Pinton Giulia, Brunelli Elisa, Murer Bruno, Puntoni Riccardo, Puntoni Matteo, Fennell Dean A, Gaudino Giovanni, Mutti Luciano, Moro Laura
Dipartimento di Scienze Chimiche, Alimentari, Farmaceutiche e Farmacologiche and Drug and Food Biotechnology Center, University of Piemonte Orientale A. Avogadro, Novara, Italy.
Cancer Res. 2009 Jun 1;69(11):4598-604. doi: 10.1158/0008-5472.CAN-08-4523.
Malignant pleural mesothelioma is an asbestos-related neoplasm with poor prognosis, refractory to current therapies, the incidence of which is expected to increase in the next decades. Female gender was identified as a positive prognostic factor among other clinical and biological prognostic markers for malignant mesothelioma, yet a role of estrogen receptors (ERs) has not been studied. Our goal was to investigate ERs expression in malignant mesothelioma and to assess whether their expression correlates with prognosis. Immunohistochemical analysis revealed intense nuclear ERbeta staining in normal pleura that was reduced in tumor tissues. Conversely, neither tumors nor normal pleura stained positive for ERalpha. Multivariate analysis of 78 malignant mesothelioma patients with pathologic stage, histologic type, therapy, sex, and age at diagnosis indicated that ERbeta expression is an independent prognostic factor of better survival. Moreover, studies in vitro confirmed that treatment with 17beta-estradiol led to an ERbeta-mediated inhibition of malignant mesothelioma cell proliferation as well as p21(CIP1) and p27(KIP1) up-regulation. Consistently cell growth was suppressed by ERbeta overexpression, causing a G(2)-M-phase cell cycle arrest, paralleled by cyclin B1 and survivin down-regulation. Our data support the notion that ERbeta acting as a tumor suppressor is of high potential relevance to prediction of disease progression and to therapeutic response of malignant mesothelioma patients.
恶性胸膜间皮瘤是一种与石棉相关的肿瘤，预后较差，对当前治疗方法具有耐药性，预计其发病率在未来几十年将会上升。在恶性间皮瘤的其他临床和生物学预后标志物中，女性被确定为一个积极的预后因素，但雌激素受体（ERs）的作用尚未得到研究。我们的目标是研究ERs在恶性间皮瘤中的表达，并评估其表达是否与预后相关。免疫组织化学分析显示，正常胸膜中ERβ呈强烈的细胞核染色，而在肿瘤组织中这种染色减少。相反，肿瘤组织和正常胸膜中ERα均未呈阳性染色。对78例恶性间皮瘤患者进行多因素分析，纳入病理分期、组织学类型、治疗方法、性别和诊断时年龄等因素，结果表明ERβ表达是生存期较好的独立预后因素。此外，体外研究证实，17β-雌二醇治疗可导致ERβ介导的恶性间皮瘤细胞增殖抑制以及p21（CIP1）和p27（KIP1）上调。同样，ERβ过表达可抑制细胞生长，导致G（2）-M期细胞周期停滞，同时细胞周期蛋白B1和生存素下调。我们的数据支持这样一种观点，即作为肿瘤抑制因子的ERβ对预测恶性间皮瘤患者的疾病进展和治疗反应具有高度潜在相关性。
