Department of Obstetrics and Gynecology, Shimane University School of Medicine, Izumo, Japan.
Am J Clin Pathol. 2012 Oct;138(4):535-44. doi: 10.1309/AJCPKDLRQ8F3EWNS.
This study examined the clinical significance of Notch3 expression and assessed its usefulness as a potential therapeutic target in chemoresistant ovarian cancer. Notch3 expression was assessed with immunohistochemical examination, and clinical variables were collected with a retrospective chart review. Notch3 siRNA or γ-secretase inhibitor was used to assess Notch3 function in ovarian cancer cell lines. Notch3 overexpression correlated with shorter progression-free/overall survival in patients with advanced stage (stage III, IV) ovarian carcinoma treated with platinum and taxane. Three of 5 patients showed increased Notch3 immunostaining in recurrent tumors compared with corresponding primary tumors. Notch3 overexpression was observed in both the cisplatin-resistant KFr13 and cisplatin/paclitaxel-resistant KFr13Tx cells. Inactivation of Notch3 by γ-secretase inhibitor or siRNA decreased cell proliferation and induced apoptosis in the KFr13 and KFr13Tx cells. Our findings suggest that Notch3 expression may be related to chemoresistance and that the Notch3 pathway may represent a novel therapeutic target for advanced stage chemoresistant ovarian cancer.
本研究探讨了 Notch3 表达的临床意义，并评估了其作为化疗耐药性卵巢癌潜在治疗靶点的用途。通过免疫组织化学检查评估 Notch3 表达，并通过回顾性图表审查收集临床变量。使用 Notch3 siRNA 或 γ-分泌酶抑制剂评估 Notch3 在卵巢癌细胞系中的功能。在接受铂类和紫杉烷治疗的晚期（III 期、IV 期）卵巢癌患者中，Notch3 过表达与无进展/总生存期缩短相关。与相应的原发性肿瘤相比，5 例患者中的 3 例在复发性肿瘤中显示 Notch3 免疫染色增加。Notch3 过表达在顺铂耐药的 KFr13 和顺铂/紫杉醇耐药的 KFr13Tx 细胞中均观察到。γ-分泌酶抑制剂或 siRNA 使 Notch3 失活可降低 KFr13 和 KFr13Tx 细胞的增殖并诱导其凋亡。我们的研究结果表明，Notch3 表达可能与化疗耐药性有关，并且 Notch3 途径可能代表晚期化疗耐药性卵巢癌的新治疗靶点。
