Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain.
Carcinogenesis. 2013 Apr;34(4):902-8. doi: 10.1093/carcin/bgs404. Epub 2013 Jan 3.
Inappropriate activation of the GLI/hedgehog (GLI/Hh) signalling occurs in several human cancers, including haematological neoplasms. However, little is known about its relevance in precursor T-cell lymphoblastic lymphomas (T-LBL) development. Moreover, the mechanisms whereby GLI/Hh signalling is activated in haematological malignancies are not fully clear. Here, we show that the gene Smoothened (SMO), the only non-redundant gene of this pathway, is up-regulated in mouse and human T-LBL. Interestingly, down-regulation of micro-RNAs mmu-miR-30a and mmu-miR-141 as well as hsa-miR-193b clearly contributes to enhance the expression of this gene in mouse and human lymphomas and, subsequently, to activate the GLI/Hh signalling. Activation of the GLI/Hh signalling in T-LBL promotes cell survival and proliferation, since inhibition of the pathway using short-hairpin-RNA-mediated SMO knockdown, or cyclopamine as a specific antagonist, significantly reduces these cellular processes. These findings suggest that sustained SMO up-regulation may contribute to T-LBL development and advocate the use of specific SMO inhibitors or microRNAs-based therapies as an attractive possibility to treat an important subset of T-LBL.
GLI/ hedgehog（GLI/Hh）信号通路的异常激活发生在几种人类癌症中，包括血液肿瘤。然而，其在前体 T 细胞淋巴母细胞淋巴瘤（T-LBL）发生中的相关性知之甚少。此外，血液恶性肿瘤中 GLI/Hh 信号通路激活的机制尚不完全清楚。在这里，我们表明 Smoothened（SMO）基因，该通路中唯一不可或缺的基因，在小鼠和人类 T-LBL 中上调。有趣的是，下调 micro-RNAs mmu-miR-30a 和 mmu-miR-141 以及 hsa-miR-193b 明显有助于增强该基因在小鼠和人类淋巴瘤中的表达，并随后激活 GLI/Hh 信号通路。T-LBL 中 GLI/Hh 信号通路的激活促进细胞存活和增殖，因为使用短发夹 RNA 介导的 SMO 敲低或 cyclopamine 作为特异性拮抗剂抑制该通路可显著降低这些细胞过程。这些发现表明持续的 SMO 上调可能有助于 T-LBL 的发生，并提倡使用特异性 SMO 抑制剂或基于 microRNA 的治疗作为治疗 T-LBL 一个重要亚群的有吸引力的可能性。
