Pádua Alves Cleidson, Fonseca Aline Simoneti, Muys Bruna Rodrigues, de Barros E Lima Bueno Rafaela, Bürger Matheus Carvalho, de Souza Jorge E S, Valente Valeria, Zago Marco Antonio, Silva Wilson Araújo
Department of Genetics and, Ribeirão Preto Medical School University of São Paulo, São Paulo, Brazil; National Institute of Science and Technology in Stem Cell and Cell Therapy and Center For Cell Based Therapy, Ribeirao Preto, São Paulo, Brazil; Center for Integrative Systems Biology-CISBi, NAP/USP, Ribeirao Preto, São Paulo, Brazil.
Stem Cells. 2013 Dec;31(12):2827-32. doi: 10.1002/stem.1547.
Hotair is a member of the recently described class of noncoding RNAs called lincRNA (large intergenic noncoding RNA). Various studies suggest that Hotair acts regulating epigenetic states by recruiting chromatin-modifying complexes to specific target sequences that ultimately leads to suppression of several genes. Although Hotair has been associated with metastasis and poor prognosis in different tumor types, a deep characterization of its functions in cancer is still needed. Here, we investigated the role of Hotair in the scenario of epithelial-to-mesenchymal transition (EMT) and in the arising and maintenance of cancer stem cells (CSCs). We found that treatment with TGF-β1 resulted in increased Hotair expression and triggered the EMT program. Interestingly, ablation of Hotair expression by siRNA prevented the EMT program stimulated by TGF-β1, and also the colony-forming capacity of colon and breast cancer cells. Furthermore, we observed that the colon CSC subpopulation (CD133(+)/CD44(+)) presents much higher levels of Hotair when compared with the non-stem cell subpopulation. These results indicate that Hotair acts as a key regulator that controls the multiple signaling mechanisms involved in EMT. Altogether, our data suggest that the role of Hotair in tumorigenesis occurs through EMT triggering and stemness acquisition.
Hotair是最近描述的一类非编码RNA，即长链基因间非编码RNA（lincRNA）的成员。各种研究表明，Hotair通过将染色质修饰复合物招募到特定靶序列来调节表观遗传状态，最终导致多个基因受到抑制。尽管Hotair已被证明与不同肿瘤类型的转移和不良预后相关，但仍需要深入了解其在癌症中的功能。在此，我们研究了Hotair在上皮-间质转化（EMT）过程以及癌症干细胞（CSC）的产生和维持中的作用。我们发现，用转化生长因子-β1（TGF-β1）处理会导致Hotair表达增加并触发EMT程序。有趣的是，通过小干扰RNA（siRNA）消除Hotair的表达可阻止TGF-β1刺激的EMT程序，以及结肠和乳腺癌细胞的集落形成能力。此外，我们观察到，与非干细胞亚群相比，结肠CSC亚群（CD133(+)/CD44(+)）中的Hotair水平要高得多。这些结果表明，Hotair作为关键调节因子，控制着EMT过程中涉及的多种信号机制。总之，我们的数据表明，Hotair在肿瘤发生中的作用是通过触发EMT和获得干性来实现的。
