title: Downregulation of microRNA-199b predicts unfavorable prognosis and emerges as a novel therapeutic target which contributes to PP2A inhibition in metastatic colorectal cancer.
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.
authors: Translational Oncology Division, Oncohealth Institute, IIS-Fundacion Jimenez Diaz, UAM, University Hospital "Fundacion Jimenez Diaz", E-28040 Madrid, Spain.
authors: Ion
authors: I
authors: Cristóbal
authors: Translational Oncology Division, Oncohealth Institute, IIS-Fundacion Jimenez Diaz, UAM, University Hospital "Fundacion Jimenez Diaz", E-28040 Madrid, Spain.
authors: Cristina
authors: C
authors: Caramés
authors: Translational Oncology Division, Oncohealth Institute, IIS-Fundacion Jimenez Diaz, UAM, University Hospital "Fundacion Jimenez Diaz", E-28040 Madrid, Spain.
authors: Raúl
authors: R
authors: Rincón
authors: Pathology Department, University Hospital "Fundacion Jimenez Diaz", Autonomous University of Madrid, E-28040 Madrid, Spain.
authors: Rebeca
authors: R
authors: Manso
authors: Pathology Department, University Hospital "Fundacion Jimenez Diaz", Autonomous University of Madrid, E-28040 Madrid, Spain.
authors: Juan
authors: J
authors: Madoz-Gúrpide
authors: Translational Oncology Division, Oncohealth Institute, IIS-Fundacion Jimenez Diaz, UAM, University Hospital "Fundacion Jimenez Diaz", E-28040 Madrid, Spain.
authors: Blanca
authors: B
authors: Torrejón
authors: Pathology Department, University Hospital "Fundacion Jimenez Diaz", Autonomous University of Madrid, E-28040 Madrid, Spain.
authors: Paula
authors: P
authors: González-Alonso
authors: Pathology Department, University Hospital "Fundacion Jimenez Diaz", Autonomous University of Madrid, E-28040 Madrid, Spain.
authors: Federico
authors: F
authors: Rojo
authors: Translational Oncology Division, Oncohealth Institute, IIS-Fundacion Jimenez Diaz, UAM, University Hospital "Fundacion Jimenez Diaz", E-28040 Madrid, Spain.
authors: Jesús
authors: J
authors: García-Foncillas
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D004268:DNA-Binding Proteins; D015536:Down-Regulation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D019073:HT29 Cells; D056488:Histone Chaperones / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D009362:Neoplasm Metastasis; D011379:Prognosis; D054648:Protein Phosphatase 2 / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D056488:Histone Chaperones; D035683:MicroRNAs; C513473:SET protein, human; D014157:Transcription Factors; C531408:mirn199 microRNA, human; D054648:Protein Phosphatase 2
keywords: PP2A; SET; miR-199b; prognosis; therapy