LncRNA-MTA2TR functions as a promoter in pancreatic cancer via driving deacetylation-dependent accumulation of HIF-1α
LncRNA-MTA2TR functions as a promoter in pancreatic cancer via driving deacetylation-dependent accumulation of HIF-1α
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LncRNA-MTA2TR 通过驱动 HIF-1 α 的脱乙酰化依赖性积累，在胰腺癌中充当启动子
DOI：
10.7150/thno.34559
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发表时间：
2019-01-01
期刊：
影响因子：
12.4
通讯作者：
Zhao, Gang
中科院分区：
文献类型：
--
作者：
Zeng, Zhu;Xu, Feng-yu;Zhao, Gang
理由：缺氧已被证明有助于癌症的侵袭性表型，而长链非编码RNA （lncRNA）在缺氧对胰腺癌（PC）肿瘤发生的贡献中的功能和调控机制尚不完全清楚。本研究的目的是揭示缺氧诱导的lncRNA-MTA2TR （MTA2转录调节RNA， af083201 .1）在PC肿瘤发生中的调节和功能作用。方法：采用lncRNA芯片技术证实MTA2TR在PC患者组织中表达。确定MTA2TR对PC细胞和异种移植模型增殖转移的影响，并进一步剖析MTA2TR促进PC的关键机制。此外，我们还评估了缺氧条件下PC细胞中MTA2TR的表达和调控。我们还评估了MTA2TR表达与PC患者临床结果之间的相关性。结果：我们发现转移相关蛋白2 （MTA2）转录调节因子lncRNA （MTA2TR）在PC患者组织中相对于配对的非癌组织过表达。此外，我们发现MTA2TR的缺失在体外和体内都能显著抑制PC细胞的增殖和侵袭。我们进一步证明，MTA2TR通过将活化转录因子3 （ATF3）募集到MTA2的启动子区域，从而通过转录上调MTA2的表达。因此，MTA2可以通过去乙酰化稳定HIF-1 α蛋白，从而进一步激活HIF-1 α的转录活性。有趣的是，我们的研究结果显示MTA2TR在缺氧条件下受HIF-1 α的转录调节。我们的临床样本进一步表明，MTA2TR的过表达与MTA2上调以及PC患者总生存期（OS）降低相关。结论：这些结果表明MTA2TR和HIF-1 α之间的反馈可能在调节PC肿瘤发生中发挥关键作用，从而可能为PC治疗提供新的途径。
Rationale: Hypoxia has been proved to contribute to aggressive phenotype of cancers, while functional and regulatory mechanism of long noncoding RNA (lncRNA) in the contribution of hypoxia on pancreatic cancer (PC) tumorigenesis is incompletely understood. The aim of this study was to uncover the regulatory and functional roles for hypoxia-induced lncRNA-MTA2TR (MTA2 transcriptional regulator RNA, AF083120.1) in the regulation of PC tumorigenesis.Methods: A lncRNA microarray confirmed MTA2TR expression in tissues of PC patients. The effects of MTA2TR on proliferation and metastasis of PC cells and xenograft models were determined, and the key mechanisms by which MTA2TR promotes PC were further dissected. Furthermore, the expression and regulation of MTA2TR under hypoxic conditions in PC cells were assessed. We also assessed the correlation between MTA2TR expression and PC patient clinical outcomes.Results: We found that metastasis associated protein 2 (MTA2) transcriptional regulator lncRNA (MTA2TR) was overexpressed in PC patient tissues relative to paired noncancerous tissues. Furthermore, we found that depletion of MTA2TR significantly inhibited PC cell proliferation and invasion both in vitro and in vivo. We further demonstrated that MTA2TR transcriptionally upregulates MTA2 expression by recruiting activating transcription factor 3 (ATF3) to the promoter area of MTA2. Consequentially, MTA2 can stabilize the HIF-1 alpha protein via deacetylation, which further activates HIF-1 alpha transcriptional activity. Interestingly, our results revealed that MTA2TR is transcriptionally regulated by HIF-1 alpha under hypoxic conditions. Our clinical samples further indicated that the overexpression of MTA2TR was correlated with MTA2 upregulation, as well as with reduced overall survival (OS) in PC patients.Conclusions: These results suggest that feedback between MTA2TR and HIF-1 alpha may play a key role in regulating PC tumorigenesis, thus potentially highlighting novel avenues PC treatment.