Denkert Carsten, Weichert Wilko, Pest Sören, Koch Ines, Licht Dirk, Köbel Martin, Reles Angela, Sehouli Jalid, Dietel Manfred, Hauptmann Steffen
Institute of Pathology and Department of Gynecology and Obstetrics, Charité Hospital, Berlin, Germany.
Cancer Res. 2004 Jan 1;64(1):189-95. doi: 10.1158/0008-5472.can-03-1987.
The human embryonic-lethal abnormal vision-like protein HuR is involved in the regulation of mRNA turnover and serves as a shuttling protein between the nucleus and the cytoplasm that stabilizes mRNAs containing adenine- and uridine-rich elements in their 3' untranslated region. We have shown recently that expression of cyclooxygenase (COX)-2 is related to poor prognosis in ovarian carcinoma. Other studies have shown that the COX-2 mRNA contains an adenine- and uridine-rich element and is stabilized by HuR. In this study, we investigated the expression and cellular distribution of HuR in 83 primary ovarian carcinomas, 16 borderline tumors of the ovary, 3 normal ovaries, and 9 ovarian carcinoma cell lines. Expression of HuR was detected in all cell lines on the mRNA and protein level and showed a predominantly nuclear staining in OVCAR-3 cells by confocal microscopy. In an immunohistochemical evaluation of human ovarian carcinomas, HuR showed a nuclear expression in 81% of tumors. In addition, a cytoplasmic expression of HuR was observed in a subgroup of 45% of ovarian carcinomas. Nuclear as well as cytoplasmic expression of HuR was significantly increased in ovarian carcinomas compared with borderline tumors or normal ovaries. In univariate analysis, a significant association between cytoplasmic HuR expression and increased COX-2 expression (P = 0.025) as well as between histological grade (P = 0.008) and mitotic activity (P = 0.002) was observed, although nuclear expression of HuR was not correlated with COX-2 expression or other clinicopathological parameters. In Kaplan-Meier survival analysis, increased cytoplasmic expression of HuR was a significant prognostic indicator for progression-free survival (P = 0.03) as well as overall survival (P = 0.007). In multivariate analysis using the Cox regression model, cytoplasmic expression of HuR was an independent prognostic parameter for reduced overall survival with a relative risk of 2.62 (95% confidence interval, 1.32-5.19). Our results suggest that there is a dysregulation of cellular distribution of the mRNA stability factor HuR in a subset of invasive ovarian carcinomas. This dysregulation appears to result in an increased expression of COX-2, an increased proliferative rate, and may lead to a reduced survival time. Additional studies are required to analyze the downstream effects of increased cytoplasmic expression of HuR. In addition, it would be interesting to investigate the prognostic role of increased cytoplasmic expression of HuR in prospective studies.
人类胚胎致死性异常视觉样蛋白HuR参与mRNA周转的调控，作为一种穿梭蛋白在细胞核与细胞质之间穿梭，可稳定其3'非翻译区含有富含腺嘌呤和尿嘧啶元件的mRNA。我们最近发现，环氧化酶（COX）-2的表达与卵巢癌预后不良有关。其他研究表明，COX-2 mRNA含有一个富含腺嘌呤和尿嘧啶的元件，并由HuR稳定。在本研究中，我们调查了HuR在83例原发性卵巢癌、16例卵巢交界性肿瘤、3例正常卵巢组织及9株卵巢癌细胞系中的表达及细胞分布情况。在所有细胞系中均检测到HuR在mRNA和蛋白水平的表达，共聚焦显微镜显示，在OVCAR-3细胞中HuR主要呈核染色。在对人卵巢癌的免疫组化评估中，81%的肿瘤中HuR呈核表达。此外，在45%的卵巢癌亚组中观察到HuR的胞质表达。与交界性肿瘤或正常卵巢相比，卵巢癌中HuR的核表达及胞质表达均显著增加。在单因素分析中，观察到HuR胞质表达增加与COX-2表达增加（P = 0.025）以及组织学分级（P = 0.008）和有丝分裂活性（P = 0.002）之间存在显著相关性，尽管HuR的核表达与COX-2表达或其他临床病理参数无关。在Kaplan-Meier生存分析中，HuR胞质表达增加是无进展生存期（P = 0.03）以及总生存期（P = 0.007）的显著预后指标。在使用Cox回归模型的多因素分析中，HuR的胞质表达是总生存期降低的独立预后参数，相对风险为2.62（95%置信区间，1.32 - 5.19）。我们的结果表明，在一部分侵袭性卵巢癌中，mRNA稳定性因子HuR的细胞分布存在失调。这种失调似乎导致COX-2表达增加、增殖率提高，并可能导致生存时间缩短。需要进一步研究来分析HuR胞质表达增加的下游效应。此外，在前瞻性研究中研究HuR胞质表达增加的预后作用将很有意义。
