Center for Chemoprevention and Cancer Drug Development, Department of Medicine, Medical Oncology Section, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
Cell Cycle. 2012 Feb 1;11(3):479-88. doi: 10.4161/cc.11.3.18994.
Chromosome instability (CIN) is found in 85% of colorectal cancers. Defects in mitotic processes are implicated in high CIN and may be critical events in colorectal tumorigenesis. Shugoshin-1 (SGO1) aids in the maintenance of chromosome cohesion and prevents premature chromosome separation and CIN. In addition, integrity of the centrosome may be compromised due to the deficiency of Cohesin and Sgo1 through the disengagement of centrioles. We report here the generation and characterization of SGO1-mutant mice and show that haploinsufficiency of SGO1 leads to enhanced colonic tumorigenesis. Complete disruption of SGO1 results in embryonic lethality, whereas SGO1+/- mice are viable and fertile. Haploinsufficiency of SGO1 results in genomic instability manifested as missegregation of chromosomes and formation of extra centrosomal foci in both murine embryonic fibroblasts and adult bone marrow cells. Enhanced CIN observed in SGO1-deficient mice resulted in an increase in formation of aberrant crypt foci (ACF) and accelerated development of tumors after exposure to azoxymethane (AOM), a colon carcinogen. Together, these results suggest that haploinsufficiency of SGO1 causes enhanced CIN, colonic preneoplastic lesions and tumorigenesis in mice. SGO1 is essential for the suppression of CIN and tumor formation.
染色体不稳定性（CIN）在 85%的结直肠癌中被发现。有丝分裂过程中的缺陷与高 CIN 有关，并且可能是结直肠肿瘤发生的关键事件。Shugoshin-1（SGO1）有助于维持染色体的凝聚力，防止染色体过早分离和 CIN。此外，由于 Cohesin 和 Sgo1 的缺陷导致中心体的完整性受损，通过中心粒的脱离。我们在这里报告了 SGO1 突变小鼠的产生和特征，并表明 SGO1 的杂合不足导致结肠肿瘤发生增强。SGO1 的完全缺失导致胚胎致死，而 SGO1+/- 小鼠是存活和可育的。SGO1 的杂合不足导致基因组不稳定性，表现为染色体的错误分离和在小鼠胚胎成纤维细胞和成年骨髓细胞中形成额外的中心体焦点。在 SGO1 缺陷小鼠中观察到的增强的 CIN 导致异常隐窝焦点（ACF）的形成增加，并在暴露于氧化偶氮甲烷（AOM）后加速肿瘤的发展，AOM 是一种结肠癌致癌物。总之，这些结果表明 SGO1 的杂合不足导致 CIN、结肠前肿瘤病变和小鼠肿瘤发生增强。SGO1 对于抑制 CIN 和肿瘤形成是必不可少的。
