PUMA Suppresses Intestinal Tumorigenesis in Mice
PUMA Suppresses Intestinal Tumorigenesis in Mice
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DOI：
10.1158/0008-5472.can-09-0262
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发表时间：
2009-06-15
期刊：
影响因子：
11.2
通讯作者：
Yu, Jian
中科院分区：
文献类型：
--
作者：
Qiu, Wei;Carson-Walter, Eleanor B.;Yu, Jian
缺陷性凋亡有助于肿瘤发生，尽管关键的分子靶点仍有待充分表征。p53依赖性细胞凋亡所必需的BH 3-only蛋白，已被证明可以抑制淋巴瘤的发生。在这项研究中，我们研究了在肠道肿瘤发生中的作用，使用两种动物模型。在氧化偶氮甲烷（AOM）/葡聚糖硫酸钠盐模型中，CD 45 A缺乏增加了结肠肿瘤的多样性和大小，但降低了β-连环蛋白热点突变的频率。由于AOM诱导的前驱病变的发生率显著升高，因此，AOM的缺乏导致了前驱病变的发生。AOM诱导p53依赖性的结肠腺泡和干细胞区室中的PUMA依赖性的细胞凋亡。此外，CD 4A缺乏显著增强APC（Min/+）小鼠远端小肠和结肠中自发性大腺瘤和微腺瘤的形成。这些结果表明PUMA介导的细胞凋亡在抑制小鼠肠道肿瘤发生中发挥着重要作用。[Cancer Res 2009;69（12）：4999-5006]
Defective apoptosis contributes to tumorigenesis, although the critical molecular targets remain to be fully characterized. PUMA, a BH3-only protein essential for p53-dependent apoptosis, has been shown to suppress lymphomagenesis. In this study, we investigated the role of PUMA in intestinal tumorigenesis using two animal models. In the azoxymethane (AOM)/dextran sulfate sodium salt model, PUMA deficiency increased the multiplicity and size of colon tumors but reduced the frequency of beta-catenin hotspot mutations. The absence of PUMA led to a significantly elevated incidence of precursor lesions induced by AOM. AOM was found to induce p53-dependent PUMA expression and PUMA-dependent apoptosis in the colonic crypts and stem cell compartment. Furthermore, PUMA deficiency significantly enhanced the formation of spontaneous macroadenomas and microadenomas in the distal small intestine and colon of APC(Min/+) mice. These results show an essential role of PUMA-mediated apoptosis in suppressing intestinal tumorigenesis in mice. [Cancer Res 2009;69(12):4999-5006]