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miR-29a inhibition normalizes HuR over-expression and aberrant AU-rich mRNA stability in invasive cancer

The activities of RNA-binding proteins are perturbed in several pathological conditions, including cancer. These proteins include tristetraprolin (TTP, ZFP36) and HuR (ELAVL1), which respectively promote the decay or stability of adenylate-uridylate-rich (AU-rich) mRNAs. Here, we demonstrated that i...

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Autores principales: Al-Ahmadi, Wijdan, Al-Ghamdi, Maha, Al-Souhibani, Norah, Khabar, Khalid SA
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley & Sons, Ltd 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3732382/
https://www.ncbi.nlm.nih.gov/pubmed/23401122
http://dx.doi.org/10.1002/path.4178
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author Al-Ahmadi, Wijdan
Al-Ghamdi, Maha
Al-Souhibani, Norah
Khabar, Khalid SA
author_facet Al-Ahmadi, Wijdan
Al-Ghamdi, Maha
Al-Souhibani, Norah
Khabar, Khalid SA
author_sort Al-Ahmadi, Wijdan
collection PubMed
description The activities of RNA-binding proteins are perturbed in several pathological conditions, including cancer. These proteins include tristetraprolin (TTP, ZFP36) and HuR (ELAVL1), which respectively promote the decay or stability of adenylate-uridylate-rich (AU-rich) mRNAs. Here, we demonstrated that increased stabilization and subsequent over-expression of HuR mRNA were coupled to TTP deficiency. These findings were observed in breast cancer cell lines with an invasive phenotype and were further confirmed in ZFP36-knockout mouse fibroblasts. We show that TTP–HuR imbalance correlated with increased expression of AU-rich element (ARE) mRNAs that code for cancer invasion genes. The microRNA miR-29a was abundant in invasive breast cancer cells when compared to non-tumourigenic cell types. When normal breast cells were treated with miR-29a, HuR mRNA and protein expression were up-regulated. MiR-29a recognized a seed target in the TTP 3′ UTR and a cell-permeable miR-29a inhibitor increased TTP activity towards HuR 3′ UTR. This led to HuR mRNA destabilization and restoration of the aberrant TTP–HuR axis. Subsequently, the cancer invasion factors uPA, MMP-1 and MMP-13, and cell invasiveness, were decreased. The TTP:HuR mRNA ratios were also perturbed in samples from invasive breast cancer patients when compared with normal tissues, and were associated with invasion gene expression. This study demonstrates that an aberrant ARE-mediated pathway in invasive cancer can be normalized by targeting the aberrant and functionally coupled TTP–HuR axis, indicating a potential therapeutic approach. Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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spelling pubmed-37323822013-08-05 miR-29a inhibition normalizes HuR over-expression and aberrant AU-rich mRNA stability in invasive cancer Al-Ahmadi, Wijdan Al-Ghamdi, Maha Al-Souhibani, Norah Khabar, Khalid SA J Pathol Original Papers The activities of RNA-binding proteins are perturbed in several pathological conditions, including cancer. These proteins include tristetraprolin (TTP, ZFP36) and HuR (ELAVL1), which respectively promote the decay or stability of adenylate-uridylate-rich (AU-rich) mRNAs. Here, we demonstrated that increased stabilization and subsequent over-expression of HuR mRNA were coupled to TTP deficiency. These findings were observed in breast cancer cell lines with an invasive phenotype and were further confirmed in ZFP36-knockout mouse fibroblasts. We show that TTP–HuR imbalance correlated with increased expression of AU-rich element (ARE) mRNAs that code for cancer invasion genes. The microRNA miR-29a was abundant in invasive breast cancer cells when compared to non-tumourigenic cell types. When normal breast cells were treated with miR-29a, HuR mRNA and protein expression were up-regulated. MiR-29a recognized a seed target in the TTP 3′ UTR and a cell-permeable miR-29a inhibitor increased TTP activity towards HuR 3′ UTR. This led to HuR mRNA destabilization and restoration of the aberrant TTP–HuR axis. Subsequently, the cancer invasion factors uPA, MMP-1 and MMP-13, and cell invasiveness, were decreased. The TTP:HuR mRNA ratios were also perturbed in samples from invasive breast cancer patients when compared with normal tissues, and were associated with invasion gene expression. This study demonstrates that an aberrant ARE-mediated pathway in invasive cancer can be normalized by targeting the aberrant and functionally coupled TTP–HuR axis, indicating a potential therapeutic approach. Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. John Wiley & Sons, Ltd 2013-05 2013-03-21 /pmc/articles/PMC3732382/ /pubmed/23401122 http://dx.doi.org/10.1002/path.4178 Text en Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. http://creativecommons.org/licenses/by/2.5/ Re-use of this article is permitted in accordance with the Creative Commons Deed, Attribution 2.5, which does not permit commercial exploitation.
spellingShingle Original Papers
Al-Ahmadi, Wijdan
Al-Ghamdi, Maha
Al-Souhibani, Norah
Khabar, Khalid SA
miR-29a inhibition normalizes HuR over-expression and aberrant AU-rich mRNA stability in invasive cancer
title miR-29a inhibition normalizes HuR over-expression and aberrant AU-rich mRNA stability in invasive cancer
title_full miR-29a inhibition normalizes HuR over-expression and aberrant AU-rich mRNA stability in invasive cancer
title_fullStr miR-29a inhibition normalizes HuR over-expression and aberrant AU-rich mRNA stability in invasive cancer
title_full_unstemmed miR-29a inhibition normalizes HuR over-expression and aberrant AU-rich mRNA stability in invasive cancer
title_short miR-29a inhibition normalizes HuR over-expression and aberrant AU-rich mRNA stability in invasive cancer
title_sort mir-29a inhibition normalizes hur over-expression and aberrant au-rich mrna stability in invasive cancer
topic Original Papers
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3732382/
https://www.ncbi.nlm.nih.gov/pubmed/23401122
http://dx.doi.org/10.1002/path.4178
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