Department of Immunology, St Jude Children's Research Hospital, Memphis, TN, USA.
Cell Death Differ. 2013 Sep;20(9):1174-82. doi: 10.1038/cdd.2013.38. Epub 2013 May 3.
Despite being the most evolutionarily conserved of the mammalian caspases, little is understood about the cellular function of caspase-2 in normal tissues or what role caspase-2 may have in the progression of human disease. It has been reported that deletion of the caspase-2 gene (Casp2), accelerates Eμ-myc lymphomagenesis in mice, and thus caspase-2 may act as a tumor suppressor in hematological malignancies. Here, we sought to extend these findings to epithelial cancers by examining the potential role of caspase-2 as a tumor suppressor in the mouse mammary carcinogenesis model; MMTV/c-neu. The rate of tumor acquisition was significantly higher in multiparous Casp2(-/-)/MMTV mice compared with Casp2(+/+)/MMTV and Casp2(+/-)/MMTV mice. Cells from Casp2(-/-)/MMTV tumors were often multinucleated and displayed bizarre mitoses and karyomegaly, while cells from Casp2(+/+)/MMTV and Casp2(+/-)/MMTV tumors never displayed this phenotype. Tumors from Casp2(-/-)/MMTV animals had a significantly higher mitotic index than tumors from Casp2(+/+)/MMTV and Casp2(+/-)/MMTV animals. Cell cycle analysis of Casp2(-/-) E1A/Ras-transformed mouse embryonic fibroblasts (MEF) also indicated a higher proliferative rate in the absence of caspase-2. In vitro assays further illustrated that MEF had increased genomic instability in the absence of caspase-2. This appears to be due to disruption of the p53 pathway because we observed a concomitant decrease in the induction of the p53 target genes, Pidd, p21 and Mdm2. Thus caspase-2 may function as a tumor suppressor, in part, through regulation of cell division and genomic stability.
尽管 caspase-2 是哺乳动物 caspases 中进化上最保守的一种，但人们对其在正常组织中的细胞功能知之甚少，也不清楚 caspase-2 在人类疾病进展中可能扮演什么角色。据报道，caspase-2 基因（Casp2）缺失会加速小鼠 Eμ-myc 淋巴瘤的发生，因此 caspase-2 可能在血液恶性肿瘤中作为肿瘤抑制因子发挥作用。在这里，我们通过研究 caspase-2 作为肿瘤抑制因子在小鼠乳腺致癌模型（MMTV/c-neu）中的潜在作用，试图将这些发现扩展到上皮癌。多胎 Casp2(-/-)/MMTV 小鼠的肿瘤获得率明显高于 Casp2(+/+)/MMTV 和 Casp2(+/-)/MMTV 小鼠。Casp2(-/-)/MMTV 肿瘤的细胞通常为多核，并显示奇异的有丝分裂和巨核，而 Casp2(+/+)/MMTV 和 Casp2(+/-)/MMTV 肿瘤的细胞从未显示出这种表型。Casp2(-/-)/MMTV 动物的肿瘤有丝分裂指数明显高于 Casp2(+/+)/MMTV 和 Casp2(+/-)/MMTV 动物的肿瘤。Casp2(-/-)E1A/Ras 转化的小鼠胚胎成纤维细胞（MEF）的细胞周期分析也表明，在没有 caspase-2 的情况下，增殖率更高。体外实验进一步表明，在没有 caspase-2 的情况下，MEF 的基因组不稳定性增加。这似乎是由于 p53 途径的破坏，因为我们观察到 p53 靶基因 Pidd、p21 和 Mdm2 的诱导同时减少。因此，caspase-2 可能部分通过调节细胞分裂和基因组稳定性来发挥肿瘤抑制因子的作用。
