Roles of Deletion of Arid1a, a Tumor Suppressor, in Mouse Ovarian Tumorigenesis
Roles of Deletion of Arid1a, a Tumor Suppressor, in Mouse Ovarian Tumorigenesis
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DOI：
10.1093/jnci/dju146
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发表时间：
2014-07-01
影响因子：
10.3
通讯作者：
Shih, Ie-Ming
中科院分区：
文献类型：
--
作者：
Guan, Bin;Rahmanto, Yohan Suryo;Shih, Ie-Ming
染色质重塑基因ARID1A被认为是一种肿瘤抑制基因，其体细胞失活突变发生在多种人类癌症中，最常见于卵巢和子宫类卵巢癌和卵巢透明细胞癌。具有ARID1A突变的肿瘤也经常携带PTEN或PIK3CA突变，表明它们在肿瘤发生中的协作。在这里，我们使用了一种条件性基因敲除小鼠模型，其中Arid1a和Pten在小鼠卵巢表面上皮中单独或组合缺失。6个月后，59.1%的Arid1a和Pten双敲除小鼠发生卵巢类上皮性或未分化癌，而其余小鼠显示卵巢表面上皮增生。相比之下，52只Arid1a或Pten纯合或杂合缺失的小鼠没有发生卵巢病变。这些结果表明，单独的Arid1a失活不足以引发肿瘤，但它需要额外的遗传改变，如Pten缺失，以驱动肿瘤发生。
The chromatin remodeling gene, ARID1A, has been implied as a tumor suppressor, and its somatic inactivating mutations occur in a wide variety of human cancers, most frequently in ovarian and uterine endometrioid and ovarian clear cell carcinomas. Tumors with ARID1A mutations also frequently harbor PTEN or PIK3CA mutations, suggesting their collaboration in tumorigenesis. Here, we used a conditional knockout mouse model in which Arid1a and Pten were deleted either individually or in combination in the mouse ovarian surface epithelium. After 6 months, 59.1% of mice with Arid1a and Pten double knockout developed ovarian endometrioid or undifferentiated carcinoma, whereas the remaining mice showed hyperplasia of ovarian surface epithelium. In contrast, 52 mice with homozygous or heterozygous deletion in either Arid1a or Pten did not develop ovarian lesions. These results demonstrate that inactivation of Arid1a alone is insufficient for tumor initiation but it requires additional genetic alteration(s) such as Pten deletion to drive tumorigenesis.