Expression of the RNA-binding protein HuR and its clinical significance in human stage I and II lung adenocarcinoma

The ubiquitously expressed RNA-binding protein Hu antigen (HuR) participates in the post-transcriptional regulation of mRNAs bearing U- and AU-rich sequences. Expression of HuR is increased in cancers of the breast, colon, ovary and lung and cytoplasmic immunoreactivity for HuR was found to be closely related to poor outcomes in patients with these tumors. Since the regulation of HuR function is closely linked to its subcellular localization, we evaluated, by quantitative immunohistochemistry, the impact on clinical outcome of both nuclear and cytoplasmic levels (integrated density: ID) of HuR and of nuclear/cytoplasmic ratio (N/C) in 54 lung adenocarcinomas from stage I and II patients. Nuclear and cytoplasmic Hur IDs and N/C were not associated with age, smoking or tumor diameter. Low N/C was significantly associated with lymph-node involvement at presentation. Cox's regression analysis showed that high cytoplasmic, but not nuclear, HuR ID and low N/C were directly associated with the risk of death and metastasis. In the multivariate analysis, low HuR N/C retained an independent negative prognostic significance relative to the risk of metastasis and death. Moreover, the levels of N/C allowed us to discriminate subjects with the highest risk of metastasis and death among patients with lung adenocarcinomas expressing high levels of cytoplasmic HuR. In conclusion, the measure of the ratio between nuclear and cytoplasmic HuR levels allows a sensitive prognostic evaluation of the clinical outcome in early stage lung adenocarcinoma patients.