Depletion of poly(A)-specific ribonuclease (PARN) inhibits proliferation of human gastric cancer cells by blocking cell cycle progression
Depletion of poly(A)-specific ribonuclease (PARN) inhibits proliferation of human gastric cancer cells by blocking cell cycle progression
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聚腺苷酸特异性核糖核酸酶 (PARN) 的消耗通过阻断细胞周期进程来抑制人胃癌细胞的增殖
DOI：
10.1016/j.bbamcr.2014.12.004
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发表时间：
2015-02-01
影响因子：
5.1
通讯作者：
Yan, Yong-Bin
中科院分区：
文献类型：
--
作者：
Zhang, Li-Na;Yan, Yong-Bin
mRNA降解的调节在细胞生长、存活、分化、死亡和衰老的转录后控制中起着至关重要的作用。脱腺苷酸化是大量高度调节的mRNA沉默和降解的限速步骤。然而，各种去腺苷酸酶的生理功能尚未完全破译。本研究中，我们发现在胃癌组织和胃癌细胞系MKN 28和AGS中，聚腺苷酸特异性核糖核酸酶（PARN）表达上调。通过稳定敲低MKN 28和AGS细胞中的内源性PARN来研究PARN的细胞功能。我们的研究结果表明，PARN的去除显着抑制两种类型的胃癌细胞的增殖和促进细胞死亡，但没有显着影响细胞的运动和侵袭。PARN的缺失通过上调p53和p21的表达水平而不是p27的表达水平将胃癌细胞阻滞在G（0）/G（1）期。P53的mRNA稳定性在两种类型的细胞中均不受PARN敲低的影响。在AGS细胞中观察到PARN耗竭对p21 mRNA的显著稳定作用，但在MKN 28细胞中未观察到。我们进一步证明了p21 3 '-UTR在AGS细胞中触发了PARN的作用。MKN 28和AGS细胞之间的不同观察结果以及各种应激条件表明，PARN的作用强烈依赖于细胞的蛋白质表达谱，这导致PARN靶向mRNA稳定性的异质性。(C)2014爱思唯尔有限公司版权所有。
Regulation of mRNA decay plays a crucial role in the post-transcriptional control of cell growth, survival, differentiation, death and senescence. Deadenylation is a rate-limiting step in the silence and degradation of the bulk of highly regulated mRNAs. However, the physiological functions of various deadenylases have not been fully deciphered. In this research, we found that poly(A)-specific ribonuclease (PARN) was upregulated in gastric tumor tissues and gastric cancer cell lines MKN28 and AGS. The cellular function of PARN was investigated by stably knocking down the endogenous PARN in the MKN28 and AGS cells. Our results showed that PARN-depletion significantly inhibited the proliferation of the two types of gastric cancer cells and promoted cell death, but did not significantly affect cell motility and invasion. The depletion of PARN arrested the gastric cancer cells at the G(0)/G(1) phase by upregulating the expression levels of p53 and p21 but not p27. The mRNA stability of p53 was unaffected by PARN-knockdown in both types of cells. A significant stabilizing effect of PARN-depletion on p21 mRNA was observed in the AGS cells but not in the MKN28 cells. We further showed that the p21 3'-UTR triggered the action of PARN in the AGS cells. The dissimilar observations between the MKN28 and AGS cells as well as various stress conditions suggested that the action of PARN strongly relied on protein expression profiles of the cells, which led to heterogeneity in the stability of PARN-targeted mRNAs. (C) 2014 Elsevier B.V. All rights reserved.