Chemically modified antisense oligonucleotide against ARL4C inhibits primary and metastatic liver tumor growth

Takeshi Harada, Shinji Matsumoto, Suguru Hirota, Hirokazu Kimura, Shinsuke Fujii, Yuuya Kasahara, Hidetoshi Gon, Toshihiko Yoshida, Tomoo Itoh, Naotsugu Haraguchi, Tsunekazu Mizushima, Takehiro Noda, Hidetoshi Eguchi, Satoshi Nojima, Eiichi Morii, Takumi Fukumoto, Satoshi Obika, Akira Kikuchi

研究成果: ジャーナルへの寄稿記事

1 引用 (Scopus)

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ADP-ribosylation factor-like 4c (ARL4C) is identified as a small GTP-binding protein, which is expressed by Wnt and EGF signaling and plays an important role in tubulogenesis of cultured cells and the ureters. ARL4C is little expressed in adult tissues, but it is highly expressed in lung cancer and colorectal cancer and shown to represent a molecular target for cancer therapy based on siRNA experiments. This study revealed that ARL4C is highly expressed in primary hepatocellular carcinoma (HCC) tumors and colorectal cancer liver metastases, and that ARL4C expression is associated with poor prognosis for these cancers. Chemically modified antisense oligonucleotides (ASO) against ARL4C effectively reduced ARL4C expression in both HCC and colorectal cancer cells and inhibited proliferation and migration of these cancer cells in vitro. ARL4C ASOs decreased the PIK3CD mRNA levels and inhibited the activity of AKT in HCC cells, suggesting that the downstream signaling of ARL4C in HCC cells is different from that in lung and colon cancer cells. In addition, subcutaneous injection of ARL4C ASO was effective in reducing the growth of primary HCC and metastatic colorectal cancer in the liver of immunodeficient mice. ARL4C ASO accumulated in cancer cells more efficiently than the surrounding normal cells in the liver and decreased ARL4C expression in the tumor. These results suggest that ARL4C ASO represents a novel targeted nucleic acid medicine for the treatment of primary and metastatic liver cancers.

元の言語英語
ページ(範囲)602-612
ページ数11
ジャーナルMolecular Cancer Therapeutics
18
発行部数3
DOI
出版物ステータス出版済み - 3 1 2019

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ADP-Ribosylation Factors
Antisense Oligonucleotides
Liver
Growth
Neoplasms
Hepatocellular Carcinoma
Liver Neoplasms
Colorectal Neoplasms
Lung Neoplasms
Subcutaneous Injections
Ureter
GTP-Binding Proteins
Epidermal Growth Factor
Colonic Neoplasms
Nucleic Acids
Small Interfering RNA
Cell Movement

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

これを引用

Chemically modified antisense oligonucleotide against ARL4C inhibits primary and metastatic liver tumor growth. / Harada, Takeshi; Matsumoto, Shinji; Hirota, Suguru; Kimura, Hirokazu; Fujii, Shinsuke; Kasahara, Yuuya; Gon, Hidetoshi; Yoshida, Toshihiko; Itoh, Tomoo; Haraguchi, Naotsugu; Mizushima, Tsunekazu; Noda, Takehiro; Eguchi, Hidetoshi; Nojima, Satoshi; Morii, Eiichi; Fukumoto, Takumi; Obika, Satoshi; Kikuchi, Akira.

:: Molecular Cancer Therapeutics, 巻 18, 番号 3, 01.03.2019, p. 602-612.

