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Title:
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The Secretion of miR-200s by a PKCζ/ADAR2 Signaling Axis Promotes Liver Metastasis in Colorectal Cancer
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Author:
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Shelton, Phillip M.; Duran, Angeles; Nakanishi, Yuki; Reina-Campos, Miguel; Kasashima, Hiroaki; Llado, Victoria; Ma, Li; Campos, Alex; García-Olmo, Damián; García-Arranz, Mariano; García-Olmo, Dolores C.; Olmedillas-López, Susana; Caceres, Javier F.; Diaz-Meco, Maria T.; Moscat, Jorge
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Notes:
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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.
Research was supported by grants from the NIH ( R01DK108743 , R01CA172025 , and R01CA207177 to J.M.; R01CA192642 and R01CA218254 to M.T.D.-M.). |
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Subject(s):
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-PRKCZ
-Atypical PKC
-ADAR2
-Colorectal cancer
-Metastasis |
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Rights:
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cc-by-nc-nd, (c) Shelton et al., 2018
http://creativecommons.org/licenses/by-nc-nd/4.0/
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Document type:
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Article
Article - Published version |
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Published by:
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Elsevier
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