Downregulation of ARID1A, a component of the SWI/SNF chromatin remodeling complex, in breast cancer.
Downregulation of ARID1A, a component of the SWI/SNF chromatin remodeling complex, in breast cancer.
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乳腺癌中SWI/SNF染色质重塑复合物的ARID1A的下调。
DOI：
10.7150/jca.16602
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发表时间：
2017
影响因子：
3.9
通讯作者：
Yoshida K
中科院分区：
文献类型：
--
作者：
Takao C;Morikawa A;Ohkubo H;Kito Y;Saigo C;Sakuratani T;Futamura M;Takeuchi T;Yoshida K
最近的研究揭示了富含AT的相互作用结构域蛋白1A（ARID 1A），乳腺SWI/SNF染色质重塑复合物的一个亚基，在各种癌症中作为肿瘤抑制因子。在这项研究中，我们首先通过免疫组化评估了ARID 1A在浸润性乳腺癌组织标本中的表达，并评估了其与乳腺癌患者预后的相关性。非肿瘤性乳腺导管上皮细胞表现出强烈的核ARID 1A染色，而在许多浸润性乳腺癌细胞中观察到ARID 1A免疫反应性的不同程度的损失。我们根据侵袭性癌细胞的百分比评分（0 - 5分）和强度评分（0 - 3分）的总和对ARID 1A免疫反应性进行评分，可能的总分为0 - 8分。有趣的是，ARID 1A表达的部分缺失（评分2至3）与患者的无病生存率显著相关。随后，我们在培养的乳腺癌细胞中进行了siRNA介导的ARID 1A敲低，随后进行了全面的基因分析和定量RT-PCR。有趣的是，在乳腺癌细胞中，ARID 1A的部分缺失导致许多基因下调，而RAB 11 FIP 1基因表达则因ARID 1A表达的部分缺失而显着上调。与此相反，ARID 1A mRNA减少50%以上则会降低RAB 11 FIP 1基因的表达。免疫印迹还表明，ARID 1A mRNA的部分下调在约20%的减少显着增加了MCF-7细胞中的RAB 11 FIP 1蛋白的表达，而超过50%的ARID 1A mRNA的减少导致培养的乳腺癌细胞中的RAB 11 FIP 1蛋白的减少。最近的研究表明，RAB 11 FIP 1过表达导致乳腺癌进展。总之，目前的研究结果表明，ARID 1A表达的部分缺失与乳腺癌患者的不利结果有关，可能是由于RAB 11 FIP 1表达增加。
Recent studies unraveled that AT-rich interactive domain-containing protein 1A (ARID1A), a subunit of the mammary SWI/SNF chromatin remodeling complex, acts as a tumor suppressor in various cancers. In this study, we first evaluated ARID1A expression by immunohistochemistry in invasive breast cancer tissue specimens and assessed the correlation with the prognosis of patients with breast cancer. Non-tumorous mammary duct epithelial cells exhibited strong nuclear ARID1A staining, whereas different degrees of loss in ARID1A immunoreactivity were observed in many invasive breast cancer cells. We scored ARID1A immunoreactivity based on the sum of the percentage score in invasive cancer cells (on a scale of 0 to 5) and the intensity score (on a scale of 0 to 3), for a possible total score of 0 to 8. Interestingly, partial loss of ARID1A expression, score 2 to 3, was significantly correlated with poor disease free survival of the patients. Subsequently, we performed siRNA-mediated ARID1A knockdown in cultured breast cancer cells followed by comprehensive gene profiling and quantitative RT-PCR. Interestingly, many genes were downregulated by partial loss of ARID1A, whereas RAB11FIP1 gene expression was significantly upregulated by partial loss of ARID1A expression in breast cancer cells. In contrast, a more than 50% reduction in ARID1A mRNA decreased RAB11FIP1gene expression. Immunoblotting also demonstrated that partial downregulation of ARID1A mRNA at approximately 20% reduction significantly increased the expression of RAB11FIP1 protein in MCF-7 cells, whereas, over 50% reduction of ARID1A mRNA resulted in reduction of RAB11FIP1 protein in cultured breast cancer cells. Recent studies reveal that RAB11FIP1 overexpression leads to breast cancer progression. Altogether, the present findings indicated that partial loss of ARID1A expression is linked to unfavorable outcome for patients with breast cancer, possibly due to increased RAB11FIP1 expression.