Suppression of Annexin A11 in Ovarian Cancer: Implications in Chemoresistance
Suppression of Annexin A11 in Ovarian Cancer: Implications in Chemoresistance
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DOI：
10.1593/neo.09286
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发表时间：
2009-06-01
期刊：
影响因子：
4.8
通讯作者：
Zhang, Zhen
中科院分区：
文献类型：
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作者：
Song, Jin;Shih, Ie-ming;Zhang, Zhen
接受以顺铂为基础的化疗的卵巢癌患者通常会产生获得性顺铂耐药性，从而导致癌症复发。我们之前报道过膜联蛋白 A11 与顺铂耐药相关，并与卵巢癌患者的肿瘤复发有关。在本研究中，我们使用小干扰 RNA 抑制卵巢癌细胞中膜联蛋白 A11 的表达，然后进行各种体外测定。我们发现膜联蛋白 A11 表达的敲低会降低卵巢癌细胞的细胞增殖和集落形成能力。膜联蛋白 A11 的表观遗传沉默赋予卵巢癌细胞顺铂耐药性。通过使用全基因组寡核苷酸微阵列对有/无抑制膜联蛋白 A11 表达的卵巢癌细胞中的顺铂反应进行全面的时程研究，我们鉴定了一组与膜联蛋白 A11 表达相关的差异表达基因以及响应顺铂暴露的一些基因表达模式。这些确定的基因/模式通过实时聚合酶链反应和免疫印迹分析得到进一步验证。其中许多如 HMOX1、TGFBI、LY6D、S100P、EIF4EBP2、DHRS2 和 PCSK9 参与细胞凋亡、细胞周期/增殖、细胞粘附/迁移、转录调控和信号转导。此外，免疫组织化学分析表明，在 142 名卵巢癌患者中，膜联蛋白 A11 免疫强度与 HMOX1 免疫反应性呈负相关。与膜联蛋白 A11 相比，HMOX1 免疫反应性与卵巢癌体外顺铂耐药性呈正相关。总的来说，膜联蛋白 A11 直接参与卵巢癌的细胞增殖和顺铂耐药。操纵膜联蛋白 A11 及其相关基因可能代表人类卵巢癌的一种新治疗策略。
Ovarian cancer patients treated with cisplatin-based chemotherapy often develop acquired cisplatin resistance and, consequently, cancer recurrence. We have previously reported that annexin A11 is associated with cisplatin resistance and related to tumor recurrence in ovarian cancer patients. In this study, we used small interfering RNA to suppress annexin A11 expression in ovarian cancer cells followed by various in vitro assays. We showed that knockdown of annexin A11 expression reduced cell proliferation and colony formation ability of ovarian cancer cells. Epigenetic silencing of annexin A11 conferred cisplatin resistance to ovarian cancer cells. Through a comprehensive time course study of cisplatin response in ovarian cancer cells with/without suppression of annexin A11 expression using whole-genome oligonucleotide microarrays, we identified a set of differentially expressed genes associated with annexin A11 expression and some patterns of gene expressions in response to cisplatin exposure. These identified genes/patterns were further validated by real-time polymerase chain reaction and immunoblot analysis. Many of them such as HMOX1, TGFBI, LY6D, S100P, EIF4EBP2, DHRS2, and PCSK9 have been involved in apoptosis, cell cycling/proliferation, cell adhesion/migration, transcription regulation, and signal transduction. In addition, immunohistochemistry analyses indicated that annexin A11 immunointensity inversely correlated with HMOX1 immunoreactivity in 142 ovarian cancer patients. In contrast to annexin A11, HMOX1 immunoreactivity positively correlated with in vitro cisplatin resistance in ovarian cancers. Collectively, annexin A11 is directly involved in cell proliferation and cisplatin resistance of ovarian cancer. Manipulation of annexin A11 and its associated genes may represent a novel therapeutic strategy in human ovarian cancers.