Department of Pathology, The University of Hong Kong, Queen Mary Hospital, Hong Kong Island, Hong Kong.
Department of Obstetrics and Gynaecology, The University of Hong Kong, Queen Mary Hospital, Hong Kong Island, Hong Kong.
Int J Cancer. 2018 Sep 15;143(6):1456-1469. doi: 10.1002/ijc.31535. Epub 2018 May 2.
Ovarian clear cell carcinoma (OCCC) is a type of epithelial ovarian cancer that is strongly associated with endometriosis, resistance against conventional chemotherapy and thus poorer prognosis. The expression of inhibitory member of the ASPP family proteins (iASPP) and Polo-like kinase (PLK)1 were significantly higher in OCCC compared to benign cystadenomas and endometriosis. Both protein expressions were found to correlate with chemoresistance in patients with OCCC while high iASPP expression alone was significantly associated with a poor patient survival. The growth of OCCC cell lines, OVTOKO and KK, were inhibited after iASPP silencing. Such effect was related to senescence triggering as evidenced by increased SA-β-Gal staining and p21 expression. Moreover, knockdown of iASPP induced PLK1 downregulation, whereas either genes' silencing sensitized the cells in response to cisplatin treatment. More prominent apoptosis was induced by cisplatin in OCCC cells after the knockdown of either iASPP or PLK1 as evidenced by the formation of more cleaved caspase 3. Heightened chemosensitivity to cisplatin after iASPP knockdown was further demonstrated in in vivo xenograft model. Additionally, both iASPP and PLK1 were shown to regulate autophagic flux as the induction of LC3B-II and LC3 puncta were much less in OCCC cells with either knockdown. Importantly, inhibition of autophagy also enhanced chemosensitivity to cisplatin in OCCC cells. These findings strongly imply that iASPP and PLK1 affect the chemoresistance of OCCC via the regulation of autophagy and apoptosis. Both iASPP and PLK1 can be potential therapeutic targets for treating OCCC in combination with conventional chemotherapy.
卵巢透明细胞癌（OCCC）是一种上皮性卵巢癌，与子宫内膜异位症密切相关，对常规化疗具有抗性，因此预后较差。与良性囊腺瘤和子宫内膜异位症相比，OCCC 中抑制性 ASPP 家族蛋白（iASPP）和 Polo 样激酶（PLK）1 的表达明显更高。这两种蛋白的表达都与 OCCC 患者的化疗耐药性相关，而高 iASPP 表达与患者的不良生存显著相关。沉默 iASPP 后，OCCC 细胞系 OVTOKO 和 KK 的生长受到抑制。这种作用与衰老的触发有关，证据是 SA-β-Gal 染色和 p21 表达增加。此外，沉默 iASPP 诱导 PLK1 下调，而敲低这两种基因均可使细胞对顺铂治疗敏感。沉默 iASPP 或 PLK1 后，顺铂诱导 OCCC 细胞凋亡更明显，这表现为 cleaved caspase 3 的形成更多。在体内异种移植模型中进一步证明了沉默 iASPP 后对顺铂的化疗敏感性增加。此外，iASPP 和 PLK1 都被证明可以调节自噬通量，因为敲低这两种基因后 OCCC 细胞中 LC3B-II 和 LC3 斑点的诱导减少。重要的是，自噬的抑制也增强了 OCCC 细胞对顺铂的化疗敏感性。这些发现强烈暗示 iASPP 和 PLK1 通过调节自噬和凋亡来影响 OCCC 的化疗耐药性。iASPP 和 PLK1 均可作为治疗 OCCC 的潜在治疗靶点，与常规化疗联合使用。
