piRNA-823 contributes to tumorigenesis by regulating de novo DNA methylation and angiogenesis in multiple myeloma
piRNA-823 contributes to tumorigenesis by regulating de novo DNA methylation and angiogenesis in multiple myeloma
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DOI：
10.1038/leu.2014.135
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发表时间：
2015-01-01
期刊：
影响因子：
11.4
通讯作者：
Hu, Y.
中科院分区：
文献类型：
--
作者：
Yan, H.;Wu, Q-L;Hu, Y.
异常的DNA高甲基化通过沉默肿瘤抑制基因而导致骨髓瘤的发生。最近，一些报告表明，一类新的非编码小RNA，称为Piwi相互作用RNAs(PiRNAs)，可能参与癌症的表观遗传调控。在本研究中，我们首次提供证据表明，piRNA-823在多发性骨髓瘤(MM)患者和细胞系中表达上调，并与临床分期呈正相关。沉默多发性骨髓瘤细胞中的pIRNA-823可诱导细胞周期调节因子和凋亡相关蛋白表达的紊乱，并伴随着体外和体内致瘤性的抑制。此外，在原代CD138-MM细胞中，piRNA-823与从头DNA甲基转移酶DNMT3A和3B直接相关。抑制pIRNA-823在MM细胞中的表达导致DNMT3A和3B在mRNA和蛋白水平上的显著降低，进而导致DNA甲基化水平的降低和甲基化沉默的肿瘤抑制因子p16(INK4A)的重新表达。此外，去除多发性骨髓瘤细胞中的piRNA-823可导致血管内皮生长因子分泌减少，从而降低促血管生成活性。总之，这些数据支持了piRNA-823在MM生物学中的致癌作用，为发展针对MM的piRNA靶向治疗策略提供了理性。
Aberrant DNA hypermethylation contributes to myelomagenesis by silencing tumor-suppressor genes. Recently, a few reports have suggested that a novel class of small non-coding RNAs, called Piwi-interacting RNAs (piRNAs), may be involved in the epigenetic regulation of cancer. In this study, for the first time we provided evidence that the expression of piRNA-823 was upregulated in multiple myeloma (MM) patients and cell lines, and positively correlated with clinical stage. Silencing piRNA-823 in MM cells induced deregulation of cell cycle regulators and apoptosis-related proteins expression, accompanied by inhibition of tumorigenicity in vitro and in vivo. Moreover, piRNA-823 was directly relevant to de novo DNA methyltransferases, DNMT3A and 3B, in primary CD138-MM cells. The inhibited expression of piRNA-823 in MM cells resulted in marked reduction of DNMT3A and 3B at both mRNA and protein levels, which in turn led to decrease in global DNA methylation and reexpression of methylation-silenced tumor suppressor, p16(INK4A). In addition, piRNA-823 abrogation in MM cells induced reduction of vascular endothelial growth factor secretion, with consequent decreased proangiogenic activity. Altogether, these data support an oncogenic role of piRNA-823 in the biology of MM, providing a rational for the development of piRNA-targeted therapeutic strategies in MM.