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Concurrent Targeting of KRAS and AKT by MiR-4689 Is a Novel Treatment Against Mutant KRAS Colorectal Cancer

KRAS mutations are a major cause of drug resistance to molecular-targeted therapies. Aberrant epidermal growth factor receptor (EGFR) signaling may cause dysregulation of microRNA (miRNA) and gene regulatory networks, which leads to cancer initiation and progression. To address the functional releva...

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Autores principales: Hiraki, Masayuki, Nishimura, Junichi, Takahashi, Hidekazu, Wu, Xin, Takahashi, Yusuke, Miyo, Masaaki, Nishida, Naohiro, Uemura, Mamoru, Hata, Taishi, Takemasa, Ichiro, Mizushima, Tsunekazu, Soh, Jae-Won, Doki, Yuichiro, Mori, Masaki, Yamamoto, Hirofumi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4354340/
https://www.ncbi.nlm.nih.gov/pubmed/25756961
http://dx.doi.org/10.1038/mtna.2015.5
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author Hiraki, Masayuki
Nishimura, Junichi
Takahashi, Hidekazu
Wu, Xin
Takahashi, Yusuke
Miyo, Masaaki
Nishida, Naohiro
Uemura, Mamoru
Hata, Taishi
Takemasa, Ichiro
Mizushima, Tsunekazu
Soh, Jae-Won
Doki, Yuichiro
Mori, Masaki
Yamamoto, Hirofumi
author_facet Hiraki, Masayuki
Nishimura, Junichi
Takahashi, Hidekazu
Wu, Xin
Takahashi, Yusuke
Miyo, Masaaki
Nishida, Naohiro
Uemura, Mamoru
Hata, Taishi
Takemasa, Ichiro
Mizushima, Tsunekazu
Soh, Jae-Won
Doki, Yuichiro
Mori, Masaki
Yamamoto, Hirofumi
author_sort Hiraki, Masayuki
collection PubMed
description KRAS mutations are a major cause of drug resistance to molecular-targeted therapies. Aberrant epidermal growth factor receptor (EGFR) signaling may cause dysregulation of microRNA (miRNA) and gene regulatory networks, which leads to cancer initiation and progression. To address the functional relevance of miRNAs in mutant KRAS cancers, we transfected exogenous KRAS(G12V) into human embryonic kidney 293 and MRC5 cells with wild-type KRAS and BRAF genes, and we comprehensively profiled the dysregulated miRNAs. The result showed that mature miRNA oligonucleotide (miR)-4689, one of the significantly down-regulated miRNAs in KRAS(G12V) overexpressed cells, was found to exhibit a potent growth-inhibitory and proapoptotic effect both in vitro and in vivo. miR-4689 expression was significantly down-regulated in cancer tissues compared to normal mucosa, and it was particularly decreased in mutant KRAS CRC tissues. miR-4689 directly targets v-ki-ras2 kirsten rat sarcoma viral oncogene homolog (KRAS) and v-akt murine thymoma viral oncogene homolog 1(AKT1), key components of two major branches in EGFR pathway, suggesting KRAS overdrives this signaling pathway through inhibition of miR-4689. Overall, this study provided additional evidence that mutant KRAS functions as a broad regulator of the EGFR signaling cascade by inhibiting miR-4689, which negatively regulates both RAS/mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K)/AKT pathways. These activities indicated that miR-4689 may be a promising therapeutic agent in mutant KRAS CRC.
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spelling pubmed-43543402015-03-17 Concurrent Targeting of KRAS and AKT by MiR-4689 Is a Novel Treatment Against Mutant KRAS Colorectal Cancer Hiraki, Masayuki Nishimura, Junichi Takahashi, Hidekazu Wu, Xin Takahashi, Yusuke Miyo, Masaaki Nishida, Naohiro Uemura, Mamoru Hata, Taishi Takemasa, Ichiro Mizushima, Tsunekazu Soh, Jae-Won Doki, Yuichiro Mori, Masaki Yamamoto, Hirofumi Mol Ther Nucleic Acids Original Article KRAS mutations are a major cause of drug resistance to molecular-targeted therapies. Aberrant epidermal growth factor receptor (EGFR) signaling may cause dysregulation of microRNA (miRNA) and gene regulatory networks, which leads to cancer initiation and progression. To address the functional relevance of miRNAs in mutant KRAS cancers, we transfected exogenous KRAS(G12V) into human embryonic kidney 293 and MRC5 cells with wild-type KRAS and BRAF genes, and we comprehensively profiled the dysregulated miRNAs. The result showed that mature miRNA oligonucleotide (miR)-4689, one of the significantly down-regulated miRNAs in KRAS(G12V) overexpressed cells, was found to exhibit a potent growth-inhibitory and proapoptotic effect both in vitro and in vivo. miR-4689 expression was significantly down-regulated in cancer tissues compared to normal mucosa, and it was particularly decreased in mutant KRAS CRC tissues. miR-4689 directly targets v-ki-ras2 kirsten rat sarcoma viral oncogene homolog (KRAS) and v-akt murine thymoma viral oncogene homolog 1(AKT1), key components of two major branches in EGFR pathway, suggesting KRAS overdrives this signaling pathway through inhibition of miR-4689. Overall, this study provided additional evidence that mutant KRAS functions as a broad regulator of the EGFR signaling cascade by inhibiting miR-4689, which negatively regulates both RAS/mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K)/AKT pathways. These activities indicated that miR-4689 may be a promising therapeutic agent in mutant KRAS CRC. Nature Publishing Group 2015-03 2015-03-10 /pmc/articles/PMC4354340/ /pubmed/25756961 http://dx.doi.org/10.1038/mtna.2015.5 Text en Copyright © 2015 American Society of Gene & Cell Therapy http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Original Article
Hiraki, Masayuki
Nishimura, Junichi
Takahashi, Hidekazu
Wu, Xin
Takahashi, Yusuke
Miyo, Masaaki
Nishida, Naohiro
Uemura, Mamoru
Hata, Taishi
Takemasa, Ichiro
Mizushima, Tsunekazu
Soh, Jae-Won
Doki, Yuichiro
Mori, Masaki
Yamamoto, Hirofumi
Concurrent Targeting of KRAS and AKT by MiR-4689 Is a Novel Treatment Against Mutant KRAS Colorectal Cancer
title Concurrent Targeting of KRAS and AKT by MiR-4689 Is a Novel Treatment Against Mutant KRAS Colorectal Cancer
title_full Concurrent Targeting of KRAS and AKT by MiR-4689 Is a Novel Treatment Against Mutant KRAS Colorectal Cancer
title_fullStr Concurrent Targeting of KRAS and AKT by MiR-4689 Is a Novel Treatment Against Mutant KRAS Colorectal Cancer
title_full_unstemmed Concurrent Targeting of KRAS and AKT by MiR-4689 Is a Novel Treatment Against Mutant KRAS Colorectal Cancer
title_short Concurrent Targeting of KRAS and AKT by MiR-4689 Is a Novel Treatment Against Mutant KRAS Colorectal Cancer
title_sort concurrent targeting of kras and akt by mir-4689 is a novel treatment against mutant kras colorectal cancer
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4354340/
https://www.ncbi.nlm.nih.gov/pubmed/25756961
http://dx.doi.org/10.1038/mtna.2015.5
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