The Secretion of miR-200s by a PKCζ/ADAR2 Signaling Axis Promotes Liver Metastasis in Colorectal Cancer
EntityUAM. Departamento de Cirugía; Instituto de Investigación Sanitaria Fundación Jiménez Díaz (IIS-FJD)
10.1016/j.celrep.2018.03.118Cell Reports 23.4 (2018): 1178-1191
Funded byResearch was supported by grants from the NIH (R01DK108743, R01CA172025, and R01CA207177 to J.M.; R01CA192642 and R01CA218254 to M.T.D.-M.)
SubjectsADAR2; atypical PKC; colorectal cancer; EMT; extracellular vesicles; metastasis; mir-200; PRKCZ; RNA editing; tumor suppressors; Medicina
Rights© 2018 The Author(s)
Esta obra está bajo una licencia de Creative Commons Reconocimiento-NoComercial-SinObraDerivada 4.0 Internacional.
Most colorectal cancer (CRC)-related deaths are due to liver metastases. PKCζ is a tumor suppressor in CRC with reduced expression in metastasis. Given the importance of microRNAs (miRNAs) in regulating cellular plasticity, we performed an unbiased screening and identified the miR-200 family as the most relevant miRNAs downregulated by PKCζ deficiency. The regulation of the intracellular levels of miR-200 by PKCζ is post-transcriptional and involves their secretion in extracellular vesicles. Here, we identified ADAR2 as a direct substrate of PKCζ in CRC cells. Phosphorylation of ADAR2 regulates its editing activity, which is required to maintain miR-200 steady-state levels, suggesting that the PKCζ/ADAR2 axis regulates miR-200 secretion through RNA editing. Loss of this axis results in epithelial-to-mesenchymal transition (EMT) and increased liver metastases, which can be inhibited in vivo by blocking miR-200 release. Therefore, the PKCζ/ADAR2 axis is a critical regulator of CRC metastases through modulation of miR-200 levels. Shelton et al. demonstrate that the loss of the tumor suppressor PKCζ in colorectal cancer cells results in the downregulation of miR-200, leading to increased epithelial-to-mesenchymal transition, cell invasion, and liver metastasis. This is mediated by an increase in miR-200 secretion through the inactivation of the RNA editing enzyme ADAR2, identifying a key vulnerability in liver metastasis
Google Scholar:Shelton, Phillip M. - Duran, Angeles - Nakanishi, Yuki - Reina-Campos, Miguel - Kasashima, Hiroaki - Llado, Victoria - Ma, Li - Campos, Alex - García Olmo, Damián - García Arranz, Mariano Andrés - García-Olmo, Dolores C. - Olmedillas-López, Susana - Cáceres, Javier F. - Diaz-Meco, Maria T. - Moscat, Jorge
This item appears in the following Collection(s)
Showing items related by title, author, creator and subject.
Clinical and molecular comparative study of colorectal cancer based on age-of-onset and tumor location: Two main criteria for subclassifying colorectal cancer Álvaro, Edurne; Cano, Juana M.; García, Juan L.; Brandáriz, Lorena; Olmedillas-López, Susana; Arriba, María; Rueda, Daniel; Rodríguez, Yolanda; Cañete, Ángel; Arribas, Julia; Inglada-Pérez, Lucía; Pérez, Jessica; Gómez, Carlos; García Arranz, Mariano Andrés; García Olmo, Damián; Goel, Ajay; Urioste, Miguel; González-Sarmiento, Rogelio; Perea, José
Cimp-positive status is more representative in multiple colorectal cancers than in unique primary colorectal cancers Tapial, Sandra; Olmedillas-López, Susana; Rueda, Daniel; Arriba, María; García, Juan L.; Vivas, Alfredo; Pérez, Jessica; Pena-Couso, Laura; Oliveira, Rocío; Rodríguez, Yolanda; García Arranz, Mariano Andrés; García Olmo, Damián; González-Sarmiento, Rogelio; Urioste, Miguel; Goel, Ajay; Perea, José