Downregulation of microRNA-199b predicts unfavorable prognosis and emerges as a novel therapeutic target which contributes to PP2A inhibition in metastatic colorectal cancer

Abstract

// Ion Cristóbal 1, * , Cristina Caramés 1, * , Raúl Rincón 1 , Rebeca Manso 2 , Juan Madoz-Gúrpide 2 , Blanca Torrejón 1 , Paula González-Alonso 2 , Federico Rojo 2 and Jesús García-Foncillas 1 1 Translational Oncology Division, Oncohealth Institute, IIS-Fundacion Jimenez Diaz, UAM, University Hospital “Fundacion Jimenez Diaz”, E-28040 Madrid, Spain 2 Pathology Department, University Hospital “Fundacion Jimenez Diaz”, Autonomous University of Madrid, E-28040 Madrid, Spain * These authors contributed equally to this work Correspondence to: Ion Cristóbal , email: ion.cristobal@fjd.es Jesús García-Foncillas, email: jgfoncillas@gmail.com Federico Rojo, email: frojo@fjd.es Keywords: miR-199b, SET, PP2A, prognosis, therapy Received: November 02, 2015      Accepted: July 17, 2016      Published: August 10, 2016 ABSTRACT The tumor suppressor microRNA-199b (miR-199b) is a negative SET regulator associated with poor outcome in some human cancers. However, its expression levels as well as potential biological and clinical significance in colorectal cancer (CRC) remain completely unexplored. The PP2A inhibitor SET has shown promising therapeutic and clinical implications in metastatic CRC (mCRC) but the molecular mechanisms underlying SET deregulation are currently unknown. We show here miR-199b downregulation in 4 out of 5 CRC SET-overexpressing cell lines and its inverse correlation with SET overexpression in CRC patients. Moreover, miR-199b led to PP2A activation through a direct SET inhibition, impaired cell viability and enhanced oxaliplatin sensitivity in CRC cells. MiR-199b was found downregulated in 25% of cases, and associated with lymph metastasis ( p = 0.049), presence of synchronous metastasis at diagnosis ( p = 0.026) and SET overexpression ( p < 0.001). Furthermore, low miR-199b levels determined shorter overall ( p < 0.001), progression-free survival ( p = 0.003) and predicted clinical benefit to oxaliplatin treatment. The miR-199b prognostic impact was particularly evident in both younger and KRAS wild-type subgroups. Multivariate analyses confirmed its independent prognostic impact. Altogether, our results show that miR-199b is a tumor suppressor whose downregulation independently determines worse outcome and emerges as a potential contributing mechanism to inhibit PP2A via SET overexpression in a subgroup of mCRC patients.