Abstract
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, in vitro. 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; P = 0.025). Clinical data were confirmed in transfected HEK293 cells, human immortalized granulosa cell line (hGL5) and the ovarian cancer cell line A2780 in vitro, 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.
Highlights
Epithelial ovarian cancer (EOC) is the most lethal gynecological malignancy and is considered the fifth leading cause of death among women [1], mainly due to late diagnosis in advanced tumor stage leading to overall poor prognosis
Our study revealed for the first time that β-arrestin 2 expression significantly correlates with impaired overall survival of ovarian cancer patients and these results are consistent with the proliferative role of β-arrestin 2 demonstrated in vitro. βarrestins are known to act as scaffold proteins controlling multiple cellular functions, such as mitogen-activated protein (MAP) kinase signaling, G protein-coupled receptors (GPCRs) trafficking and transcriptional modulations [38, 39]
Several studies demonstrated that β-arrestins are involved in carcinogenesis of the ovary [11, 18] and other types of cancer [10, 12,13,14,15,16,17]
Summary
Epithelial ovarian cancer (EOC) is the most lethal gynecological malignancy and is considered the fifth leading cause of death among women [1], mainly due to late diagnosis in advanced tumor stage leading to overall poor prognosis. Standard treatment for advanced EOC consists of primary cytoreductive surgery, followed by platinum-based combination chemotherapy followed by targeted therapies like the anti-angiogenic antibody bevacizumab or PARP inhibitors. The most reliable prognostic factors include volume of post-operative residual disease, tumor stage diagnosed according to the International Federation of Gynecology and Obstetrics (FIGO) staging system, patient’s age and histology [2,3,4,5,6,7]. Taking the heterogeneity of ovarian cancer into account appears crucial for developing new prognostic and therapeutic strategies
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