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.
Highlights
The liver is an organ that develops primary and metastatic tumors
We examined whether ADP-ribosylation factor-like 4c (ARL4C) is involved in the proliferation of cancer cells in the liver and if ARL4C antisense oligonucleotides (ASO) could
The key findings were: (i) ARL4C is a prognostic factor for Hepatocellular carcinoma (HCC) and colorectal cancer; (ii) ARL4C upregulated PIK3CD in HCC; and (iii) ARL4C ASO inhibited liver tumor formation in two independent mouse models
Summary
The liver is an organ that develops primary and metastatic tumors. Hepatocellular carcinoma (HCC) is the fifth common type of cancer worldwide and the third leading cause of cancer death [1]. The median survival is approximately 6 to 20 months after diagnosis for the intermediate and advanced stages, and the 5-year survival of patients with HCC is less than 30%. Even after apparently curative surgical resection, recurrent HCC develops in 80% of patients within 5 years because of intrahepatic metastasis. For unresectable HCC, different treatment modalities are available, including radiation, radioembolization, systemic chemo-. Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).
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