Downregulation of microRNA-199b predicts unfavorable prognosis and emerges as a novel therapeutic target which contributes to PP2A inhibition in metastatic colorectal cancer
Entity
UAM. Departamento de Medicina; Instituto de Investigación Sanitaria Fundación Jiménez Díaz (IIS-FJD)Publisher
Impact Journals LLCDate
2016-08-10Citation
10.18632/oncotarget.11174
Oncotarget 8.25 (2017): 40169-40180
ISSN
1949-2553DOI
10.18632/oncotarget.11174Editor's Version
https://doi.org/10.18632/oncotarget.11174Subjects
MicroRNA-199b; Colorectal cancer; PP2A inhibitor; Metastatic; Inhibition; Downregulation; MedicinaRights
© Cristóbal et al.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
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Google Scholar:Cristóbal, Ion
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Caramés, Cristina
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Rincón, Raúl
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Manso, Rebeca
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Madoz-Gúrpide, Juan
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Torrejón, Blanca
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González-Alonso, Paula
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Rojo, Federico
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García-Foncillas López, Jesús Miguel