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Chemically modified MIR143-3p exhibited anti-cancer effects by impairing the KRAS network in colorectal cancer cells

Kirsten rat sarcoma virus (KRAS) mutations are frequently detected in many cancers and are major driver genes. Therefore, KRAS inhibitors have been the subject of extensive research. We developed chemically modified MIR143-3p (MIR143#12), which exhibits higher anticancer activity and nuclease resist...

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Autores principales: Sugito, Nobuhiko, Heishima, Kazuki, Akao, Yukihiro
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society of Gene & Cell Therapy 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9507988/
https://www.ncbi.nlm.nih.gov/pubmed/36189421
http://dx.doi.org/10.1016/j.omtn.2022.09.001
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author Sugito, Nobuhiko
Heishima, Kazuki
Akao, Yukihiro
author_facet Sugito, Nobuhiko
Heishima, Kazuki
Akao, Yukihiro
author_sort Sugito, Nobuhiko
collection PubMed
description Kirsten rat sarcoma virus (KRAS) mutations are frequently detected in many cancers and are major driver genes. Therefore, KRAS inhibitors have been the subject of extensive research. We developed chemically modified MIR143-3p (MIR143#12), which exhibits higher anticancer activity and nuclease resistance than other commercial inhibitors. MIR143#12 potently suppressed cell growth in colorectal and pancreatic cancer cell lines via apoptosis induced by repression of the entire rat sarcoma virus (RAS) network, which was achieved by silencing KRAS, Son of sevenless homolog 1 (SOS1), AKT, and extracellular signal-regulated kinase (ERK). We investigated the mechanistic advantages of MIR143#12 in various KRAS mutant colorectal cancer cell lines. Its effects were stronger than those of knockdown of KRAS alone in colon cancer cells because silencing of KRAS by small interfering RNA (siRNA) did not decrease the protein expression levels of AKT or ERKs. The KRAS mRNA recruitment system, called the “positive circuit” under effector signaling pathways, may contribute to insensitivity of KRAS mutant cancers to MIR143#12 and siRNAs. In an in vivo study, we newly demonstrated that MIR143#12 induced neoangiogenesis in the tumor microenvironment with growth suppression. Based on the present results, it is crucial to down-regulate not only KRAS but also the entire KRAS signaling network, which may be accomplished by MIR143#12.
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spelling pubmed-95079882022-09-30 Chemically modified MIR143-3p exhibited anti-cancer effects by impairing the KRAS network in colorectal cancer cells Sugito, Nobuhiko Heishima, Kazuki Akao, Yukihiro Mol Ther Nucleic Acids Original Article Kirsten rat sarcoma virus (KRAS) mutations are frequently detected in many cancers and are major driver genes. Therefore, KRAS inhibitors have been the subject of extensive research. We developed chemically modified MIR143-3p (MIR143#12), which exhibits higher anticancer activity and nuclease resistance than other commercial inhibitors. MIR143#12 potently suppressed cell growth in colorectal and pancreatic cancer cell lines via apoptosis induced by repression of the entire rat sarcoma virus (RAS) network, which was achieved by silencing KRAS, Son of sevenless homolog 1 (SOS1), AKT, and extracellular signal-regulated kinase (ERK). We investigated the mechanistic advantages of MIR143#12 in various KRAS mutant colorectal cancer cell lines. Its effects were stronger than those of knockdown of KRAS alone in colon cancer cells because silencing of KRAS by small interfering RNA (siRNA) did not decrease the protein expression levels of AKT or ERKs. The KRAS mRNA recruitment system, called the “positive circuit” under effector signaling pathways, may contribute to insensitivity of KRAS mutant cancers to MIR143#12 and siRNAs. In an in vivo study, we newly demonstrated that MIR143#12 induced neoangiogenesis in the tumor microenvironment with growth suppression. Based on the present results, it is crucial to down-regulate not only KRAS but also the entire KRAS signaling network, which may be accomplished by MIR143#12. American Society of Gene & Cell Therapy 2022-09-07 /pmc/articles/PMC9507988/ /pubmed/36189421 http://dx.doi.org/10.1016/j.omtn.2022.09.001 Text en © 2022 The Author(s) https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Original Article
Sugito, Nobuhiko
Heishima, Kazuki
Akao, Yukihiro
Chemically modified MIR143-3p exhibited anti-cancer effects by impairing the KRAS network in colorectal cancer cells
title Chemically modified MIR143-3p exhibited anti-cancer effects by impairing the KRAS network in colorectal cancer cells
title_full Chemically modified MIR143-3p exhibited anti-cancer effects by impairing the KRAS network in colorectal cancer cells
title_fullStr Chemically modified MIR143-3p exhibited anti-cancer effects by impairing the KRAS network in colorectal cancer cells
title_full_unstemmed Chemically modified MIR143-3p exhibited anti-cancer effects by impairing the KRAS network in colorectal cancer cells
title_short Chemically modified MIR143-3p exhibited anti-cancer effects by impairing the KRAS network in colorectal cancer cells
title_sort chemically modified mir143-3p exhibited anti-cancer effects by impairing the kras network in colorectal cancer cells
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9507988/
https://www.ncbi.nlm.nih.gov/pubmed/36189421
http://dx.doi.org/10.1016/j.omtn.2022.09.001
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