Regulator of chromosome condensation 2 (RCC2) is a protein located in the centrosome, which ensures that cell division proceeds properly. Previous reports show that RCC2 is overexpressed in some cancers and could play a key role in tumor development, but the mechanisms concerning how this occurs are not understood. Furthermore, no evidence exists regarding its role in esophageal cancer. We studied the relevance of RCC2 in esophageal cancer growth and its regulation on Sox2, an important transcription factor promoting esophageal cancer. RCC2 was overexpressed in esophageal tumors compared with normal tissue, and this overexpression was associated with tumorigenicity by increasing cell proliferation, anchorage-independent growth, and migration. These oncogenic effects were accompanied by overexpression of Sox2. RCC2 upregulated and stabilized Sox2 expression and its target genes by inhibiting ubiquitination-mediated proteasome degradation. Likewise, RCC2 increased the transcriptional activity and promoter binding of Sox2. In vivo studies indicated that RCC2 and Sox2 were overexpressed in esophageal tumors compared with normal tissue, and this upregulation occurs in the esophageal basal cell layer for both proteins. In conditional knockout mice, RCC2 deletion decreased the tumor nodule formation and progression in the esophagus compared with wild-type mice. Proliferating cell nuclear antigen expression, a cell proliferation marker, was also downregulated in RCC2 knockout mice. Overall, our data show for the first time that RCC2 is an important protein for the stabilization and transcriptional activation of Sox2 and further promotion of malignancy in esophageal cancer. Implications: This study shows that RCC2 controls Sox2 expression and transcriptional activity to mediate esophageal cancer formation.

中文翻译：

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RCC2 通过调节 Sox2 转录因子的活性和表达促进食管癌生长

染色体凝聚调节因子 2 (RCC2) 是一种位于中心体中的蛋白质，可确保细胞分裂正常进行。先前的报告表明，RCC2 在某些癌症中过度表达，并且可能在肿瘤发展中发挥关键作用，但有关如何发生的机制尚不清楚。此外，没有证据表明其在食管癌中的作用。我们研究了 RCC2 在食管癌生长中的相关性及其对 Sox2 的调节，Sox2 是促进食管癌的重要转录因子。与正常组织相比，RCC2 在食管肿瘤中过表达，这种过表达通过增加细胞增殖、不依赖锚定的生长和迁移与致瘤性相关。这些致癌作用伴随着 Sox2 的过度表达。RCC2 通过抑制泛素化介导的蛋白酶体降解，上调和稳定 Sox2 表达及其靶基因。同样，RCC2 增加了 Sox2 的转录活性和启动子结合。体内研究表明，与正常组织相比，RCC2 和 Sox2 在食管肿瘤中过度表达，并且这种上调发生在两种蛋白质的食管基底细胞层中。在条件敲除小鼠中，与野生型小鼠相比，RCC2 缺失减少了食道中肿瘤结节的形成和进展。增殖细胞核抗原表达（一种细胞增殖标志物）在 RCC2 基因敲除小鼠中也被下调。总体，我们的数据首次表明RCC2是稳定和转录激活Sox2以及进一步促进食管癌恶性的重要蛋白质。意义：本研究表明 RCC2 控制 Sox2 表达和转录活性以介导食管癌的形成。