Veskimäe K, Scaravilli M, Niininen W, Karvonen H, Jaatinen S, Nykter M, Visakorpi T, Mäenpää J, Ungureanu D, Staff S
Department of Obstetrics and Gynecology, Tampere University Hospital, Tampere, Finland.
BioMediTech Institute, University of Tampere, Tampere, Finland.; Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland.
Transl Oncol. 2018 Oct;11(5):1160-1170. doi: 10.1016/j.tranon.2018.07.010. Epub 2018 Jul 26.
Ovarian cancer has the highest mortality rate of all gynecologic malignancies. Identification of new biomarkers is highly needed due to its late diagnosis and high recurrence rate. The objective of this study was to identify mechanisms of therapy resistance and potential biomarkers by analyzing mRNA and protein expression from samples derived from patients with platinum-sensitive and -resistant ovarian cancer (total cohort n = 53). The data revealed new candidates for targeted therapies, such as GREB1 and ROR2. We showed that the development of platinum resistance correlated with upregulation of ROR2, whereas GREB1 was downregulated. Moreover, we demonstrated that high levels of ROR2 in platinum-resistant samples were associated with upregulation of Wnt5a, STAT3 and NF-kB levels, suggesting that a crosstalk between the non-canonical Wnt5a-ROR2 and STAT3/NF-kB signaling pathways. Upregulation of ROR2, Wnt5a, STAT3 and NF-kB was further detected in a platinum-resistant cell-line model. The results of the present study provided insight into molecular mechanisms associated with platinum resistance that could be further investigated to improve treatment strategies in this clinically challenging gynecological cancer.
卵巢癌是所有妇科恶性肿瘤中死亡率最高的。由于其诊断较晚且复发率高，因此迫切需要鉴定新的生物标志物。本研究的目的是通过分析铂敏感和铂耐药卵巢癌患者样本（总队列n = 53）中的mRNA和蛋白质表达，来确定治疗耐药机制和潜在的生物标志物。数据揭示了新的靶向治疗候选物，如GREB1和ROR2。我们发现铂耐药的发生与ROR2的上调相关，而GREB1则下调。此外，我们证明铂耐药样本中高水平的ROR2与Wnt5a、STAT3和NF-κB水平的上调有关，这表明非经典Wnt5a-ROR2与STAT3/NF-κB信号通路之间存在串扰。在铂耐药细胞系模型中进一步检测到ROR2、Wnt5a、STAT3和NF-κB的上调。本研究结果为与铂耐药相关的分子机制提供了见解，可进一步研究以改善这种具有临床挑战性的妇科癌症的治疗策略。
