期刊
CELL REPORTS
卷 23, 期 4, 页码 1178-1191出版社
CELL PRESS
DOI: 10.1016/j.celrep.2018.03.118
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资金
- NIH [R01DK108743, R01CA172025, R01CA207177, R01CA192642, R01CA218254]
- Medical Research Council [MC_UU_00007/7, MC_PC_U127584479] Funding Source: researchfish
- MRC [MC_PC_U127584479, MC_UU_00007/7] Funding Source: UKRI
Most colorectal cancer (CRC)-related deaths are due to liver metastases. PKC zeta 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 zeta deficiency. The regulation of the intracellular levels of miR-200 by PKC zeta is post-transcriptional and involves their secretion in extracellular vesicles. Here, we identified ADAR2 as a direct substrate of PKC zeta in CRC cells. Phosphorylation of ADAR2 regulates its editing activity, which is required to maintain miR-200 steady-state levels, suggesting that the PKC zeta/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 zeta/ADAR2 axis is a critical regulator of CRC metastases through modulation of miR-200 levels.
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