TY - JOUR
T1 - Chemically modified antisense oligonucleotide against ARL4C inhibits primary and metastatic liver tumor growth
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
N1 - Funding Information:
on Innovative Areas "Integrated analysis and regulation of cellular diversity" to A. Kikuchi (2018-2019; No. 18H05101) from the Ministry of Education, Culture, Sports, Science and Technology of Japan; by the Project Promoting Support for Drug Discovery to A. Kikuchi (2015-2018; No. DNW-15005) from the Japan Agency for Medical Research and Development, AMED, by Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives, Osaka University to A. Kikuchi; and by grants from the Yasuda Memorial Foundation to A. Kikuchi.
Publisher Copyright:
© 2019 American Association for Cancer Research.
PY - 2019/3
Y1 - 2019/3
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.
AB - 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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U2 - 10.1158/1535-7163.MCT-18-0824
DO - 10.1158/1535-7163.MCT-18-0824
M3 - Article
C2 - 30647122
AN - SCOPUS:85065235435
VL - 18
SP - 602
EP - 612
JO - Molecular Cancer Therapeutics
JF - Molecular Cancer Therapeutics
SN - 1535-7163
IS - 3
ER -
