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miR-4443 Participates in the Malignancy of Breast Cancer
PURPOSE: Chemo-resistance is the leading cause of failure in cancer therapy, however, much remains to be understood about the intrinsic mechanisms. In the present study, we discovered the novel miR-4443 that regulated malignancy of breast cancer both in vitro and in vivo. METHODS: We examined the ex...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4978484/ https://www.ncbi.nlm.nih.gov/pubmed/27504971 http://dx.doi.org/10.1371/journal.pone.0160780 |
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author | Chen, Xiu Zhong, Shan-liang Lu, Peng Wang, Dan-dan Zhou, Si-ying Yang, Su-jin Shen, Hong-yu Zhang, Lei Zhang, Xiao-hui Zhao, Jian-hua Tang, Jin-hai |
author_facet | Chen, Xiu Zhong, Shan-liang Lu, Peng Wang, Dan-dan Zhou, Si-ying Yang, Su-jin Shen, Hong-yu Zhang, Lei Zhang, Xiao-hui Zhao, Jian-hua Tang, Jin-hai |
author_sort | Chen, Xiu |
collection | PubMed |
description | PURPOSE: Chemo-resistance is the leading cause of failure in cancer therapy, however, much remains to be understood about the intrinsic mechanisms. In the present study, we discovered the novel miR-4443 that regulated malignancy of breast cancer both in vitro and in vivo. METHODS: We examined the expression of miR-4443 in MDA-MB-231/S and MDA-MB-231 Epirubicin-resistant cell lines with 76 breast cancer formalin-fixed paraffin-embedded tissues by real-time PCR. Also, we investigated the loss- and gain-functions of miR-4443 by MTT assay and flow cytometry. Furthermore, we detected miR-4443 mediated tissue inhibitor of metalloproteinase 2 expression in cells by TargetScan, RT-qPCR and western blot. RESULTS: We identified the up-regulated expression of miR-4443 in Epi-resistant cell lines versus MDA-MB-231/S cell(Epi versus S) and in post-chemotherapy FFPE tissues, along with statistically differential expressions in PR(partial response) versus SD(stable disease)/PD(progressive disease) patients. Overexpression of miR-4443 increased the IC50 value of Epi for the target cells transfected, while inhibition of miR-4443 could restored sensitivity of the target cells to Epi. Besides, down-regulation of endogenous miR-4443 by miRNA-inhibitors significantly enhanced Epi-induced apoptosis while up-regulation of miR-4443 by miRNA-mimics lead to less Epi-induced apoptotic cells. Consequently, changes in TIMP2 mRNA and protein expression revealed that miR-4443 mimics suppressed expression of TIMP2 and induced migration in breast cancer cells. Furthermore, TIMP2 expression associated with better prognosis(HR = 0.721, 95%CI: 0.529–0.983). CONCLUSIONS: We revealed that miR-4443 induced malignancy of breast cancer mainly in chemo-resistance aspect for the very first time, providing a novel biomarker in breast cancer diagnosis and therapy. |
format | Online Article Text |
id | pubmed-4978484 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-49784842016-08-25 miR-4443 Participates in the Malignancy of Breast Cancer Chen, Xiu Zhong, Shan-liang Lu, Peng Wang, Dan-dan Zhou, Si-ying Yang, Su-jin Shen, Hong-yu Zhang, Lei Zhang, Xiao-hui Zhao, Jian-hua Tang, Jin-hai PLoS One Research Article PURPOSE: Chemo-resistance is the leading cause of failure in cancer therapy, however, much remains to be understood about the intrinsic mechanisms. In the present study, we discovered the novel miR-4443 that regulated malignancy of breast cancer both in vitro and in vivo. METHODS: We examined the expression of miR-4443 in MDA-MB-231/S and MDA-MB-231 Epirubicin-resistant cell lines with 76 breast cancer formalin-fixed paraffin-embedded tissues by real-time PCR. Also, we investigated the loss- and gain-functions of miR-4443 by MTT assay and flow cytometry. Furthermore, we detected miR-4443 mediated tissue inhibitor of metalloproteinase 2 expression in cells by TargetScan, RT-qPCR and western blot. RESULTS: We identified the up-regulated expression of miR-4443 in Epi-resistant cell lines versus MDA-MB-231/S cell(Epi versus S) and in post-chemotherapy FFPE tissues, along with statistically differential expressions in PR(partial response) versus SD(stable disease)/PD(progressive disease) patients. Overexpression of miR-4443 increased the IC50 value of Epi for the target cells transfected, while inhibition of miR-4443 could restored sensitivity of the target cells to Epi. Besides, down-regulation of endogenous miR-4443 by miRNA-inhibitors significantly enhanced Epi-induced apoptosis while up-regulation of miR-4443 by miRNA-mimics lead to less Epi-induced apoptotic cells. Consequently, changes in TIMP2 mRNA and protein expression revealed that miR-4443 mimics suppressed expression of TIMP2 and induced migration in breast cancer cells. Furthermore, TIMP2 expression associated with better prognosis(HR = 0.721, 95%CI: 0.529–0.983). CONCLUSIONS: We revealed that miR-4443 induced malignancy of breast cancer mainly in chemo-resistance aspect for the very first time, providing a novel biomarker in breast cancer diagnosis and therapy. Public Library of Science 2016-08-09 /pmc/articles/PMC4978484/ /pubmed/27504971 http://dx.doi.org/10.1371/journal.pone.0160780 Text en © 2016 Chen et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Chen, Xiu Zhong, Shan-liang Lu, Peng Wang, Dan-dan Zhou, Si-ying Yang, Su-jin Shen, Hong-yu Zhang, Lei Zhang, Xiao-hui Zhao, Jian-hua Tang, Jin-hai miR-4443 Participates in the Malignancy of Breast Cancer |
title | miR-4443 Participates in the Malignancy of Breast Cancer |
title_full | miR-4443 Participates in the Malignancy of Breast Cancer |
title_fullStr | miR-4443 Participates in the Malignancy of Breast Cancer |
title_full_unstemmed | miR-4443 Participates in the Malignancy of Breast Cancer |
title_short | miR-4443 Participates in the Malignancy of Breast Cancer |
title_sort | mir-4443 participates in the malignancy of breast cancer |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4978484/ https://www.ncbi.nlm.nih.gov/pubmed/27504971 http://dx.doi.org/10.1371/journal.pone.0160780 |
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