title: Upregulation of the Non-Coding RNA OTUB1-isoform 2 Contributes to Gastric Cancer Cell Proliferation and Invasion and Predicts Poor Gastric Cancer Prognosis.
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.
authors.forename: Yi-qin
authors.initials: YQ
authors.lastname: Wang
authors.affiliation: ;
authors.forename: Qiong-yan
authors.initials: QY
authors.lastname: Zhang
authors.affiliation: ;
authors.forename: Wei-wei
authors.initials: WW
authors.lastname: Weng
authors.affiliation: ;
authors.forename: Yong
authors.initials: Y
authors.lastname: Wu
authors.affiliation: ;
authors.forename: Yu-Si
authors.initials: YS
authors.lastname: Yang
authors.affiliation: ;
authors.forename: Chen
authors.initials: C
authors.lastname: Shen
authors.forename: Xiao-chen
authors.initials: XC
authors.lastname: Chen
authors.affiliation: ;
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.affiliation: ;
authors.forename: Kai-jing
authors.initials: KJ
authors.lastname: Liu
authors.affiliation: ;
authors.forename: Mi-die
authors.initials: MD
authors.lastname: Xu
authors.affiliation: ;
authors.forename: Wei-qi
authors.initials: WQ
authors.lastname: Sheng
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics / Q000502:physiology; D049109:Cell Proliferation / Q000235:genetics / Q000502:physiology; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D000072017:Deubiquitinating Enzymes; D018572:Disease-Free Survival; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008819:Mice, Nude; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism*; D062085:RNA, Long Noncoding / Q000378:metabolism*; D013274:Stomach Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
chemical_list: D014408:Biomarkers, Tumor; D020033:Protein Isoforms; D062085:RNA, Long Noncoding; D000072017:Deubiquitinating Enzymes; C538826:OTUB1 protein, human; D003546:Cysteine Endopeptidases
keywords: OTUB1-isoform 2; gastric cancer; invasion.; prognosis; proliferation