Chemically Modified Antisense Oligonucleotide Against ARL4C Inhibits Primary and Metastatic Liver Tumor Growth
Chemically Modified Antisense Oligonucleotide Against ARL4C Inhibits Primary and Metastatic Liver Tumor Growth
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DOI：
10.1158/1535-7163.mct-18-0824
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发表时间：
2019-03-01
影响因子：
5.7
通讯作者：
Kikuchi, Akira
中科院分区：
文献类型：
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作者：
Harada, Takeshi;Matsumoto, Shinji;Kikuchi, Akira
ADP核糖化因子样蛋白4c(ARL4C)是一种小的GTP结合蛋白，通过Wnt和EGF信号转导途径表达，在培养细胞和输尿管小管的发生中起重要作用。ARL4C在成人组织中表达很少，但在肺癌和结直肠癌中高表达，根据siRNA实验表明，它代表了癌症治疗的分子靶点。本研究揭示ARL4C在原发性肝细胞癌和结直肠癌肝转移中的高表达，并且ARL4C的表达与这些癌症的预后不良有关。针对ARL4C的化学修饰的反义寡核苷酸(ASO)有效地降低了肝癌细胞和结直肠癌细胞中ARL4C的表达，并在体外抑制了这些癌细胞的增殖和迁移。ARL4C ASOS降低肝癌细胞中PIK3CD的mRNA水平，抑制AKT活性，提示ARL4C在肝癌细胞中的下游信号转导途径与肺癌和结肠癌细胞不同。此外，皮下注射ARL4C ASO可有效抑制免疫缺陷小鼠肝内原发肝癌和转移性结直肠癌的生长。ARL4C ASO在肿瘤细胞中的积聚比在肝脏周围正常细胞中更有效，并降低了肿瘤中ARL4C的表达。这些结果表明，ARL4C ASO是一种新的靶向核酸药物，用于治疗原发性和转移性肝癌。
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.