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Coxsackie and adenovirus receptor is a critical regulator for the survival and growth of oral squamous carcinoma cells

Oncogene volume 33, pages 1274–1286 (2014)Cite this article

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Abstract

Coxsackie and adenovirus receptor (CAR) is essential for adenovirus infection to target cells, and its constitutive expression in various cancerous and normal tissues has been reported. Recently, the biological role of CAR in human cancers of several different origins has been investigated with respect to tumor progression, metastasis and tumorigenesis. However, its biological function in tumor cells remains controversial. Here we report the critical role of CAR in growth regulation of oral squamous cell carcinomas (SCCs) in vitro and in vivo via the specific interaction with Rho-associated protein kinase (ROCK). Loss of endogenous CAR expression by knockdown using specific small interfering RNA (siRNA) against CAR facilitates growth suppression of SCC cells due to cell dissociation, followed by apoptosis. The consequent morphological reaction was reminiscent of anoikis, rather than epithelial–mesenchymal transition, and the dissociation of oral SCC cells was triggered not by lack of contact with extracellular matrix, but by loss of cell-to-cell contact caused by abnormal translocation of E-cadherin from surface membrane to cytoplasm. Immunoprecipitation assays of the CAR-transfected oral SCC cell line, HSC-2, with or without ROCK inhibitor (Y-27632) revealed that CAR directly associates with ROCKI and ROCKII, which results in inhibition of ROCK activity and contributes to maintenance of cell-to-cell adhesion for their growth and survival. Based on these findings, in vivo behavior of CAR-downregulated HSC-2 cells from siRNA knockdown was compared with that of normally CAR-expressing cells in intraperitoneally xenografted mouse models. The mice engrafted with CAR siRNA-pretreated HSC-2 cells showed poor formation of metastatic foci in contrast to those implanted with the control siRNA-pretreated cells. Thus, CAR substantially has an impact on growth and survival of oral SCC cells as a negative regulator of ROCK in vitro and in vivo.

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Acknowledgements

We thank Dr Hitoshi Ohno (Takeda General Hospital, Kyoto, Japan), Professor Hirohisa Yano (Department of Pathology, Kurume University School of Medicine, Japan) and Dr Atsushi Natsume (Department of Neurosurgery, Nagoya University Graduate School of Medicine, Japan) for kindly providing us lymphoma cell line, hepatocellular carcinoma cell lines and glioma cell lines, respectively, and Dr Yasushi Yatabe (Department of Pathology and Molecular Diagnostics, Aichi Cancer Center Hospital) for advice.

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Author notes

  1. K Saito and M Sakaguchi: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Oncological Pathology, Aichi Cancer Center Research Institute, Nagoya, Japan

    K Saito, H Iioka, M Matsui, H Nakanishi & E Kondo

  2. Department of Cell Biology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan

    M Sakaguchi & N H Huh

  3. Division of Translational Research, Advanced Medical Research Center, Aichi Medical University, Nagakute, Japan

    H Iioka

  4. Department of Epidemiology, Program in Health and Community Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan

    E Kondo

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  1. K Saito
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Correspondence to E Kondo.

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Saito, K., Sakaguchi, M., Iioka, H. et al. Coxsackie and adenovirus receptor is a critical regulator for the survival and growth of oral squamous carcinoma cells. Oncogene 33, 1274–1286 (2014). https://doi.org/10.1038/onc.2013.66

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