title: HuR cytoplasmic expression is associated with increased cyclin A expression and inferior disease-free survival in patients with gastrointestinal stromal tumours (GISTs).
abstract: OBJECTIVE
  HuR is an RNA-binding protein that post-transcriptionally modulates the expression of various target genes involved in carcinogenesis, such as CCNA2, which encodes cyclin A. The aim of this study was to evaluate the significance of HuR expression and subcellular localization in a large cohort of gastrointestinal stromal tumours (GISTs).
  
  
  RESULTS
  HuR immunostaining was assessable for nuclear and cytoplasmic expression in 341 cases on tissue microarrays of primary GISTs, of which 318, 296 and 193 cases were also characterized for Ki67 labelling, cyclin A immunoexpression, and KIT and PDGFRA receptor tyrosine kinase (RTK) genotypes, respectively. The results of HuR nuclear and cytoplasmic expression were correlated with disease-free survival (DFS) and clinicopathological, immunohistochemical and RTK genotypic variables. HuR cytoplasmic expression was present in 42% of primary GISTs, and was significantly related to epithelioid histology, larger tumour size, NIH risk category, and nuclear expression of Ki67 and cyclin A. Importantly, HuR cytoplasmic expression (P < 0.001) and cyclin A overexpression (P < 0.001) were strongly associated with worse DFS. Both variables remained independently predictive of adverse outcome [P = 0.020 and risk ratio (RR) 2.605 for cytoplasmic HuR; P = 0.026 and RR 2.763 for cyclin A].
  
  
  CONCLUSIONS
  HuR cytoplasmic expression not only correlates with adverse prognosticators and cyclin A overexpression, but also independently predicts worse DFS, indicating a causative role in conferring tumour aggressiveness.
authors.affiliation: Department of Pathology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan; Department of Pathology, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Yu-Ching
authors.initials: YC
authors.lastname: Wei
authors.forename: Fong-Fu
authors.initials: FF
authors.lastname: Chou
authors.forename: Chien-Feng
authors.initials: CF
authors.lastname: Li
authors.forename: Wei-Ming
authors.initials: WM
authors.lastname: Li
authors.forename: Yen-Yang
authors.initials: YY
authors.lastname: Chen
authors.forename: Jui
authors.initials: J
authors.lastname: Lan
authors.forename: Shau-Hsuan
authors.initials: SH
authors.lastname: Li
authors.forename: Fu-Min
authors.initials: FM
authors.lastname: Fang
authors.forename: Tsung-Hui
authors.initials: TH
authors.lastname: Hu
authors.forename: Shih-Chen
authors.initials: SC
authors.lastname: Yu
authors.forename: Hock-Liew
authors.initials: HL
authors.lastname: Eng
authors.forename: Yih-Huei
authors.initials: YH
authors.lastname: Uen
authors.forename: Yu-Fang
authors.initials: YF
authors.lastname: Tian
authors.forename: Jui-Chu
authors.initials: JC
authors.lastname: Wang
authors.forename: Hsuan-Ying
authors.initials: HY
authors.lastname: Huang
mesh_terms: D014408:Biomarkers, Tumor / Q000032:analysis; D019925:Cyclin A / Q000096:biosynthesis*; D003593:Cytoplasm / Q000378:metabolism; D018572:Disease-Free Survival; D051959:ELAV Proteins / Q000096:biosynthesis*; D005260:Female; D046152:Gastrointestinal Stromal Tumors / Q000235:genetics / Q000378:metabolism* / Q000401:mortality*; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics; D046888:Tissue Array Analysis
chemical_list: D014408:Biomarkers, Tumor; D019925:Cyclin A; D051959:ELAV Proteins; D019009:Proto-Oncogene Proteins c-kit; D020796:Receptor, Platelet-Derived Growth Factor alpha
keywords: GIST; HuR; cyclin A; prognosis; receptor tyrosine kinase