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Long noncoding RNA PVT1-214 promotes proliferation and invasion of colorectal cancer by stabilizing Lin28 and interacting with miR-128.
Oncogene ( IF 6.9 ) Pub Date : 2019-Jan-01 , DOI: 10.1038/s41388-018-0432-8
Feng He 1, 2, 3 , Zhi Song 3, 4 , Huacui Chen 1, 3, 5 , Zhuanpeng Chen 1 , Ping Yang 1 , Wanglin Li 1 , Zhi Yang 1 , Tong Zhang 1 , Fei Wang 1 , Jianchang Wei 1 , Fang Wei 1 , Qiang Wang 1 , Jie Cao 1, 5
Affiliation  

Long noncoding RNAs (lncRNAs) are implicated in human cancer, but their mechanisms of action are largely unknown. In this study, we investigated lncRNA alterations that contribute to colorectal cancer (CRC) through microarray expression profiling in CRC patient samples. Here, we report that the CRC-associated lncRNA PVT1-214 is a key regulator of CRC development and progression; patients with high PVT1-214 expression had a shorter survival and poorer prognosis. In vitro and in vivo investigation of the role of PVT1-214 revealed a complex integrated phenotype affecting cell growth, stem-like properties, migration, and invasion. Furthermore, using RNA pull-down and mass spectrometry, we found that Lin28 (also known as Lin28A), a highly conserved RNA-binding protein, is associated with PVT1-214. Strikingly, we found that PVT1-214 not only upregulated Lin28 protein expression in CRC cells by stabilizing Lin28, but also participated in crosstalk with Lin28 mRNA through competition for miR-128 binding, imposing an additional level of post-transcriptional regulation. In addition, we further show that PVT1-214 repressed expression of let-7 family miRNAs, which was abrogated by Lin28 knockdown. Taken together, our findings support a model in which the PVT1-214/Lin28/let-7 axis serves as a critical regulator of CRC pathogenesis, which may simulate a new direction for CRC therapeutic development.

中文翻译:

长链非编码 RNA PVT1-214 通过稳定 Lin28 并与 miR-128 相互作用促进结直肠癌的增殖和侵袭。

长链非编码 RNA (lncRNA) 与人类癌症有关,但其作用机制在很大程度上是未知的。在这项研究中,我们通过 CRC 患者样本中的微阵列表达谱研究了导致结直肠癌 (CRC) 的 lncRNA 改变。在这里,我们报告了 CRC 相关的 lncRNA PVT1-214 是 CRC 发展和进展的关键调节因子;PVT1-214高表达的患者生存期较短,预后较差。PVT1-214 作用的体外和体内研究揭示了影响细胞生长、干细胞样特性、迁移和侵袭的复杂综合表型。此外,使用 RNA pull-down 和质谱法,我们发现 Lin28(也称为 Lin28A)是一种高度保守的 RNA 结合蛋白,与 PVT1-214 相关。引人注目的是,我们发现 PVT1-214 不仅通过稳定 Lin28 上调 CRC 细胞中的 Lin28 蛋白表达,而且还通过竞争 miR-128 结合参与与 Lin28 mRNA 的串扰,施加额外的转录后调控水平。此外,我们进一步表明 PVT1-214 抑制了 let-7 家族 miRNA 的表达,这被 Lin28 敲低所废除。总之,我们的研究结果支持了一个模型,其中 PVT1-214/Lin28/let-7 轴作为 CRC 发病机制的关键调节因子,这可能模拟 CRC 治疗发展的新方向。我们进一步表明 PVT1-214 抑制了 let-7 家族 miRNA 的表达,这被 Lin28 敲低消除了。总之,我们的研究结果支持了一个模型,其中 PVT1-214/Lin28/let-7 轴作为 CRC 发病机制的关键调节因子,这可能模拟 CRC 治疗发展的新方向。我们进一步表明 PVT1-214 抑制了 let-7 家族 miRNA 的表达,这被 Lin28 敲低消除了。总之,我们的研究结果支持了一个模型,其中 PVT1-214/Lin28/let-7 轴作为 CRC 发病机制的关键调节因子,这可能模拟 CRC 治疗发展的新方向。
更新日期:2018-08-03
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