Children's Cancer Institute Australia, Lowy Cancer Research Centre, UNSW Australia, Kensington, New South Wales, Australia.
School of Women's and Children's Health, UNSW Australia, Kensington, New South Wales, Australia.
Int J Cancer. 2020 Oct 15;147(8):2225-2238. doi: 10.1002/ijc.33005. Epub 2020 May 8.
Epithelial ovarian cancer (EOC) is a complex disease comprising discrete histological and molecular subtypes, for which survival rates remain unacceptably low. Tailored approaches for this deadly heterogeneous disease are urgently needed. Efflux pumps belonging to the ATP-binding cassette (ABC) family of transporters are known for roles in both drug resistance and cancer biology and are also highly targetable. Here we have investigated the association of ABCC4/MRP4 expression to clinical outcome and its biological function in endometrioid and serous tumors, common histological subtypes of EOC. We found high expression of ABCC4/MRP4, previously shown to be directly regulated by c-Myc/N-Myc, was associated with poor prognosis in endometrioid EOC (P = .001) as well as in a subset of serous EOC with a "high-MYCN" profile (C5/proliferative; P = .019). Transient siRNA-mediated suppression of MRP4 in EOC cells led to reduced growth, migration and invasion, with the effects being most pronounced in endometrioid and C5-like serous cells compared to non-C5 serous EOC cells. Sustained knockdown of MRP4 also sensitized endometrioid cells to MRP4 substrate drugs. Furthermore, suppression of MRP4 decreased the growth of patient-derived EOC cells in vivo. Together, our findings provide the first evidence that MRP4 plays an important role in the biology of Myc-associated ovarian tumors and highlight this transporter as a potential therapeutic target for EOC.
上皮性卵巢癌 (EOC) 是一种复杂的疾病，包括离散的组织学和分子亚型，其生存率仍然低得不可接受。迫切需要针对这种致命异质性疾病的针对性方法。已知属于 ATP 结合盒 (ABC) 家族转运蛋白的外排泵在药物耐药性和癌症生物学中都具有作用，并且也是高度可靶向的。在这里，我们研究了 ABCC4/MRP4 表达与临床结局的关联及其在子宫内膜样和浆液性肿瘤（EOC 的常见组织学亚型）中的生物学功能。我们发现，先前被证明直接受 c-Myc/N-Myc 调节的 ABCC4/MRP4 的高表达与子宫内膜样 EOC 的不良预后相关（P =.001），以及具有“高-MYCN”特征的部分浆液性 EOC 中（C5/增殖；P =.019）。EOC 细胞中 MRP4 的瞬时 siRNA 介导抑制导致生长、迁移和侵袭减少，与非 C5 浆液性 EOC 细胞相比，在子宫内膜样和 C5 样浆液性细胞中效果最为明显。MRP4 的持续敲低也使子宫内膜样细胞对 MRP4 底物药物敏感。此外，抑制 MRP4 减少了体内患者来源的 EOC 细胞的生长。总之，我们的研究结果首次提供了证据表明，MRP4 在 Myc 相关卵巢肿瘤的生物学中发挥重要作用，并强调了该转运蛋白作为 EOC 的潜在治疗靶点。
