Endocrine Oncology Section, Surgery Branch, National Cancer Institute, NIH, HHS, Clinical Research Center, Building 10-CRC, Room 3-3940, 10 Center Drive, MSC 1201, Bethesda, Maryland 20892, USA.
Endocr Relat Cancer. 2011 Nov 28;18(6):731-42. doi: 10.1530/ERC-11-0181. Print 2011.
Cancer gender disparities have been observed for a variety of human malignancies. Thyroid cancer is one such example where there is a dramatic difference in the incidence, aggressiveness, and death rate by gender. The molecular basis for gender disparity is poorly understood. To address this, we performed genome-wide gene expression profiling in matched papillary thyroid cancer (PTC) samples and identified nine candidate genes differentially expressed by gender. One of these genes was CDC23 that was upregulated in PTC in men compared with women. Because the function and expression of CDC23 is unknown in eukaryotic cells, we further characterized the expression of CDC23 in normal, hyperplastic, and PTC tissue samples. We found CDC23 was overexpressed in PTC and absent in normal and hyperplastic thyroid tissue. In thyroid cancer cells, functional knockdown of CDC23 resulted in an increase in the number of cells in both the S and G(2)M phases of the cell cycle, and an inhibition of cellular proliferation, tumor spheroid formation, and anchorage-independent growth. Cellular arrest in both S and G(2)M phases was associated with significant cyclin B1 and securin protein accumulation after CDC23 knockdown. Moreover, the effect of CDC23 on cellular proliferation and cell cycle progression was reversed on triple knockdown studies of CDC23, cyclin B1, and securin. Our data taken together suggests CDC23 has important biologic effects on cell proliferation and cell cycle progression. The effect of CDC23 on cellular proliferation and cell cycle progression is mediated, at least in part, by cyclin B1 and securin protein levels. Therefore, we propose that CDC23 is a critical regulator of cell cycle and cell growth, and may be involved in thyroid cancer initiation and progression, and may explain the different tumor biology observed by gender.
已经观察到多种人类恶性肿瘤存在癌症的性别差异。甲状腺癌就是一个这样的例子，其发病率、侵袭性和死亡率存在显著的性别差异。性别差异的分子基础尚未被充分理解。为了解决这个问题，我们对匹配的甲状腺乳头状癌（PTC）样本进行了全基因组基因表达谱分析，确定了 9 个性别差异表达的候选基因。其中一个基因是 CDC23，它在男性 PTC 中上调，而在女性中下调。由于 CDC23 在真核细胞中的功能和表达尚不清楚，我们进一步研究了 CDC23 在正常、增生和 PTC 组织样本中的表达。我们发现 CDC23 在 PTC 中过表达，而在正常和增生的甲状腺组织中不存在。在甲状腺癌细胞中，CDC23 的功能敲低导致细胞周期 S 和 G(2)M 期的细胞数量增加，细胞增殖、肿瘤球体形成和锚定非依赖性生长受到抑制。CDC23 敲低后，S 和 G(2)M 期的细胞周期停滞与细胞周期蛋白 B1 和 securin 蛋白的显著积累有关。此外，在 CDC23、细胞周期蛋白 B1 和 securin 的三重敲低研究中，CDC23 对细胞增殖和细胞周期进程的影响被逆转。我们的数据表明，CDC23 对细胞增殖和细胞周期进程具有重要的生物学影响。CDC23 对细胞增殖和细胞周期进程的影响至少部分是通过细胞周期蛋白 B1 和 securin 蛋白水平介导的。因此，我们提出 CDC23 是细胞周期和细胞生长的关键调节剂，可能参与甲状腺癌的发生和进展，并可能解释性别观察到的不同肿瘤生物学。
