Scurr Lyndee L, Guminski Alexander D, Chiew Yoke-Eng, Balleine Rosemary L, Sharma Raghwa, Lei Ying, Pryor Kylie, Wain Gerard V, Brand Alison, Byth Karen, Kennedy Catherine, Rizos Helen, Harnett Paul R, deFazio Anna
Westmead Institute for Cancer Research, University of Sydney at the Westmead Millennium Institute, Westmead Hospital, Westmead, NSW, Australia.
Clin Cancer Res. 2008 Nov 1;14(21):6924-32. doi: 10.1158/1078-0432.CCR-07-5189.
The standard of care for ovarian cancer includes platinum-based chemotherapy. It is not possible, however, to predict clinical platinum sensitivity or to design rational strategies to overcome resistance. We used a novel approach to identify altered gene expression associated with high sensitivity to cisplatin, to define novel targets to sensitize tumor cells to platins and ultimately improve the effectiveness of this widely used class of chemotherapeutics.
Using differential display PCR, we identified genes differentially expressed in a mutagenized cell line with unusual sensitivity to cisplatin. The most highly differentially expressed gene was selected, and its role in determining cisplatin sensitivity was validated by gene transfection and small interfering RNA (siRNA) approaches, by association of expression levels with cisplatin sensitivity in cell lines, and by association of tumor expression levels with survival in a retrospective cohort of 71 patients with serous ovarian adenocarcinoma.
The most highly differently expressed gene identified was ANKRD1, ankyrin repeat domain 1 (cardiac muscle). ANKRD1 mRNA levels were correlated with platinum sensitivity in cell lines, and most significantly, decreasing ANKRD1 using siRNA increased cisplatin sensitivity >2-fold. ANKRD1 was expressed in the majority of ovarian adenocarcinomas tested (62/71, 87%), and higher tumor levels of ANKRD1 were found in patients with worse outcome (overall survival, P=0.013).
These findings suggest that ANKRD1, a gene not previously associated with ovarian cancer or with response to chemotherapy, is associated with treatment outcome, and decreasing ANKRD1 expression, or function, is a potential strategy to sensitize tumors to platinum-based drugs.
卵巢癌的标准治疗方案包括铂类化疗。然而，目前尚无法预测临床铂敏感性，也无法设计合理策略来克服耐药性。我们采用了一种新方法来鉴定与顺铂高敏感性相关的基因表达变化，以确定使肿瘤细胞对铂类药物敏感的新靶点，并最终提高这类广泛应用的化疗药物的疗效。
利用差异显示PCR技术，我们在对顺铂具有异常敏感性的诱变细胞系中鉴定出差异表达的基因。选择差异表达最显著的基因，通过基因转染和小干扰RNA（siRNA）方法、细胞系中表达水平与顺铂敏感性的相关性以及在71例浆液性卵巢腺癌患者的回顾性队列中肿瘤表达水平与生存率的相关性，验证其在决定顺铂敏感性中的作用。
鉴定出差异表达最显著的基因是锚蛋白重复结构域1（心肌）ANKRD1。ANKRD1 mRNA水平与细胞系中的铂敏感性相关，最重要的是，使用siRNA降低ANKRD1水平可使顺铂敏感性提高2倍以上。ANKRD1在大多数检测的卵巢腺癌中表达（62/71，87%），ANKRD1肿瘤水平较高的患者预后较差（总生存期，P = 0.013）。
这些发现表明，ANKRD1这个以前与卵巢癌或化疗反应无关的基因与治疗结果相关，降低ANKRD1的表达或功能是使肿瘤对铂类药物敏感的潜在策略。
