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Synthetic miR-143 Inhibits Growth of HER2-Positive Gastric Cancer Cells by Suppressing KRAS Networks Including DDX6 RNA Helicase

Gastric cancer (GC) is one of the most common cancers worldwide. In the clinical setting, the identification of HER2 overexpression in GC was a significant finding, as trastuzumab, an anti-HER2 drug, provides a survival advantage to HER2-positive GC patients. In HER2-postive GC, the dysregulation of...

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Autores principales: Tokumaru, Yoshihisa, Tajirika, Toshihiro, Sugito, Nobuhiko, Kuranaga, Yuki, Shinohara, Haruka, Tsujino, Takuya, Matsuhashi, Nobuhisa, Futamura, Manabu, Akao, Yukihiro, Yoshida, Kazuhiro
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6479539/
https://www.ncbi.nlm.nih.gov/pubmed/30959742
http://dx.doi.org/10.3390/ijms20071697
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author Tokumaru, Yoshihisa
Tajirika, Toshihiro
Sugito, Nobuhiko
Kuranaga, Yuki
Shinohara, Haruka
Tsujino, Takuya
Matsuhashi, Nobuhisa
Futamura, Manabu
Akao, Yukihiro
Yoshida, Kazuhiro
author_facet Tokumaru, Yoshihisa
Tajirika, Toshihiro
Sugito, Nobuhiko
Kuranaga, Yuki
Shinohara, Haruka
Tsujino, Takuya
Matsuhashi, Nobuhisa
Futamura, Manabu
Akao, Yukihiro
Yoshida, Kazuhiro
author_sort Tokumaru, Yoshihisa
collection PubMed
description Gastric cancer (GC) is one of the most common cancers worldwide. In the clinical setting, the identification of HER2 overexpression in GC was a significant finding, as trastuzumab, an anti-HER2 drug, provides a survival advantage to HER2-positive GC patients. In HER2-postive GC, the dysregulation of PI3K/AKT and MAPK/ERK signaling pathways has been reported, and inhibition of these pathways is an important therapeutic strategy. MiR-143 is known to act as a tumor suppressor in several cancers, such as bladder cancer, breast cancer, colorectal cancer, and gastric cancer. In the current study, we developed a novel chemically-modified miR-143 and explored the functions of this synthetic miR-143 (syn-miR-143) in HER2-positive gastric cancer. The expression level of miR-143 was down-regulated in GC cell lines, including HER2-positive GC cell lines, MKN7, and KATO-III. The ectopic expression of miR-143 in those cell lines suppressed cell growth through systemic silencing of KRAS and its effector signaling molecules, AKT and ERK. Furthermore, syn-miR-143 indirectly down-regulated the expression of HER2, an upstream molecule of KRAS, through silencing DEAD/H-box RNA helicase 6 (DDX6), RNA helicase, which enhanced HER2 protein expression at the translational step in HER2-positive GC cells. These findings suggested that syn-miR-143 acted as a tumor suppressor through the impairment of KRAS networks including the DDX6.
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spelling pubmed-64795392019-04-29 Synthetic miR-143 Inhibits Growth of HER2-Positive Gastric Cancer Cells by Suppressing KRAS Networks Including DDX6 RNA Helicase Tokumaru, Yoshihisa Tajirika, Toshihiro Sugito, Nobuhiko Kuranaga, Yuki Shinohara, Haruka Tsujino, Takuya Matsuhashi, Nobuhisa Futamura, Manabu Akao, Yukihiro Yoshida, Kazuhiro Int J Mol Sci Article Gastric cancer (GC) is one of the most common cancers worldwide. In the clinical setting, the identification of HER2 overexpression in GC was a significant finding, as trastuzumab, an anti-HER2 drug, provides a survival advantage to HER2-positive GC patients. In HER2-postive GC, the dysregulation of PI3K/AKT and MAPK/ERK signaling pathways has been reported, and inhibition of these pathways is an important therapeutic strategy. MiR-143 is known to act as a tumor suppressor in several cancers, such as bladder cancer, breast cancer, colorectal cancer, and gastric cancer. In the current study, we developed a novel chemically-modified miR-143 and explored the functions of this synthetic miR-143 (syn-miR-143) in HER2-positive gastric cancer. The expression level of miR-143 was down-regulated in GC cell lines, including HER2-positive GC cell lines, MKN7, and KATO-III. The ectopic expression of miR-143 in those cell lines suppressed cell growth through systemic silencing of KRAS and its effector signaling molecules, AKT and ERK. Furthermore, syn-miR-143 indirectly down-regulated the expression of HER2, an upstream molecule of KRAS, through silencing DEAD/H-box RNA helicase 6 (DDX6), RNA helicase, which enhanced HER2 protein expression at the translational step in HER2-positive GC cells. These findings suggested that syn-miR-143 acted as a tumor suppressor through the impairment of KRAS networks including the DDX6. MDPI 2019-04-05 /pmc/articles/PMC6479539/ /pubmed/30959742 http://dx.doi.org/10.3390/ijms20071697 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Tokumaru, Yoshihisa
Tajirika, Toshihiro
Sugito, Nobuhiko
Kuranaga, Yuki
Shinohara, Haruka
Tsujino, Takuya
Matsuhashi, Nobuhisa
Futamura, Manabu
Akao, Yukihiro
Yoshida, Kazuhiro
Synthetic miR-143 Inhibits Growth of HER2-Positive Gastric Cancer Cells by Suppressing KRAS Networks Including DDX6 RNA Helicase
title Synthetic miR-143 Inhibits Growth of HER2-Positive Gastric Cancer Cells by Suppressing KRAS Networks Including DDX6 RNA Helicase
title_full Synthetic miR-143 Inhibits Growth of HER2-Positive Gastric Cancer Cells by Suppressing KRAS Networks Including DDX6 RNA Helicase
title_fullStr Synthetic miR-143 Inhibits Growth of HER2-Positive Gastric Cancer Cells by Suppressing KRAS Networks Including DDX6 RNA Helicase
title_full_unstemmed Synthetic miR-143 Inhibits Growth of HER2-Positive Gastric Cancer Cells by Suppressing KRAS Networks Including DDX6 RNA Helicase
title_short Synthetic miR-143 Inhibits Growth of HER2-Positive Gastric Cancer Cells by Suppressing KRAS Networks Including DDX6 RNA Helicase
title_sort synthetic mir-143 inhibits growth of her2-positive gastric cancer cells by suppressing kras networks including ddx6 rna helicase
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6479539/
https://www.ncbi.nlm.nih.gov/pubmed/30959742
http://dx.doi.org/10.3390/ijms20071697
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