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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...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society of Gene & Cell Therapy
2022
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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. |
format | Online Article Text |
id | pubmed-9507988 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | American Society of Gene & Cell Therapy |
record_format | MEDLINE/PubMed |
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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