Small RNA sequencing and functional characterization reveals MicroRNA-143 tumor suppressor activity in liposarcoma.
Small RNA sequencing and functional characterization reveals MicroRNA-143 tumor suppressor activity in liposarcoma.
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DOI：
10.1158/0008-5472.can-11-0890
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发表时间：
2011-09-01
期刊：
影响因子：
11.2
通讯作者：
Singer S
中科院分区：
文献类型：
--
作者：
Ugras S;Brill E;Jacobsen A;Hafner M;Socci ND;Decarolis PL;Khanin R;O'Connor R;Mihailovic A;Taylor BS;Sheridan R;Gimble JM;Viale A;Crago A;Antonescu CR;Sander C;Tuschl T;Singer S
脂肪肉瘤仍然是最常见的间叶性癌症，该病患者的死亡率为 60%。为了解决目前缺乏治疗选择的问题，我们开始了一项与脂肪肉瘤发生相关的 microRNA (miRNA) 表达改变的研究，目的是利用差异表达的 miRNA 及其调节的基因产物作为潜在的治疗靶点。通过小 RNA 文库深度测序和基于杂交的安捷伦微阵列，对正常脂肪组织、高分化脂肪肉瘤和去分化脂肪肉瘤样本中的 MicroRNA 表达进行了分析。表达谱可将脂肪肉瘤与正常脂肪组织区分开来，并与去分化疾病良好分化。我们在测序和微阵列分析中定义了 40 多种在去分化脂肪肉瘤中失调的 miRNA。上调的 miRNA 包括两种与癌症相关的物种（miR-21、miR-26a），下调的 miRNA 包括脂肪组织中高度丰富的两种物种（miR-143、miR-145）。在去分化脂肪肉瘤细胞中恢复 miR-143 表达可抑制增殖、诱导细胞凋亡并降低 BCL2、TOP2A、PRC1 和 PLK1 的表达。 PRC1 及其对接伙伴 PLK1 的下调表明 miR-143 抑制这些细胞中的胞质分裂。为了支持这一观点，PLK1 抑制剂治疗可有效诱导脂肪肉瘤细胞 G2/M 生长停滞和细胞凋亡。综上所述，我们的研究结果表明，针对 miR-143 或其靶标的 miR-143 重新表达载体或选择剂可能对去分化脂肪肉瘤具有治疗价值。
Liposarcoma remains the most common mesenchymal cancer, with a mortality rate of 60% among patients with this disease. To address the present lack of therapeutic options, we embarked upon a study of microRNA (miRNA) expression alterations associated with liposarcomagenesis with the goal of exploiting differentially expressed miRNAs and the gene products they regulate as potential therapeutic targets. MicroRNA expression was profiled in samples of normal adipose tissue, well-differentiated liposarcoma, and dedifferentiated liposarcoma by both deep sequencing of small RNA libraries and hybridization-based Agilent microarrays. The expression profiles discriminated liposarcoma from normal adipose tissue and well-differentiated from dedifferentiated disease. We defined over 40 miRNAs that were dysregulated in dedifferentiated liposarcomas in both the sequencing and the microarray analysis. The upregulated miRNAs included two cancer-associated species (miR-21, miR-26a), and the downregulated miRNAs included two species that were highly abundant in adipose tissue (miR-143, miR-145). Restoring miR-143 expression in dedifferentiated liposarcoma cells inhibited proliferation, induced apoptosis, and decreased expression of BCL2, TOP2A, PRC1, and PLK1. The downregulation of PRC1 and its docking partner PLK1 suggests that miR-143 inhibits cytokinesis in these cells. In support of this idea, treatment with a PLK1 inhibitor potently induced G2/M growth arrest and apoptosis in liposarcoma cells. Taken together, our findings suggest that miR-143 re-expression vectors or selective agents directed at miR-143 or its targets may have therapeutic value in dedifferentiated liposarcoma.