HuR cytoplasmic expression is associated with increased cyclin A expression and inferior disease‐free survival in patients with gastrointestinal stromal tumours (GISTs)

Abstract

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). 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]. 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.