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Arl4c expression in colorectal and lung cancers promotes tumorigenesis and may represent a novel therapeutic target

Oncogene volume 34, pages 4834–4844 (2015)Cite this article

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Abstract

We recently demonstrated that expression of ADP-ribosylation factor (ARF)-like 4c (Arl4c) induced by a combination of Wnt/β-catenin and epidermal growth factor/Ras signaling in normal epithelial cells grown in three-dimensional culture promotes cellular migration and proliferation, resulting in formation of tube-like structures, suggesting the involvement of Arl4c in epithelial morphogenesis. It is conceivable that there could be a common mechanism between epithelial morphogenesis and carcinogenesis. Therefore the current study was conducted to investigate whether Arl4c might be involved in tumorigenesis. Immunohistochemical analyses of tissue specimens obtained from colorectal and lung cancer patients revealed that Arl4c was not observed in non-tumor regions but was strongly expressed at high frequencies in tumor lesions. Inhibition of Wnt/β-catenin or Ras/mitogen-activated protein kinase signaling reduced Arl4c mRNA levels in HCT116 colorectal cancer cells and A549 lung cancer cells. Knockdown of Arl4c inhibited Rac activity and also prevented nuclear localization of yes-associated protein (YAP)/transcriptional co-activator with PDZ-binding motif (TAZ) in these cancer cells. Arl4c-depleted cancer cells consistently showed decreased migration, invasion and proliferation capabilities both in vitro and in vivo. Furthermore, direct injection of Arl4c small interfering RNA (siRNA) into HCT116 cell-derived tumors (in vivo treatment with siRNA) inhibited tumor growth in immunodeficient mice. These results suggest that Arl4c is involved in tumorigenesis and might represent a novel therapeutic target for suppressing proliferation and invasion of colorectal and lung cancer cells.

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Acknowledgements

We thank Dr Y Shintani and Dr K Shojima for valuable discussions regarding Arl4c expression and their technical assistance. We also thank Dr T Kobayashi, Dr W Yasui and Dr K Matsumoto for donating cells. This work was supported by Grants-in-Aid for Scientific Research to AK (2013–2014) (No. 25250018), SF (2014) (No. 26861547) and SM (2013–2014) (No. 25860211) and for Scientific Research on Innovative Areas to AK (2011–2014) (No. 23112004) from the Ministry of Education, Science and Culture of Japan and by grants from the Uehara Memorial Foundation.

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Authors and Affiliations

  1. Department of Molecular Biology and Biochemistry, Graduate School of Medicine, Osaka University, Suita, Japan,

    S Fujii, S Matsumoto & A Kikuchi

  2. Interdisciplinary Program for Biomedical Sciences (IPBS), Institute for Academic Initiatives, Osaka University, Suita, Japan

    S Fujii

  3. Department of Pathology, Graduate School of Medicine, Osaka University, Suita, Japan,

    S Nojima & E Morii

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  1. S Fujii
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Correspondence to A Kikuchi.

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Competing interests

SF, SM and AK have received research funds from Shionogi and Co., Ltd. The remaining authors declare no conflict of interest.

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Fujii, S., Matsumoto, S., Nojima, S. et al. Arl4c expression in colorectal and lung cancers promotes tumorigenesis and may represent a novel therapeutic target. Oncogene 34, 4834–4844 (2015). https://doi.org/10.1038/onc.2014.402

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