Expression of the embryonic lethal abnormal vision‐like protein HuR in human mesothelioma

Abstract

BACKGROUND. The human embryonic lethal abnormal vision (ELAV)‐like protein HuR is a messenger RNA (mRNA)‐binding protein that controls the stability of certain transcripts, including cyclooxygenase2 (COX‐2). METHODS. To investigate a possible contribution of dysregulation of mRNA stability to the progression of cancer and to COX‐2 over expression in mesothelioma, the authors studied expression of COX‐2 and HuR in 5 mesothelioma cell lines (MSTO, NCI, Ist‐Mes1, Ist‐Mes2, and MPP89) and in a group of 29 human mesothelioma specimens that were characterized previously for COX‐2 expression. RESULTS. All 5 cell lines expressed HuR, whereas COX‐2 was not detectable in MSTO or NCI cells. Treatment with cytokines induced a shift in systolic HuR protein levels in MPP89 and Ist‐Mes2 cells that was accompanied by an increase in the expression of COX‐2 mRNA and protein. In Ist‐Mes1 cells, cytokine stimulation did not cause the passage of HuR from nucleus to cytoplasm, and the synthesis of COX‐2 did not increase. In tumor tissues, immunohistochemistry revealed a positive, statistically significant correlation between high COX‐2 expression and cytoplasmic localization of HuR (P = .016). Moreover, on univariate analysis, overall survival was found to be influenced strongly by cytoplasmic HuR localization (P = .004). CONCLUSIONS. The current results suggested that HuR plays a role in tumor progression in mesothelioma and that COX‐2 may be a target of its activity in neoplastic cells. Together, these observations indicate that strategies aiming toward the modulation of HuR may have a potential clinical benefit in mesothelioma. Cancer 2008. © 2008 American Cancer Society.

Cytoplasmic HuR expression correlates with angiogenesis, lymphangiogenesis, and poor outcome in lung cancer

“…Our results are in line with previous findings of cytoplasmic overexpression of HuR in breast [19], ovarian [17], mesothelioma [16], and colorectal cancer [18], and our results indicate that subcellular localization of HuR is deregulated in a subset of lung cancers. Because angiogenesis and lymphangiogenesis correlated with cytoplasmic HuR expression, and high LVD and MVD have been shown to be linked to reduced survival in patients with lung cancer [22], one plausible explanation for this phenomenon is that HuR mediates its effect, at least in part, by induction of tumor-associated lymphangiogenesis and angiogenesis.…”

“…There are usually one or several AREs in the 3 0 UTR of these mRNAs that provide the binding sites for HuR, resulting in an increased mRNA half-life [15]. In addition, HuR gene overexpression occurs in a variety of malignant cancers and is related to tumor progression and poor prognosis in patients with mesothelioma [16], ovarian [17], and colon cancer [18]. Based on the known functions of HuR, we believe that HuR might exert an important function in cell cycle regulation, apoptosis, angiogenesis, inflammation, and tumor growth.…”

Cyclooxygenase-2, Epidermal Growth Factor Receptor, and Aromatase Signaling in Inflammation and Mesothelioma

“…In cancer cells, it was previously shown that altered posttranscriptional regulation of COX-2 is mediated by increased cytoplasmic mRNA binding of the mRNA stability factor HuR (33). In malignant mesothelioma, the cytoplasmic expression of HuR was significantly correlated with high COX-2 expression and with poor survival (34). Finally, COX-2 has been proposed to exert its influence on mesangial cell proliferation in vitro by a novel mechanism involving the tumor suppressor p53 and the cell-cycle inhibitors p21 and p27 (35).…”

The Role of Cyclooxygenase-2, Epidermal Growth Factor Receptor and Aromatase in Malignant Mesothelioma

“…In cancer cells, it was demonstrated previously that altered post-transcriptional regulation of COX-2 is mediated by increased cytoplasmic mRNA binding of the mRNA stability factor HuR (Dixon et al, 2001). In MM, the cytoplasmic expression of HuR was correlated significantly with high COX-2 expression and with poor survival (Stoppoloni et al,2008). Finally, COX-2 has been proposed to exert its influence on mesangial cell proliferation in vitro by a novel mechanism involving the tumor suppressor p53 and the cell cycle inhibitors p21 and p27 (Zahner et al, 2002).…”