研究成果: ジャーナルへの寄稿記事

Harada, T, Matsumoto, S, Hirota, S, Kimura, H, Fujii, S, Kasahara, Y, Gon, H, Yoshida, T, Itoh, T, Haraguchi, N, Mizushima, T, Noda, T, Eguchi, H, Nojima, S, Morii, E, Fukumoto, T, Obika, S & Kikuchi, A 2019, 'Chemically modified antisense oligonucleotide against ARL4C inhibits primary and metastatic liver tumor growth', Molecular Cancer Therapeutics, 巻. 18, 番号 3, pp. 602-612. https://doi.org/10.1158/1535-7163.MCT-18-0824
Harada, Takeshi ; Matsumoto, Shinji ; Hirota, Suguru ; Kimura, Hirokazu ; Fujii, Shinsuke ; Kasahara, Yuuya ; Gon, Hidetoshi ; Yoshida, Toshihiko ; Itoh, Tomoo ; Haraguchi, Naotsugu ; Mizushima, Tsunekazu ; Noda, Takehiro ; Eguchi, Hidetoshi ; Nojima, Satoshi ; Morii, Eiichi ; Fukumoto, Takumi ; Obika, Satoshi ; Kikuchi, Akira. / Chemically modified antisense oligonucleotide against ARL4C inhibits primary and metastatic liver tumor growth. :: Molecular Cancer Therapeutics. 2019 ; 巻 18, 番号 3. pp. 602-612.
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abstract = "ADP-ribosylation factor-like 4c (ARL4C) is identified as a small GTP-binding protein, which is expressed by Wnt and EGF signaling and plays an important role in tubulogenesis of cultured cells and the ureters. ARL4C is little expressed in adult tissues, but it is highly expressed in lung cancer and colorectal cancer and shown to represent a molecular target for cancer therapy based on siRNA experiments. This study revealed that ARL4C is highly expressed in primary hepatocellular carcinoma (HCC) tumors and colorectal cancer liver metastases, and that ARL4C expression is associated with poor prognosis for these cancers. Chemically modified antisense oligonucleotides (ASO) against ARL4C effectively reduced ARL4C expression in both HCC and colorectal cancer cells and inhibited proliferation and migration of these cancer cells in vitro. ARL4C ASOs decreased the PIK3CD mRNA levels and inhibited the activity of AKT in HCC cells, suggesting that the downstream signaling of ARL4C in HCC cells is different from that in lung and colon cancer cells. In addition, subcutaneous injection of ARL4C ASO was effective in reducing the growth of primary HCC and metastatic colorectal cancer in the liver of immunodeficient mice. ARL4C ASO accumulated in cancer cells more efficiently than the surrounding normal cells in the liver and decreased ARL4C expression in the tumor. These results suggest that ARL4C ASO represents a novel targeted nucleic acid medicine for the treatment of primary and metastatic liver cancers.",
author = "Takeshi Harada and Shinji Matsumoto and Suguru Hirota and Hirokazu Kimura and Shinsuke Fujii and Yuuya Kasahara and Hidetoshi Gon and Toshihiko Yoshida and Tomoo Itoh and Naotsugu Haraguchi and Tsunekazu Mizushima and Takehiro Noda and Hidetoshi Eguchi and Satoshi Nojima and Eiichi Morii and Takumi Fukumoto and Satoshi Obika and Akira Kikuchi",
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AU - Harada, Takeshi

AU - Matsumoto, Shinji

AU - Hirota, Suguru

AU - Kimura, Hirokazu

AU - Fujii, Shinsuke

AU - Kasahara, Yuuya

AU - Gon, Hidetoshi

AU - Yoshida, Toshihiko

AU - Itoh, Tomoo

AU - Haraguchi, Naotsugu

AU - Mizushima, Tsunekazu

AU - Noda, Takehiro

AU - Eguchi, Hidetoshi

AU - Nojima, Satoshi

AU - Morii, Eiichi

AU - Fukumoto, Takumi

AU - Obika, Satoshi

AU - Kikuchi, Akira

PY - 2019/3/1

Y1 - 2019/3/1

N2 - ADP-ribosylation factor-like 4c (ARL4C) is identified as a small GTP-binding protein, which is expressed by Wnt and EGF signaling and plays an important role in tubulogenesis of cultured cells and the ureters. ARL4C is little expressed in adult tissues, but it is highly expressed in lung cancer and colorectal cancer and shown to represent a molecular target for cancer therapy based on siRNA experiments. This study revealed that ARL4C is highly expressed in primary hepatocellular carcinoma (HCC) tumors and colorectal cancer liver metastases, and that ARL4C expression is associated with poor prognosis for these cancers. Chemically modified antisense oligonucleotides (ASO) against ARL4C effectively reduced ARL4C expression in both HCC and colorectal cancer cells and inhibited proliferation and migration of these cancer cells in vitro. ARL4C ASOs decreased the PIK3CD mRNA levels and inhibited the activity of AKT in HCC cells, suggesting that the downstream signaling of ARL4C in HCC cells is different from that in lung and colon cancer cells. In addition, subcutaneous injection of ARL4C ASO was effective in reducing the growth of primary HCC and metastatic colorectal cancer in the liver of immunodeficient mice. ARL4C ASO accumulated in cancer cells more efficiently than the surrounding normal cells in the liver and decreased ARL4C expression in the tumor. These results suggest that ARL4C ASO represents a novel targeted nucleic acid medicine for the treatment of primary and metastatic liver cancers.

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