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

Abstract

HuR is a ubiquitously expressed RNA-binding protein that stabilizes the mRNAs of certain genes and regulates the translation to proteins. Elevated cytoplasmic expression of HuR has been suggested to be associated with reduced survival in a wide variety of human carcinomas. However, the clinical significance of HuR expression in lung cancer remains unknown. In this study, we examined HuR expression in 132 patients with non-small cell lung carcinoma (NSCLC) by means of immunohistochemistry and correlated clinicopathologic data, lymphatic microvessel density (LVD), or microvessel density (MVD) with HuR immunostaining. HuR was expressed in 80.3% (106/132) of cases and was predominantly localized in the nucleus. Cytoplasmic HuR expression occurred in 40.9% (54/132) of NSCLC specimens and was associated with high MVD and LVD. In univariate analysis, cytoplasmic HuR, but not nuclear HuR expression was found to significantly influence the relapse-free survival and overall survival. In addition, cytoplasmic expression of HuR was identified as an independent prognostic factor for survival in multivariate analysis. Our data provide evidence for a clinically prognostic role of HuR in NSCLC and demonstrate an association between HuR expression, and angiogenesis and lymphangiogenesis.

High Expression of HuR in Cytoplasm, but Not Nuclei, Is Associated with Malignant Aggressiveness and Prognosis in Bladder Cancer

“…Our results support former situation in patients with bladder cancer. As a mechanism underlying such pathological activities of HuR, regulation of angiogenesis has been suggested in various cancers [3], [4]. Special attention was paid to the relationships between HuR expression, malignant potential and pathological features because stimulation of angiogenesis has been linked to tumor growth and progression in patients with several malignancies, including bladder cancer [13], [22].…”

“…In addition, HuR has been found to be involved in the regulation of angiogenesis by interacting with the transcripts of numerous angiogenesis-promoting factors, and is also known to correlate with lymphangiogenesis in a variety of pathological conditions, including cancer [3], [4]. Based on these facts, it has been suggested that HuR plays important roles in carcinogenesis, tumor growth, metastasis, and prognosis in malignancies.…”

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

“…In lung cancer, several teams reported significant cytoplasmic HuR overexpressions in the cancer tissues, with an impact on the prognosis of the disease. In a series of 132 NSCLC, Wang et al found that cytoplasmic expression of HuR was an independent prognostic factor for survival in multivariate analysis [24,25]. Similarly, Lauriola et al showed, in 54 lung adenocarcinomas of stage I and II, an unfavorable independent prognostic value of the cytoplasmic, but not the nuclear expression of HuR [22].…”

“…In lung cancer, several studies have reported the prognostic value of cytoplasmic HuR [22][23][24][25][26]. If most of the evidence associates cytoplasmic HuR to cancer proliferation, the unfavorable prognostic value of nuclear HuR has, on the other hand, been demonstrated in ovarian [27] and colo-rectal carcinomas [28].…”

HuR-Regulated mRNAs Associated with Nuclear hnRNP A1-RNP Complexes

“…Based on studies with individual mRNAs, HuR has been initially implicated in regulating alternative pre-mRNA splicing and cleavage/polyadenylation events [13,21,42,57,58]. At a transcriptome-wide level, the recently applied combined methods of PAR-CLIP and RIP-Chip assays unraveled a surprisingly large number of RNA-HuR interactions occurring in introns (1/3 of all associations) with many of them in the proximity of 3′ splice sites [22,41,42].…”