The Secretion of miR-200s by a PKCζ/ADAR2 Signaling Axis Promotes Liver Metastasis in Colorectal Cancer

Phillip M Shelton, Angeles Duran, Yuki Nakanishi, Miguel Reina-Campos, Hiroaki Kasashima, Victoria Llado, Li Ma, Alex Campos, Damián García-Olmo, Mariano García-Arranz, Dolores C García-Olmo, Susana Olmedillas-López, Javier F Caceres, Maria T Diaz-Meco, Jorge Moscat

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)1178-1191
Number of pages14
JournalCell Reports
Volume23
Issue number4
DOIs
Publication statusPublished - 24 Apr 2018

Keywords

  • Journal Article

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