Wu Xiaoqing, Zhi Xiaogai, Ji Minghua, Wang Qingling, Li Yujuan, Xie Jingyan, Zhao Shuli
Nanjing First Hospital, Nanjing Medical University Nanjing, China.
Jiangsu Cancer Hospital Nanjing, China.
Am J Cancer Res. 2015 Jan 15;5(2):629-38. eCollection 2015.
The paclitaxel/cisplatin combination therapy commonly is used as the first-line treatment for advanced ovarian cancer patients. Midkine (MK), known as a novel tumor biomarker, has been elevated in the serum of patients with epithelial ovarian cancer (EOC). In this study, we aimed to detect the expression of MK in EOC tissues and evaluate clinical value of MK in diagnosis and therapy of EOC. We perform immunohistochemistry analysis to detect MK in EOC sample with postoperative platinum/paclitaxel combination therapy, we found that 71.4% (85 in 119 samples) of these samples were MK positive (> 10% of the cells were stained), and the expression of MK was significantly associated with disease histology (P = 0.038) as well as differentiation grade (P < 0.001). Moreover, MK positive samples show much more sensitive to cisplatin/paclitaxel combination therapy, compared with MK negative samples (P = 0.029). Those results indicated that MK expression might correlate with paclitaxel and/or cisplatin cytotoxicity in clinical therapy of EOC. Then, we evaluated the sensitivity to cisplatin and paclitaxel in 5 ovarian cancer cell lines (ES2, A2870, HO-8910, SKOV3 and SW626), and ES2, the highest MK expression among those cell lines, show the most sensitive to paclitaxel and cisplatin. Further, we confirmed this correlation between MK and paclitaxel and/or cisplatin cytotoxicity with the gain- and lost- of function. Finally, we demonstrated that MK enhanced the cytotoxicity of paclitaxel and/or cisplatin by accumulated cisplatin and paclitaxel through inhibited the expression of multidrug resistance-associated protein 3 (MRP3). In conclusion, MK could be an effective biomarker in diagnosis and therapy of EOC, especially for the drug selection at the time of initial diagnosis.
紫杉醇/顺铂联合疗法通常用作晚期卵巢癌患者的一线治疗方法。中期因子（MK）作为一种新型肿瘤生物标志物，在上皮性卵巢癌（EOC）患者血清中水平升高。在本研究中，我们旨在检测EOC组织中MK的表达，并评估MK在EOC诊断和治疗中的临床价值。我们进行免疫组织化学分析以检测接受铂/紫杉醇联合术后治疗的EOC样本中的MK，发现这些样本中有71.4%（119个样本中的85个）为MK阳性（>10%的细胞被染色），且MK的表达与疾病组织学（P = 0.038）以及分化程度（P < 0.001）显著相关。此外，与MK阴性样本相比，MK阳性样本对顺铂/紫杉醇联合疗法更为敏感（P = 0.029）。这些结果表明，在EOC临床治疗中，MK表达可能与紫杉醇和/或顺铂的细胞毒性相关。然后，我们评估了5种卵巢癌细胞系（ES2、A2870、HO - 8910、SKOV3和SW626）对顺铂和紫杉醇的敏感性，其中ES2是这些细胞系中MK表达最高的，对紫杉醇和顺铂最为敏感。进一步地，我们通过功能获得和缺失实验证实了MK与紫杉醇和/或顺铂细胞毒性之间的这种相关性。最后，我们证明MK通过抑制多药耐药相关蛋白3（MRP3）的表达，积累顺铂和紫杉醇，从而增强了紫杉醇和/或顺铂的细胞毒性。总之，MK可能是EOC诊断和治疗中的一种有效生物标志物，特别是在初始诊断时的药物选择方面。
