Myc/Max dependent intronic long antisense noncoding RNA, EVA1A-AS, suppresses the expression of Myc/Max dependent anti-proliferating gene EVA1A in a U2 dependent manner
Myc/Max dependent intronic long antisense noncoding RNA, EVA1A-AS, suppresses the expression of Myc/Max dependent anti-proliferating gene EVA1A in a U2 dependent manner
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DOI：
10.1038/s41598-019-53944-2
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发表时间：
2019-11-21
影响因子：
4.6
通讯作者：
Doan Duy Hai Tran
中科院分区：
文献类型：
--
作者：
Niehus, Svenja E.;Allister, Aldrige B.;Doan Duy Hai Tran
Myc基因与大多数类型的人类癌性肿瘤的发病机制有关。Myc/Max激活大量促肿瘤基因;然而，它也诱导抗增殖基因。当抗增殖基因被Myc激活时，癌细胞只有在下调时才能存活。肝细胞癌（HCC）特异性内含子长非编码反义（lnc-AS）RNA，即EVA 1A-AS基因，位于编码抗增殖因子的EVA 1A基因（伊娃-1同源物A）的第二内含子（I2）内。事实上，正常肝脏中表达EVA 1A，但不表达EVA 1A-AS。EVA 1A-AS的耗尽通过EVA 1A的上调而抑制HepG 2细胞的细胞增殖。EVA 1A的过表达通过微管灾难导致细胞在G2/M期死亡。此外，在365例原发性HCC中，抑制的EVA 1A表达水平与分化程度呈负相关，而EVA 1A-AS表达水平与患者生存率呈正相关。值得注意的是，EVA 1A和EVA 1A-AS都被Myc/Max复合物激活。Eva 1A-AS在EVA 1A I2的3 '剪接位点附近以相反方向转录。第二个内含子不以U2依赖的方式剪接，EVA 1A mRNA不输出。因此，Myc/Max依赖性抗增殖基因EVA 1A由Myc/Max依赖性反义非编码RNA控制，用于HCC存活。
The Myc gene has been implicated in the pathogenesis of most types of human cancerous tumors. Myc/Max activates large numbers of pro-tumor genes; however it also induces anti-proliferation genes. When anti-proliferation genes are activated by Myc, cancer cells can only survive if they are downregulated. Hepatocellular carcinoma (HCC) specific intronic long noncoding antisense (lnc-AS) RNA, the EVA1A-AS gene, is located within the second intron (I2) of the EVA1A gene (EVA-1 homolog A) that encodes an anti-proliferation factor. Indeed, EVA1A, but not EVA1A-AS, is expressed in normal liver. Depletion of EVA1A-AS suppressed cell proliferation of HepG2 cells by upregulation of EVA1A. Overexpression of EVA1A caused cell death at the G2/M phase via microtubule catastrophe. Furthermore, suppressed EVA1A expression levels are negatively correlated with differentiation grade in 365 primary HCCs, while EVA1A-AS expression levels are positively correlated with patient survival. Notably, both EVA1A and EVA1A-AS were activated by the Myc/Max complex. Eva1A-AS is transcribed in the opposite direction near the 3'splice site of EVA1A I2. The second intron did not splice out in a U2 dependent manner and EVA1A mRNA is not exported. Thus, the Myc/Max dependent anti-proliferating gene, EVA1A, is controlled by Myc/Max dependent anti-sense noncoding RNA for HCC survival.