Upregulation of the Non-Coding RNA OTUB1-isoform 2 Contributes to Gastric Cancer Cell Proliferation and Invasion and Predicts Poor Gastric Cancer Prognosis.
Upregulation of the Non-Coding RNA OTUB1-isoform 2 Contributes to Gastric Cancer Cell Proliferation and Invasion and Predicts Poor Gastric Cancer Prognosis.
复制标题
非编码 RNA OTUB1-亚型 2 的上调有助于胃癌细胞增殖和侵袭并预测胃癌不良预后
DOI：
10.7150/ijbs.13540
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发表时间：
2016
影响因子：
9.2
通讯作者：
Sheng WQ
中科院分区：
文献类型：
--
作者：
Wang YQ;Zhang QY;Weng WW;Wu Y;Yang YS;Shen C;Chen XC;Wang L;Liu KJ;Xu MD;Sheng WQ
背景：去泛素酶OTUB1在癌症中起着重要的致瘤作用并促进肿瘤进展。然而，对于非编码RNA OTUB1-isoform 2的异常表达、临床意义和生物学功能了解较少。我们旨在评估胃癌中OTUB1-isoform 2的表达水平及其与临床病理特征和患者生存的可能相关性，以揭示其在胃癌进展中的生物学作用。方法：对156例胃癌病例标本进行总RNA提取，并进行RT-qPCR检测。采用卡方检验分析计算病理参数与OTUB1-isoform 2 mRNA水平的相关性。采用Kaplan-Meier和Cox比例风险分析分析总生存率（OS）和无病生存率（DFS）。分离细胞核和细胞质rna，检测otub1 -亚型2的亚细胞定位。我们还评估了OTUB1-isoform 2过表达是否影响体外细胞增殖、细胞周期进展、肿瘤细胞侵袭和迁移以及体内裸鼠异种移植和转移模型。结果：otub1 -异构体2在胃癌组织中的表达水平高于瘤旁腺组织。otub1 - isoform2表达水平与肿瘤大小、淋巴结转移及TNM分期密切相关。较高的OTUB1-isoform 2表达水平导致OS和DFS发生率显著降低，多因素分析显示OTUB1-isoform 2是DFS的独立危险因素。otub1 -异构体2主要定位于细胞核。胃癌细胞中OTUB1-isoform 2异位过表达通过诱导G1-S转化、抑制细胞凋亡、促进肿瘤细胞侵袭迁移等方式刺激增殖。最后，在裸鼠模型中，OTUB1-isoform 2过表达促进肿瘤生长和肿瘤转移。结论：本研究提示otub1 -亚型2独立预测胃癌不良预后并促进肿瘤进展。非编码RNA OTUB1-isoform 2应该成为未来分子治疗的靶标。
Background: The deubiquitinase OTUB1 plays critical oncogenic roles and facilitates tumor progression in cancer. However, less is known regarding the aberrant expression, clinical significance and biological functions of the non-coding RNA OTUB1-isoform 2. We aimed to evaluate the OTUB1-isoform 2 levels in gastric cancer and their possible correlation with clinicopathologic features and patient survival to reveal its biological effects in gastric cancer progression. Methods: Total RNA extraction was performed on 156 gastric cancer case samples, and RT-qPCR was conducted. Chi-square test analysis was used to calculate the correlation between pathological parameters and the OTUB1-isoform 2 mRNA levels. Kaplan-Meier and Cox proportional hazards analyses were used to analyze the overall survival (OS) and disease-free survival (DFS) rates. Nuclear and cytoplasmic RNAs were isolated to detect the subcellular localization of OTUB1-isoform 2. We also assessed whether overexpression of OTUB1-isoform 2 influenced in vitro cell proliferation, cell cycle progression, tumor cell invasion and migration, as well as in vivo nude mouse xenograft and metastasis models. Results: The OTUB1-isoform 2 expression levels were higher in the gastric cancer samples than in the paratumorous gland samples. OTUB1-isoform 2 expression levels tightly correlated with tumor size, lymph node metastasis and TNM staging. Higher OTUB1-isoform 2 expression levels led to significantly poorer OS and DFS rates, and a multivariate analysis revealed that OTUB1-isoform 2 was an independent risk factor for DFS. OTUB1-isoform 2 was predominantly localized in the cell nucleus. Ectopic overexpression of OTUB1-isoform 2 in gastric cancer cells stimulated proliferation by inducing G1-S transition, suppression of cell apoptosis and promotion of tumor cell invasion and migration. Finally, OTUB1-isoform 2 overexpression promoted tumor growth and tumor metastasis in nude mice models. Conclusions: Our study suggests that OTUB1-isoform 2 independently predicts poor prognosis and promotes tumor progression in gastric cancer. The non-coding RNA OTUB1-isoform 2 should be targeted in future molecular therapies.