title: Coxsackie and adenovirus receptor is a critical regulator for the survival and growth of oral squamous carcinoma cells.
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.
authors.affiliation: Division of Oncological Pathology, Aichi Cancer Center Research Institute, Nagoya, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Saito
authors.affiliation: Department of Cell Biology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Sakaguchi
authors.affiliation: 1] Division of Oncological Pathology, Aichi Cancer Center Research Institute, Nagoya, Japan [2] Division of Translational Research, Advanced Medical Research Center, Aichi Medical University, Nagakute, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Iioka
authors.affiliation: Division of Oncological Pathology, Aichi Cancer Center Research Institute, Nagoya, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Matsui
authors.affiliation: Division of Oncological Pathology, Aichi Cancer Center Research Institute, Nagoya, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Nakanishi
authors.affiliation: Department of Cell Biology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan.
authors.forename: N H
authors.initials: NH
authors.lastname: Huh
authors.affiliation: 1] Division of Oncological Pathology, Aichi Cancer Center Research Institute, Nagoya, Japan [2] Department of Epidemiology, Program in Health and Community Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: E
authors.initials: E
authors.lastname: Kondo
mesh_terms: D000818:Animals; D015703:Antigens, CD; D017209:Apoptosis; D015820:Cadherins / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000378:metabolism* / Q000556:secondary; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein / Q000502:physiology*; D005260:Female; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009062:Mouth Neoplasms / Q000378:metabolism* / Q000473:pathology; D009368:Neoplasm Transplantation; D010534:Peritoneal Neoplasms / Q000378:metabolism* / Q000556:secondary; D011485:Protein Binding; D021381:Protein Transport; D034741:RNA, Small Interfering / Q000235:genetics; D054460:rho-Associated Kinases / Q000378:metabolism
chemical_list: D015703:Antigens, CD; C513384:CDH1 protein, human; D015820:Cadherins; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D034741:RNA, Small Interfering; D054460:rho-Associated Kinases