Inactivation of Arid1a in the endometrium is associated with endometrioid tumorigenesis through transcriptional reprogramming
Inactivation of Arid1a in the endometrium is associated with endometrioid tumorigenesis through transcriptional reprogramming
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DOI：
10.1038/s41467-020-16416-0
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发表时间：
2020-06-01
影响因子：
16.6
通讯作者：
Shih, Ie-Ming
中科院分区：
文献类型：
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作者：
Rahmanto, Yohan Suryo;Shen, Wenjing;Shih, Ie-Ming
ARID1A是一种SWI/SNF染色质重塑基因，其体细胞失活突变在人类子宫内膜相关恶性肿瘤中普遍存在。为了阐明ARID1A有害突变在肿瘤发生中的作用机制，我们建立了子宫内膜ARID1A和/或Pten条件性缺失的基因工程小鼠模型。对来自这些小鼠模型的子宫内膜癌及其前体的转录转录分析显示，与人类子宫内膜样癌非常相似。我们确定了由ARID1A控制的转录网络，并对子宫内膜肿瘤的发展有影响。为了验证小鼠模型的研究结果，我们分析了ARID1A(WT)和ARID1A(KO)人子宫内膜上皮细胞。利用系统生物学方法和功能研究，我们证明了ARID1A缺失导致了转化生长因子-β肿瘤抑制功能的丧失，并且ARID1A/转化生长因子-β轴的失活促进了PTEN缺失的子宫内膜肿瘤细胞的迁移和侵袭。这些发现为ARID1A失活如何加速子宫内膜肿瘤的进展和扩散提供了分子洞察力，子宫内膜肿瘤是癌症死亡的主要原因。
Somatic inactivating mutations of ARID1A, a SWI/SNF chromatin remodeling gene, are prevalent in human endometrium-related malignancies. To elucidate the mechanisms underlying how ARID1A deleterious mutation contributes to tumorigenesis, we establish genetically engineered murine models with Arid1a and/or Pten conditional deletion in the endometrium. Transcriptomic analyses on endometrial cancers and precursors derived from these mouse models show a close resemblance to human uterine endometrioid carcinomas. We identify transcriptional networks that are controlled by Arid1a and have an impact on endometrial tumor development. To verify findings from the murine models, we analyze ARID1A(WT) and ARID1A(KO) human endometrial epithelial cells. Using a system biology approach and functional studies, we demonstrate that ARID1A-deficiency lead to loss of TGF-beta tumor suppressive function and that inactivation of ARID1A/TGF-beta axis promotes migration and invasion of PTEN-deleted endometrial tumor cells. These findings provide molecular insights into how ARID1A inactivation accelerates endometrial tumor progression and dissemination, the major causes of cancer mortality.