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

Abstract

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 (cytoplasmicÀ nuclear; P ¼ 0.004), cytoplasmic HuR (P ¼ 0.018), total HuR (cytoplasmic þ nuclear; P ¼ 0.009), and difference of HuR (P ¼ 0.020). COX-2 was inversely correlated with nuclear survivin (P ¼ 0.006). In a univariate analysis by log-rank test, survival was associated with cytoplasmic survivin (adenocarcinoma, Po0.001; squamous cell carcinoma, P ¼ 0.005), difference of survivin (adenocarcinoma, Po0.001; squamous cell carcinoma, P ¼ 0.014), and COX-2 (squamous cell carcinoma, P ¼ 0.001). Survival was inversely associated with nuclear survivin (adenocarcinoma, P ¼ 0.006, squamous cell carcinoma, P ¼ 0.014). In a multivariate survival analysis, cytoplasmic survivin (adenocarcinoma, P ¼ 0.002; squamous cell carcinoma, P ¼ 0.015) and COX-2 (squamous cell carcinoma, P ¼ 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.

Methyl(R217)HuR and MCM6 are inversely correlated and are prognostic markers in non small cell lung carcinoma

“…They found that in normal intestinal epithelium, miR-16 bound to COX-2 mRNA and inhibited its expression via promoting cox-2 mRNA decay, and that when HuR was overexpressed, miR16 could no longer bound to the cox-2 transcript, leading to COX-2 overexpression [40]. In lung cancer, similar interplays between HuR and COX-2 have been reported as well [23,38]. Other putative miR16 targets include BCL2 and NF-kappaB1/MMP-9 signaling pathway [41].…”

“…Recently, in a series of 81 surgically resected NSCLC, Giaginis et al reported that total HuR overexpression was correlated with poor clinical outcome [23]. On the contrary, Kim et al did not find any significant correlation between HuR and prognosis, despite the inclusion of 244 cases of NSCLC [38]. In our study, we found a significant cytoplasmic overexpression of HuR in tumor tissues vs. the adjacent normal tissue, but we found no significant correlation between the cytoplasmic staining of HuR and survival.…”

MiR-291b-3p Induces Apoptosis in Liver Cell Line NCTC1469 by Reducing the Level of RNA-binding Protein HuR

“…However, HuR exerts its effects in two distinctive ways. First, HuR can act as a positive regulator of gene expression by increasing the stability of target mRNAs, such as cox-2, cyclin D1, p21 and so on [13,41,42]. However, HuR has also been found to decrease the translation efficiency of some mRNAs, such as TNFα, c-myc, and p27 [43,44,45].…”

Post-transcriptional regulation of cytokine and growth factor signaling in cancer

“…Overexpression of the stabilizing protein ELAVL1 is strongly associated with proliferation: in cancer cell models, mice and in humans [61–66]. In fact, the link between ELAVL1 and cancer was initially discovered through observations of increased TNFα, VEGF, TGFβ, COX2, and CXCL8 mRNA expression in colon or brain cancer cells [67–69].…”