Establishment and Characterization of a Novel Multidrug Resistant Human Ovarian Cancer Cell Line With Heterogenous MRP7 Overexpression.
Establishment and Characterization of a Novel Multidrug Resistant Human Ovarian Cancer Cell Line With Heterogenous MRP7 Overexpression.
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DOI：
10.3389/fonc.2021.731260
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发表时间：
2021
影响因子：
4.7
通讯作者：
Chen ZS
中科院分区：
文献类型：
--
作者：
Wang JQ;Wu ZX;Yang Y;Li JS;Yang DH;Fan YF;Chen ZS
卵巢癌是妇科恶性肿瘤中死亡率最高的一种。手术减瘤后化疗是主要的治疗方法。然而，复发性卵巢癌患者由于对化疗药物的敏感性降低而可能表现出对化疗的耐药性。三磷酸腺苷（ATP）结合盒（ABC）转运蛋白作为多药耐药（MDR）介导剂已被广泛研究，因为它们负责多种抗癌药物的外排。多药耐药蛋白7（MRP 7，或ABCC 10）是在2001年发现的，并揭示了运输化疗药物。到目前为止，关于其在卵巢癌中的作用，只有有限的知识。本研究通过构建MRP 7重组质粒，建立了MRP 7高表达的卵巢癌细胞株SKOV 3/MRP 7。SKOV 3/MRP 7细胞系对紫杉醇、多西他赛、长春新碱和长春瑞滨等多种抗癌药物耐药，最高耐药倍数为8倍。通过外排-蓄积试验进一步确定MRP 7蛋白的生物学功能。MTT结果显示，MRP 7的抑制剂千金藤素可逆转SKOV 3/MRP 7细胞的耐药性。此外，我们还发现，MRP 7的过表达增强了迁移和上皮间质转化（EMT）的诱导。总之，我们建立了卵巢癌MDR的体外模型，并建议MRP 7过表达作为该细胞系化疗耐药的主要机制。我们的研究结果表明，MRP 7与卵巢癌MDR的潜在关系。
Ovarian cancer is one of the leading female malignancies which accounts for the highest mortality rate among gynecologic cancers. Surgical cytoreduction followed by chemotherapy is the mainstay of treatment. However, patients with recurrent ovarian cancer are likely to exhibit resistance to chemotherapy due to reduced sensitivity to chemotherapeutic drugs. Adenosine triphosphate (ATP)-binding cassette (ABC) transporters have been extensively studied as multidrug resistance (MDR) mediators since they are responsible for the efflux of various anticancer drugs. Multidrug resistance protein 7 (MRP7, or ABCC10) was discovered in 2001 and revealed to transport chemotherapeutic drugs. Till now, only limited knowledge was obtained regarding its roles in ovarian cancer. In this study, we established an MRP7-overexpressing ovarian cancer cell line SKOV3/MRP7 via transfecting recombinant MRP7 plasmids. The SKOV3/MRP7 cell line was resistant to multiple anticancer drugs including paclitaxel, docetaxel, vincristine and vinorelbine with a maximum of 8-fold resistance. Biological function of MRP7 protein was further determined by efflux-accumulation assays. Additionally, MTT results showed that the drug resistance of the SKOV3/MRP7 cells was reversed by cepharanthine, a known inhibitor of MRP7. Moreover, we also found that the overexpression of MRP7 enhanced the migration and epithelial-mesenchymal transition (EMT) induction. In conclusion, we established an in vitro model of MDR in ovarian cancer and suggested MRP7 overexpression as the leading mechanism of chemoresistance in this cell line. Our results demonstrated the potential relationship between MRP7 and ovarian cancer MDR.
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