Int J Biol Sci 2016; 12(5):545-557. doi:10.7150/ijbs.13540

Research Paper

Upregulation of the Non-Coding RNA OTUB1-isoform 2 Contributes to Gastric Cancer Cell Proliferation and Invasion and Predicts Poor Gastric Cancer Prognosis

Yi-qin Wang1*, Qiong-yan Zhang2,3*, Wei-wei Weng2,3*, Yong Wu2,3, Yu-si Yang2,3, Chen Shen2,3, Xiao-Chen Chen1, Lei Wang2,3, Kai-jing Liu3,4, Mi-die Xu2,3✉, Wei-qi Sheng2,3✉

1. Department of Pathology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, 200011, China
2. Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China;
3. Department of Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China;
4. Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.
* Yi-qin Wang, Qiong-yan Zhang and Wei-wei Weng shared the first-authorships of this article.

Abstract

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.

Keywords: OTUB1-isoform 2, gastric cancer, prognosis, proliferation, invasion.

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How to cite this article:
Wang Yq, Zhang Qy, Weng Ww, Wu Y, Yang Ys, Shen C, Chen XC, Wang L, Liu Kj, Xu Md, Sheng Wq. Upregulation of the Non-Coding RNA OTUB1-isoform 2 Contributes to Gastric Cancer Cell Proliferation and Invasion and Predicts Poor Gastric Cancer Prognosis. Int J Biol Sci 2016; 12(5):545-557. doi:10.7150/ijbs.13540. Available from http://www.ijbs.com/v12p0545.htm