Induction of the RNA regulator LIN28A is required for the growth and pathogenesis of RESTless breast tumors.
Induction of the RNA regulator LIN28A is required for the growth and pathogenesis of RESTless breast tumors.
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DOI：
10.1158/0008-5472.can-11-1639
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发表时间：
2012-07-01
期刊：
影响因子：
11.2
通讯作者：
Roopra A
中科院分区：
文献类型：
--
作者：
Gunsalus KT;Wagoner MP;Meyer K;Potter WB;Schoenike B;Kim S;Alexander CM;Friedl A;Roopra A
大约 20% 的乳腺癌中转录因子 REST 丢失。尽管已知这些“无休息”肿瘤具有高度侵袭性并且包括所有肿瘤亚型，但潜在的致瘤机制仍然未知。在这项研究中，我们证明 REST 的缺失会导致乳腺癌细胞系和人类乳腺肿瘤中已知的肿瘤发展启动子 LIN28A 的上调。我们发现 LIN28A 是癌细胞中 REST 的直接转录靶标，REST 的缺失会导致 LIN28A 表达增加，并在体外和体内增强肿瘤生长，这些效应依赖于 LIN28A 表达的增强。缺乏 REST 表达的肿瘤具有局部侵袭性，这与在人类 RESTless 肿瘤中观察到的淋巴结受累增加一致。临床上，与非 RESTless 肿瘤相比，人类 RESTless 乳腺肿瘤的 LIN28A 表达也显着增强。因此，我们的研究结果证明了 REST-LIN28A 轴在肿瘤侵袭中的关键作用，并表明 REST 丢失与体内致瘤性之间存在因果关系。
The transcription factor REST is lost in approximately 20% of breast cancers. Although it is known that these “RESTless” tumors are highly aggressive and include all tumor subtypes, the underlying tumorigenic mechanisms remain unknown. In this study, we demonstrate that loss of REST results in up-regulation of LIN28A, a known promoter of tumor development, in breast cancer cell lines and human breast tumors. We found that LIN28A was a direct transcriptional target of REST in cancer cells and that loss of REST resulted in increased LIN28A expression and enhanced tumor growth both in vitro and in vivo, effects that were dependent on heightened LIN28A expression. Tumors lacking REST expression were locally invasive, consistent with the increased lymph node involvement observed in human RESTless tumors. Clinically, human RESTless breast tumors also displayed significantly enhanced LIN28A expression when compared with non-RESTless tumors. Our findings therefore demonstrate a critical role for the REST-LIN28A axis in tumor aggression and suggest a causative relationship between REST loss and tumorigenicity in vivo.