MicroRNA-383 regulates the apoptosis of tumor cells through targeting Gadd45g.
MicroRNA-383 regulates the apoptosis of tumor cells through targeting Gadd45g.
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MicroRNA-383通过靶向Gadd45g调节肿瘤细胞的凋亡。
DOI：
10.1371/journal.pone.0110472
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Qian B
中科院分区：
文献类型：
--
作者：
Zhao L;Gu H;Chang J;Wu J;Wang D;Chen S;Yang X;Qian B
MicroRNAs （miRNAs）是一类小的非编码单链RNA分子，在转录后水平上抑制基因表达。Gadd45g（生长阻滞和DNA损伤诱导45 γ）是一种应激反应蛋白，涉及多种生物过程，包括DNA修复、细胞周期和细胞分化。在这项工作中，我们发现miR-383是Gadd45g的负调节因子。强制表达miR-383通过结合3 ‘非翻译区（3 ’ -UTR）降低Gadd45g的表达，而抑制miR-383则增加Gadd45g的表达。miR-383的存在增加了乳腺癌细胞对DNA损伤的细胞敏感性，这是通过不含3 ' -UTR的Gadd45g的异位表达来挽救的。miR-383还调节胚胎干细胞（ES）中Gadd45g的表达，但不调节基因毒性应激下胚胎干细胞的凋亡。miR-383进一步被证明通过靶向Gadd45g负性调节ES细胞分化，Gadd45g随后调节多能性相关基因。综上所述，我们的研究表明，miR-383在肿瘤细胞和胚胎干细胞中都是Gadd45g的负调节因子，但在调节细胞凋亡方面具有不同的功能。miR-383可作为肿瘤化疗中的抗肿瘤药物。我们首次证明miR-383可以通过直接靶向Gadd45g mRNA的3-UTR区域特异性调控Gadd45g的表达，这一调控过程在人类肿瘤细胞和小鼠胚胎干细胞中保守。这两种成分有可能在癌症化疗中用作抗肿瘤药物。
MicroRNAs (miRNAs) are a class of small non-coding single-stranded RNA molecules that inhibit gene expression at post-transcriptional level. Gadd45g (growth arrest and DNA-damage-inducible 45 gamma) is a stress-response protein, which has been implicated in several biological processes, including DNA repair, the cell cycle and cell differentiation. In this work, we found that miR-383 is a negative regulator of Gadd45g. Forced expression of miR-383 decreased the expression of Gadd45g through binding to the 3′ untranslated region (3′-UTR), whereas inhibition of miR-383 increased Gadd45g expression. The presence of miR-383 increased the cellular sensitivity to DNA damage in breast cancer cells, which was rescued by ectopic expression of Gadd45g without the 3′-UTR. miR-383 also regulates the expression of Gadd45g in embryonic stem (ES) cells, but not their apoptosis under genotoxic stress. miR-383 was further showed to negatively regulate ES cell differentiation via targeting Gadd45g, which subsequently modulates the pluripotency-associated genes. Taken together, our study demonstrates that miR-383 is a negative regulator of Gadd45g in both tumor cells and ES cells, however, has distinct function in regulating cell apoptosis. miR-383 may be used as antineoplastic agents in cancer chemotherapy. We demonstrate for the first time that miR-383 can specifically regulates the expression of Gadd45g by directly targeting to the 3-UTR region of Gadd45g mRNA, a regulatory process conserved in human tumor cells and mouse embryonic stem cells. These two compotents can be potentially used as antineoplastic agents in cancer chemotherapy.
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