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

Abstract

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‐50 is required for papilloma development in the two‐stage skin carcinogenesis model

“…Our previous study demonstrated the essential function of Cenp‐r in the two‐stage skin carcinogenesis model 23 . In this study, our expression analysis suggested that Cenp‐50/U functions might be opposite to those of Cenp‐r in skin carcinogenesis (Figure 1).…”

“…This finding suggests that Cenp‐50/U functions as an oncogene in papilloma development, but loses this function at the late papilloma stage and in malignant conversion. We previously reported that Cenp‐r deficiency increases early‐stage papillomas and reduces the conversion of benign papillomas into malignant tumors 23 . These results suggest that Cenp‐50/U functions as an oncogene, whereas Cenp‐r functions as a tumor suppressor in early papilloma development.…”

“…We have demonstrated previously the essential role of Cenp‐r, which forms a complex with other Cenp‐O proteins (Cenp‐O/P/Q/R/U), in the two‐stage skin carcinogenesis model. Cenp‐r functions as a tumor suppressor in early papilloma development, but as an oncogene at the late papilloma stage and in malignant conversion 23 . Based on this study, we hypothesized that other Cenp‐O complex proteins function in skin carcinogenesis.…”

Possible Roles of Proinflammatory Signaling in Keratinocytes Through Aryl Hydrocarbon Receptor Ligands for the Development of Squamous Cell Carcinoma

“…Since the AhR ligands, FICZ, and DMBA, are reported to promote carcinogenesis in SCC ( 11 ), we firstly employed immunohistochemical staining of CYP1A1 and AhR in 10 cases in each condition (cutaneous SCC, AK, and normal skin). Atypical keratinocytes in AK ( Figures 1A,B ) and cutaneous SCC ( Figures 1C,D ) expressed CYP1A1, whereas normal keratinocytes between the follicular bulbs in AK ( Figure 1A ), surgical margin of cutaneous SCC ( Figure 1E ), or normal skin ( Figure 1F ) did not express CYP1A1.…”

“…7,12-Dimethylbenz[a]anthracene (DMBA), another type of AhR ligand that is typically found in cigarette smoke, is widely known to induce cutaneous SCC in mouse skin together with 12-O-Tetradecanoylphorbol 13-acetate (TPA) ( 11 , 12 ). The majority of DMBA-induced SCCs possess mutations in oncogenes including Hras, Kras, and Rras ( 13 , 14 ), which are detected in human SCC located in cervical, esophageal, and lung tissues, among others.…”