Lewis y和CAM-DR相关标志物的膜表达是上皮性卵巢癌化疗耐药和预后不良的独立因素。
Membranous expressions of Lewis y and CAM-DR-related markers are independent factors of chemotherapy resistance and poor prognosis in epithelial ovarian cancer.
作者信息
Zhu Lian-Cheng, Gao Jian, Hu Zhen-Hua, Schwab Carlton L, Zhuang Hui-Yu, Tan Ming-Zi, Yan Li-Mei, Liu Juan-Juan, Zhang Dan-Ye, Lin Bei
机构信息
Department of Obstetrics and Gynecology, Shengjing Hospital Affiliated to China Medical University 36 Sanhao Street, Shenyang, Liaoning, 110004, China.
Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine 333 Cedar Street, PO Box 208063, New Haven, Connecticut 06520-8063, USA.
出版信息
Am J Cancer Res. 2015 Jan 15;5(2):830-43. eCollection 2015.
BACKGROUND
Chemotherapy resistance is a common problem faced by patients diagnosed with epithelial ovarian cancer (EOC). Currently there are no specific or sensitive clinical biomarkers that maybe implemented to identify chemotherapy resistance and give insight to prognosis. The aim of this study is to investigate the roles of Lewis y antigen and the markers associated with cell-adhesion-mediated drug resistance (CAM-DR) in patients with EOC.
METHODS
92 EOC patients who were treated with systemic chemotherapy after cytoreductive surgery were included in this analysis. Patients were divided into two groups, chemotherapy sensitive (n = 56) and resistant (n = 36). Immunohistochemical (IHC) staining for Lewis y and CAM-DR-related cell surface proteins including CD44, CD147, HE4 (Human epididymis protein 4), integrin α5, β1, αv and β3 were conducted on tissues collected during primary debulking surgery. Using multivariate logistic regressions, IHC results were compared to clinical variables and chemotherapy resistance to determine possible correlations. The relationships between IHC expression and progression-free survival (PFS) and overall survival (OS) were analyzed using Kaplan-Meier method and Cox regression analysis.
RESULTS
Membranous expression of Lewis y and all these CAM-DR-related markers were significantly higher in the resistant group than that of the sensitive group (all P < 0.01). Multivariate regression analysis revealed that high expression of Lewis y, CD44, HE4, integrin α5 and β1 as well as advanced FIGO stage were independent risk factors for chemotherapy resistance (all P < 0.05). Advanced FIGO stage, lymph node metastasis and high expression of Lewis y, CD44, CD147, HE4, integrin α5, β1 were associated with a shorter PFS and OS (all P < 0.05). Moreover, multivariate COX analysis demonstrated that the following variates were independent predictors of worse PFS and OS survival: late FIGO stage (P = 0.013, 0.049), high expressions of Lewis y (P = 0.010, 0.036), HE4 (P = 0.006, 0.013) and integrin β1 (PFS, P = 0.003), integrin α5 (OS, P = 0.019).
CONCLUSION
Membranous expression of Lewis y and CAM-DR-related markers including CD44, CD147, HE4, integrin α5, β1, αv and β3 are associated with the development of chemotherapy resistance. High expression of Lewis y antigen and CAM-DR-related markers including CD44, CD147, HE4, integrin α5 and β1 are independent markers for PFS and OS, in which Lewis y and HE4 are the most significant.
背景
化疗耐药是上皮性卵巢癌（EOC）患者面临的常见问题。目前尚无可用于识别化疗耐药并洞察预后的特异性或敏感性临床生物标志物。本研究旨在探讨Lewis y抗原及与细胞黏附介导的耐药性（CAM-DR）相关标志物在EOC患者中的作用。
方法
本分析纳入了92例接受减瘤手术后全身化疗的EOC患者。患者分为两组，化疗敏感组（n = 56）和耐药组（n = 36）。对初次肿瘤细胞减灭术时采集的组织进行Lewis y及与CAM-DR相关的细胞表面蛋白（包括CD44、CD147、人附睾蛋白4（HE4）、整合素α5、β1、αv和β3）的免疫组织化学（IHC）染色。使用多因素逻辑回归分析，将IHC结果与临床变量及化疗耐药性进行比较，以确定可能的相关性。采用Kaplan-Meier法和Cox回归分析评估IHC表达与无进展生存期（PFS）和总生存期（OS）之间的关系。
结果
耐药组中Lewis y及所有这些与CAM-DR相关标志物的膜表达均显著高于敏感组（所有P < 0.01）。多因素回归分析显示，Lewis y、CD44、HE4、整合素α5和β1的高表达以及较高的国际妇产科联盟（FIGO）分期是化疗耐药的独立危险因素（所有P < 0.05）。较高的FIGO分期、淋巴结转移以及Lewis y、CD44、CD147、HE4、整合素α5、β1的高表达与较短的PFS和OS相关（所有P < 0.05）。此外，多因素COX分析表明，以下变量是PFS和OS生存较差的独立预测因素：晚期FIGO分期（P = 0.013，0.049）、Lewis y高表达（P = 0.010，0.036）、HE4高表达（P = 0.006，0.013）以及整合素β1（PFS，P = 0.003）、整合素α5（OS，P = 0.019）。
结论
Lewis y及与CAM-DR相关的标志物（包括CD44、CD147、HE4、整合素α5、β1、αv和β3）的膜表达与化疗耐药的发生相关。Lewis y抗原及与CAM-DR相关的标志物（包括CD44、CD147、HE4、整合素α5和β1）的高表达是PFS和OS的独立标志物，其中Lewis y和HE4最为显著。
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