Elevated Hu-Antigen Receptor (HuR) Expression is Associated with Tumor Aggressiveness and Poor Prognosis but not with COX-2 Expression in Invasive Breast Carcinoma Patients

Abstract

Hu-antigen R (HuR), a RNA-binding protein, is considered to play a crucial role in tumor development and progression by stabilizing or regulating a group of cellular mRNAs of cancer-related genes, such as cyclooxygenase-2 (COX-2). The present study aimed to evaluate the clinical significance of HuR and COX-2 expression in invasive breast carcinoma. HuR and COX-2 protein expression was assessed immunohistochemically on paraffin-embedded breast cancer tissue sections obtained from 121 patients and was statistically analyzed with clinicopathological parameters, estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2), as well as with tumor cells' proliferative capacity and overall and disease-free patients' survival. High HuR expression was positively associated with larger tumor size and advanced disease stage (p = 0.0234 and p = 0.0361, respectively), being more frequently observed in ER negative cases (p = 0.0208). High COX-2 expression was negatively associated with histological (p < 0.0001) and nuclear (p = 0.0033) grade and tumor cells' proliferative rate (p = 0.0015), being more frequently observed in luminal-A compared to other molecular subtypes (p = 0.0221). High HuR expression was associated with poor overall and disease-free patients' survival at both univariate (log-rank test, p = 0.0092 and p = 0.0004, respectively) and multivariate (Cox-regression analysis, p = 0.0223 and p = 0.0004, respectively) level. On the other hand, high COX-2 expression was associated with favorable overall and disease-free patients' survival merely at univariate level (log-rank test, p = 0.0389 and p = 0.0154, respectively). HuR expression was not associated with COX-2 expression (Spearman R = 0.1489, p = 0.1032). The present data support evidence that HuR is associated with tumor aggressiveness and poor prognosis in breast carcinoma, reinforcing its potential as promising therapeutic target in this type of neoplasia.

Human antigen R promotes lung fibroblast differentiation to myofibroblasts and increases extracellular matrix production

“…Indeed, the histological evaluation shows that in nonmalignant (normal) tissue, HuR is predominantly found in the nucleus, whereas in cancerous tumors, HuR is cytoplasmic (Stoppoloni et al, 2008; J. Wang et al, 2009). This increase in cytoplasmic HuR also strongly correlates with higher tumor grade and poorer patient outcomes (Giaginis et al, 2017), including worse prognosis (Stoppoloni et al, 2008; J. Wang et al, 2009). Our data show that there is a notable increase in cytoplasmic HuR in vimentin‐positive cells from IPF lung compared to the largely nuclear HuR in control (nonfibrotic) lung.…”

“…Studies have shown that myofibroblasts from patients with IPF have increased protein translation, especially from messenger RNA (mRNA) that encodes ECM (Larsson et al, 2008). Although the importance of posttranscriptional events in the context of pulmonary fibrosis remains largely unknown, several RNA binding proteins, including human antigen R (HuR), have been shown to play an important role in the etiology of several human pathologies (Giaginis et al, 2017). HuR is a member of the Hu/embryonic lethal, abnormal vision (ELAV) family of RNA binding proteins that is encoded by the ELAVL1 gene.…”

“…In the lung, HuR is found in many cell types, including epithelial cells and fibroblasts (Fan et al, 2011; Zago et al, 2013). Members of the ELAV family control the fate of mRNA by modulating their turnover (stability or decay), localization, and translation (Giaginis et al, 2017; Mukherjee et al, 2011; W. Wang et al, 2002). HuR is best‐known to stabilize target mRNA by binding to adenylate‐and uridylate‐rich elements in the 3’‐untranslated regions (Myer et al, 1997).…”

Decreased human antigen�R expression confers resistance to�tyrosine kinase inhibitors in epidermal growth factor receptor-mutant lung cancer by inhibiting Bim expression

“…HuR has been reported to be associated with numerous human carcinomas, including breast (40), liver (41), pancreatic (42), ovarian (43,44) and colorectal cancer, as well as NScLc (45,46). Recently published studies indicated that elevated HuR expression is associated with aggressiveness and poor prognosis in patients with invasive breast carcinoma and lung carcinoma (47,48). Furthermore, HuR also stabilizes mRNAs encoding crucial regulators of cellular proliferation, differentiation and stress response, such as cyclins (49), cyclooxygenase-2 (50,51), p21 (52), HER2 (53) and Bcl-2 (54,55).…”

Non-specific protein modifications may be novel mechanism underlying bioactive phytochemicals

“…( 71 ) Also, a COX-2 mRNA AU-rich element-binding protein, Hu-antigen R (HuR), has been shown to have a detrimental effect on COX-2 mRNA half-life. ( 72 ) In another study, we prepared sepharose beads, which zerumbone bound to. ( 73 ) A competitive pull-down assay of cell lysate from RAW264.7 mouse macrophages incubated with zerumbone-bound sepharose beads with or without increased concentration of zerumbone was then conducted.…”