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

ABSTRACT: Most colorectal cancer (CRC)-related deaths are due to liver metastases. PKC? 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 PKC? deficiency. The regulation of the intracellular levels of miR-200 by PKC? is post-transcriptional and involves their secretion in extracellular vesicles. Here, we identified ADAR2 as a direct substrate of PKC? in CRC cells. Phosphorylation of ADAR2 regulates its editing activity, which is required to maintain miR-200 steady-state levels, suggesting that the PKC?/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 PKC?/ADAR2 axis is a critical regulator of CRC metastases through modulation of miR-200 levels.

SUBMITTER: Shelton PM 

PROVIDER: S-EPMC5958623 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature