate during tumor progression in order to favor tumor growth and allow dissemination. This study reconciles the contradictory biologic functions of miR-146a in melanoma progression and unravels distinct molecular mechanisms that need to be considered for therapeutic interventions.
Implications: miR-146a controls melanoma progression in a dual way, promoting growth and inhibiting dissemination;
however, it is poorly expressed in CTCs, resulting in overall tumor spreading and distant-site colonization. Mol Cancer Res;
14(6); 548–62. 2016 AACR.