Okumura Kazuhiro, Kagawa Naoko, Saito Megumi, Yoshizawa Yasuhiro, Munakata Haruka, Isogai Eriko, Fukagawa Tatsuo, Wakabayashi Yuichi
Department of Carcinogenesis Research, Division of Experimental Animal Research, Chiba Cancer Center Research Institute, Chiba, Japan.
Department of Molecular Genetics, National Institute of Genetics, The Graduate University for Advanced Studies, Mishima, Japan.
Cancer Sci. 2017 Nov;108(11):2142-2148. doi: 10.1111/cas.13348. Epub 2017 Aug 30.
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是CENP - O复合体的一个组成部分，该复合体包括CENP - O、CENP - P、CENP - Q、CENP - R和CENP - U，并且在脊椎动物的整个细胞周期中都恒定地定位于动粒。缺乏CENP - R的鸡DT40细胞能够存活，并且对有丝分裂的影响非常小。为了研究CENP - R在体内的功能作用，我们培育了缺乏CENP - R的小鼠（Cenp - r）。Cenp - r基因纯合或杂合缺失突变的小鼠能够存活且健康，在生长和形态上没有明显缺陷，这表明Cenp - r对于正常发育不是必需的。因此，为了研究Cenp - r基因在皮肤癌发生中的作用，我们使Cenp - r小鼠接受7,12 - 二甲基苯并(a)蒽（DMBA）/TPA化学致癌方案，并监测肿瘤的发展。结果，Cenp - r小鼠最初形成的乳头状瘤明显比对照野生型小鼠多。然而，Cenp - r小鼠的乳头状瘤显示增殖细胞减少，凋亡细胞增加。结果，它们没有长大，一些乳头状瘤出现了显著的消退。此外，Cenp - r小鼠的乳头状瘤向鳞状细胞癌恶性转化的频率较低。这些结果表明Cenp - r在癌症发展中具有双向功能：在早期发育阶段，Cenp - r作为肿瘤抑制因子发挥作用，但在乳头状瘤的扩展和进展过程中，它作为肿瘤促进因子发挥作用。
