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

doi:10.1016/j.celrep.2018.03.118

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 journal › Article › peer-review

Abstract / Description of output

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 language	English
Pages (from-to)	1178-1191
Number of pages	14
Journal	Cell Reports
Volume	23
Issue number	4
DOIs	https://doi.org/10.1016/j.celrep.2018.03.118
Publication status	Published - 24 Apr 2018

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Journal Article

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10.1016/j.celrep.2018.03.118

The Secretion of miR_200s by a PKCz ADAR2Final published version, 6.82 MBLicence: Creative Commons: Attribution (CC-BY)

Post-transcriptional regulation of Gene Expression
Caceres, J.
1/04/18 → 31/03/23
Project: Research

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Shelton, P. M., Duran, A., Nakanishi, Y., Reina-Campos, M., Kasashima, H., Llado, V., Ma, L., Campos, A., García-Olmo, D., García-Arranz, M., García-Olmo, D. C., Olmedillas-López, S., Caceres, J. F., Diaz-Meco, M. T., & Moscat, J. (2018). The Secretion of miR-200s by a PKCζ/ADAR2 Signaling Axis Promotes Liver Metastasis in Colorectal Cancer. Cell Reports, 23(4), 1178-1191. https://doi.org/10.1016/j.celrep.2018.03.118

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

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.",

keywords = "Journal Article",

author = "Shelton, {Phillip M} and Angeles Duran and Yuki Nakanishi and Miguel Reina-Campos and Hiroaki Kasashima and Victoria Llado and Li Ma and Alex Campos and Dami{\'a}n Garc{\'i}a-Olmo and Mariano Garc{\'i}a-Arranz and Garc{\'i}a-Olmo, {Dolores C} and Susana Olmedillas-L{\'o}pez and Caceres, {Javier F} and Diaz-Meco, {Maria T} and Jorge Moscat",

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Shelton, PM, Duran, A, Nakanishi, Y, Reina-Campos, M, Kasashima, H, Llado, V, Ma, L, Campos, A, García-Olmo, D, García-Arranz, M, García-Olmo, DC, Olmedillas-López, S, Caceres, JF, Diaz-Meco, MT & Moscat, J 2018, 'The Secretion of miR-200s by a PKCζ/ADAR2 Signaling Axis Promotes Liver Metastasis in Colorectal Cancer', Cell Reports, vol. 23, no. 4, pp. 1178-1191. https://doi.org/10.1016/j.celrep.2018.03.118

TY - JOUR

T1 - The Secretion of miR-200s by a PKCζ/ADAR2 Signaling Axis Promotes Liver Metastasis in Colorectal Cancer

AU - Shelton, Phillip M

AU - Duran, Angeles

AU - Nakanishi, Yuki

AU - Reina-Campos, Miguel

AU - Kasashima, Hiroaki

AU - Llado, Victoria

AU - Ma, Li

AU - Campos, Alex

AU - García-Olmo, Damián

AU - García-Arranz, Mariano

AU - García-Olmo, Dolores C

AU - Olmedillas-López, Susana

AU - Caceres, Javier F

AU - Diaz-Meco, Maria T

AU - Moscat, Jorge

PY - 2018/4/24

Y1 - 2018/4/24

N2 - 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.

AB - 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.

KW - Journal Article

U2 - 10.1016/j.celrep.2018.03.118

DO - 10.1016/j.celrep.2018.03.118

M3 - Article

C2 - 29694894

SN - 2211-1247

VL - 23

SP - 1178

EP - 1191

JO - Cell Reports

JF - Cell Reports

IS - 4

ER -

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

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Post-transcriptional regulation of Gene Expression

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