Upregulation Of Estrogen Receptor Beta Protein But Not Mrna Predicts Poor Prognosis And May Be Associated With Enhanced Translation In Non-Small Cell Lung Cancer: A Systematic Review And Meta-Analysis

Background: An increasing number of original studies suggest that estrogen receptor beta (ER beta) expression may be related to non-small cell lung cancer (NSCLC) prognosis; however, the evidence remains inconclusive and conflicting. We aimed to systematically evaluate the expression and prognostic value of ER beta in NSCLC, and to explain the inconsistency between ER beta protein and mRNA level.Methods: PubMed, Embase, and Web of Science databases were searched for studies (published before October 6, 2020) reporting the prognostic value of ER beta protein expression in NSCLC. The pooled hazard ratios (HRs) with 95% confidence intervals (CIs) for overall survival (OS) were calculated. Transcriptome and survival data of lung adenocarcinoma patients were obtained from public databases for differential expression and survival analyses. Immunohistochemistry (IHC) was performed to examine the ER beta protein expression in 39 NSCLC patients. Western blotting and RT-qPCR were performed to analyze ER beta expression in two paired NSCLC and normal adjacent tissue samples. The effect of methyltransferase-like 13 (METTL3) on ER beta expression was investigated in a lung cancer cell line.Results: Meta-analysis of 23 studies with a total of 3744 patients demonstrated that high protein expression of overall ER beta and cytoplasmic ER beta indicated poor OS (HR: 1.05, 95% CI: 1.00 to 1.10; HR: 1.48, 95% CI: 1.13 to 1.95) in NSCLC. For lung adenocarcinoma especially, high protein expression of both overall/ cytoplasmic ER beta and nuclear ER beta suggested poor OS (HR: 1.54, 95% CI: 1.05 to 2.25; 1.36, 95% CI: 1.03 to 1.80). Bioinformatics analysis indicated the expression of ER beta mRNA was not associated with the prognosis of lung adenocarcinoma. Analysis of public databases showed that ER beta mRNA is not highly expressed in tumor tissues, however, IHC results revealed that ER beta protein is highly expressed in NSCLC tissues. We validated this inconsistency in ER beta expression in paired tumors and normal adjacent tissues from patients. Moreover, METTL3 knockdown in the A549 cell line downregulated ER beta protein expression but not ERB mRNA expression.Conclusions: Our study elucidated the inconsistency between ER beta protein and mRNA expression levels and their prognostic values. The results indicated that METTL3-driven enhanced translation in NSCLC may cause this inconsistency.