Department of Obstetrics and Gynecology, University Hospital, LMU Munich, Munich, Germany.
Department of Obstetrics and Gynecology, University Hospital Augsburg, Augsburg, Germany.
Front Endocrinol (Lausanne). 2020 Sep 18;11:554733. doi: 10.3389/fendo.2020.554733. eCollection 2020.
Establishing reliable prognostic factors as well as specific targets for new therapeutic approaches is an urgent requirement in advanced ovarian cancer. For several tumor entities, the ubiquitously spread scaffold protein β-arrestin 2, a multifunctional scaffold protein regulating signal transduction and internalization of activated G protein-coupled receptors (GPCRs), has been considered with rising interest for carcinogenesis. Therefore, we aimed to elucidate the prognostic impact of β-arrestin 2 and its functional role in ovarian cancer. β-arrestin 2 expression was analyzed in a subset of 156 samples of ovarian cancer patients by immunohistochemistry. Cytoplasmic expression levels were correlated with clinical as well as pathological characteristics and with prognosis. The biologic impact of β-arrestin 2 on cell proliferation and survival was evaluated, . Following transient transfection by increasing concentrations of plasmid encoding β-arrestin 2, different cell lines were evaluated in cell viability and death. β-arrestin 2 was detected in all histological ovarian cancer subtypes with highest intensity in clear cell histology. High β-arrestin 2 expression levels correlated with high-grade serous histology and the expression of the gonadotropin receptors FSHR and LHCGR, as well as the membrane estrogen receptor GPER and hCGβ. Higher cytoplasmic β-arrestin 2 expression was associated with a significantly impaired prognosis (median 29.88 vs. 50.64 months; = 0.025). Clinical data were confirmed in transfected HEK293 cells, human immortalized granulosa cell line (hGL5) and the ovarian cancer cell line A2780 , where the induction of β-arrestin 2 cDNA expression enhanced cell viability, while the depletion of the molecule by siRNA resulted in cell death. Reflecting the role of β-arrestin 2 in modulating GPCR-induced proliferative and anti-apoptotic signals, we propose β-arrestin 2 as an important prognostic factor and also as a promising target for new therapeutic approaches in advanced ovarian cancer.
在晚期卵巢癌中，建立可靠的预后因素以及新治疗方法的特定靶点是当务之急。对于几种肿瘤实体，普遍存在的支架蛋白β-arrestin 2 已成为人们越来越感兴趣的致癌因素，β-arrestin 2 是一种多功能支架蛋白，可调节激活的 G 蛋白偶联受体（GPCR）的信号转导和内化。因此，我们旨在阐明β-arrestin 2 的预后影响及其在卵巢癌中的功能作用。通过免疫组织化学分析了 156 例卵巢癌患者样本中的一小部分β-arrestin 2 的表达。细胞质表达水平与临床和病理特征以及预后相关。通过增加质粒编码β-arrestin 2 的浓度，评估了β-arrestin 2 对细胞增殖和存活的生物学影响。在瞬时转染后，评估了不同细胞系的细胞活力和死亡。β-arrestin 2 在所有组织学卵巢癌亚型中均有检测到，在透明细胞组织学中强度最高。高β-arrestin 2 表达水平与高级别浆液性组织学以及促性腺激素受体 FSHR 和 LHCGR 的表达以及膜雌激素受体 GPER 和 hCGβ 相关。细胞质中β-arrestin 2 表达水平较高与预后显著受损相关（中位数 29.88 与 50.64 个月； = 0.025）。在转染的 HEK293 细胞、人永生化颗粒细胞系（hGL5）和卵巢癌细胞系 A2780 中证实了临床数据，其中β-arrestin 2 cDNA 表达的诱导增强了细胞活力，而 siRNA 耗尽该分子导致细胞死亡。反映了β-arrestin 2 在调节 GPCR 诱导的增殖和抗凋亡信号中的作用，我们提出β-arrestin 2 作为一个重要的预后因素，也是晚期卵巢癌新治疗方法的有前途的靶点。
