Expression of HuR, COX-2, and survivin in lung cancers; cytoplasmic HuR stabilizes cyclooxygenase-2 in squamous cell carcinomas

Hu antigen R (HuR) is a member of the human family of embryonic-lethal, abnormal vision-like proteins, which serves as an mRNA-binding protein. In the cytoplasm, HuR can stabilize the mRNA of cyclooxygenase-2 (COX-2), an enzyme that catalyses the synthesis of prostaglandins and is associated with promotion of carcinogenesis and tumor cell resistance to apoptosis. Intracellular (cytoplasmic and nuclear) localization of survivin has a prognostic significance as an apoptosis inhibitor and a regulator of cell division in tumors. Patients with 151 squamous cell carcinomas and 93 adenocarcinomas underwent lobectomy or pneumonectomy with hilar and mediastinal lymph node sampling. Paraffin-embedded tumor sections were retrieved for evaluation of nuclear and cytoplasmic staining of survivin and HuR, and cytoplasmic staining of COX-2. In squamous cell carcinomas, COX-2 expression was correlated with a difference of survivin (cytoplasmic-nuclear; P=0.004), cytoplasmic HuR (P=0.018), total HuR (cytoplasmic+nuclear; P=0.009), and difference of HuR (P=0.020). COX-2 was inversely correlated with nuclear survivin (P=0.006). In a univariate analysis by log-rank test, survival was associated with cytoplasmic survivin (adenocarcinoma, P<0.001; squamous cell carcinoma, P=0.005), difference of survivin (adenocarcinoma, P<0.001; squamous cell carcinoma, P=0.014), and COX-2 (squamous cell carcinoma, P=0.001). Survival was inversely associated with nuclear survivin (adenocarcinoma, P=0.006, squamous cell carcinoma, P=0.014). In a multivariate survival analysis, cytoplasmic survivin (adenocarcinoma, P=0.002; squamous cell carcinoma, P=0.015) and COX-2 (squamous cell carcinoma, P=0.020) were determined as independent prognostic factors. Cytoplasmic HuR expression is associated with COX-2 expression in squamous cell carcinomas. The expression of COX-2 in squamous cell carcinomas, and cytoplasmic survivin in adenocarcinomas and squamous cell carcinomas could be useful independent prognostic markers. Modern Pathology (2011) 24, 1336-1347; doi:10.1038/modpathol.2011.90; published online 13 May 2011