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

Shelton, Phillip M. et al.

Cell reports. Volume 23:Number 4 (2018, April 24th); pp 1178-1191 -- Elsevier

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  • Title:
    The Secretion of miR-200s by a PKCζ/ADAR2 Signaling Axis Promotes Liver Metastasis in Colorectal Cancer
  • Author: 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
  • Found In: Cell reports. Volume 23:Number 4 (2018, April 24th); pp 1178-1191
  • Journal Title: Cell reports
  • Subjects: Biology--Periodicals; Life sciences--Periodicals; PRKCZ--atypical PKC--ADAR2--colorectal cancer--metastasis--EMT--mir-200--extracellular vesicles--tumor suppressors--RNA editing; Dewey: 571.6; Dewey: 571.6
  • Rights: Licensed
  • Publication Details: Elsevier
  • Abstract: Summary 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. Graphical Abstract Highlights Loss of PKCζ results in increased secretion of miR-200s, EMT, and liver metastases PKCζ phosphorylates and activates ADAR2 gene editing activity PKCζ-phosphorylated ADAR2 promotes the accumulation of miR-200s ADAR2 regulation is a key vulnerability of PKCζ-deficient cancer cells 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.
  • Identifier: System Number: ETOCvdc_100065824259.0x000001; Journal ISSN: 2211-1247; 10.1016/j.celrep.2018.03.118
  • Publication Date: 2018
  • Physical Description: Electronic
  • UIN: ETOCvdc_100065824259.0x000001

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