CENP‐R acts bilaterally as a tumor suppressor and as an oncogene in the two‐stage skin carcinogenesis model

• Published in: Cancer science Vol. 108; no. 11; pp. 2142 - 2148
• Main Authors: Okumura, Kazuhiro, Kagawa, Naoko, Saito, Megumi, Yoshizawa, Yasuhiro, Munakata, Haruka, Isogai, Eriko, Fukagawa, Tatsuo, Wakabayashi, Yuichi
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.11.2017; John Wiley and Sons Inc
• Subjects: 9,10-Dimethyl-1,2-benzanthracene; 9,10-Dimethyl-1,2-benzanthracene - toxicity; Animals; Anthracene; Apoptosis; Breast cancer; Carcinogenesis; Carcinogenesis - chemically induced; Carcinogenesis - genetics; Carcinogenesis - pathology; Carcinoma, Squamous Cell - chemically induced; Carcinoma, Squamous Cell - genetics; Carcinoma, Squamous Cell - pathology; Cell cycle; Cell Proliferation - genetics; Cell Transformation, Neoplastic - genetics; CENP; Centromere - genetics; Chromosomes; Defects; Growth factors; Humans; Kinetochores; Laboratory animals; Localization; malignant conversion; Mice; Mice, Knockout; Mitosis; mouse model; Mutation; Nuclear Proteins - genetics; Oncogene Proteins - genetics; Oncogenes; Original; Ovarian cancer; papilloma; Proteins; Rodents; Skin Neoplasms - chemically induced; Skin Neoplasms - genetics; Skin Neoplasms - pathology; Squamous cell carcinoma; Transgenic animals; Tumor suppressor genes; Tumor Suppressor Proteins - genetics; Tumors; two‐stage skin carcinogenesis; United States > US; two-stage skin carcinogenesis; CENP; mouse model; malignant conversion; papilloma
• ISSN: 1347-9032; 1349-7006
• DOI: 10.1111/cas.13348

CENP‐R is a component of the CENP‐O complex, including CENP‐O, CENP‐P, CENP‐Q, CENP‐R, and CENP‐U and is constitutively localized to kinetochores throughout the cell cycle in vertebrates. CENP‐R‐deficient chicken DT40 cells are viable and show a very minor effect on mitosis. To investigate the functional roles of CENP‐R in vivo, we generated CENP‐R‐deficient mice (Cenp‐r−/−). Mice heterozygous or homozygous for Cenp‐r null mutation are viable and healthy, with no apparent defect in growth and morphology, indicating Cenp‐r is not essential for normal development. Accordingly, to investigate the role of the Cenp‐r gene in skin carcinogenesis, we subjected Cenp‐r−/− mice to the 7,12‐dimethylbenz(a)anthracene (DMBA)/TPA chemical carcinogenesis protocol and monitored tumor development. As a result, Cenp‐r−/− mice initially developed significantly more papillomas than control wild‐type mice. However, papillomas in Cenp‐r−/− mice showed a decrease of proliferative cells and an increase of apoptotic cells. As a result, they did not grow bigger and some papillomas showed substantial regression. Furthermore, papillomas in Cenp‐r−/− mice showed lower frequency of malignant conversion to squamous cell carcinomas. These results indicate Cenp‐r functions bilaterally in cancer development: during early developmental stages, Cenp‐r functions as a tumor suppressor, but during the expansion and progression of papillomas it functions as a tumor‐promoting factor. Cenp‐r functions bilaterally in cancer development: during early developmental stages, Cenp‐r behaves as a tumor suppressor, but during the expansion and progression of papillomas it behaves as a tumor‐promoting factor.