Zou Wei, Ma Xiangdong, Yang Hong, Hua Wei, Chen Biliang, Cai Guoqing
Department of Obstetrics and Gynecology, Xijing Hospital, the Fourth Military Medical University, Xi'an 710032, P.R. China.
Exp Biol Med (Maywood). 2017 Mar;242(5):497-504. doi: 10.1177/1535370216685007. Epub 2017 Jan 5.
Ovarian cancer is the highest mortality rate of all female reproductive malignancies. Drug resistance is a major cause of treatment failure in malignant tumors. Hepatitis B X-interacting protein acts as an oncoprotein, regulates cell proliferation, and migration in breast cancer. We aimed to investigate the effects and mechanisms of hepatitis B X-interacting protein on resistance to cisplatin in human ovarian cancer cell lines. The mRNA and protein levels of hepatitis B X-interacting protein were detected using RT-PCR and Western blotting in cisplatin-resistant and cisplatin-sensitive tissues, cisplatin-resistant cell lines A2780/CP and SKOV3/CP, and cisplatin-sensitive cell lines A2780 and SKOV3. Cell viability and apoptosis were measured to evaluate cellular sensitivity to cisplatin in A2780/CP cells. Luciferase reporter gene assay was used to determine the relationship between hepatitis B X-interacting protein and CD147. The in vivo function of hepatitis B X-interacting protein on tumor burden was assessed in cisplatin-resistant xenograft models. The results showed that hepatitis B X-interacting protein was highly expressed in ovarian cancer of cisplatin-resistant tissues and cells. Notably, knockdown of hepatitis B X-interacting protein significantly reduced cell viability in A2780/CP compared with cisplatin treatment alone. Hepatitis B X-interacting protein and cisplatin cooperated to induce apoptosis and increase the expression of c-caspase 3 as well as the Bax/Bcl-2 ratio. We confirmed that hepatitis B X-interacting protein up-regulated CD147 at the protein expression and transcriptional levels. Moreover, we found that hepatitis B X-interacting protein was able to activate the CD147 promoter through Sp1. In vivo, depletion of hepatitis B X-interacting protein decreased the tumor volume and weight induced by cisplatin. Taken together, these results indicate that hepatitis B X-interacting protein promotes cisplatin resistance and regulated CD147 via Sp1 in ovarian cancer cell lines. Impact statement We found that hepatitis B X-interacting protein (HBXIP) was able to activate the CD147 promoter through Sp1. In vivo, depletion of HBXIP decreased the tumor volume and weight induced by CP. Taken together, these results indicate that HBXIP promotes cisplatin resistance and regulated CD147 via Sp1 in ovarian cancer cell lines.
卵巢癌是所有女性生殖系统恶性肿瘤中死亡率最高的。耐药性是恶性肿瘤治疗失败的主要原因。乙型肝炎X相互作用蛋白作为一种癌蛋白，在乳腺癌中调节细胞增殖和迁移。我们旨在研究乙型肝炎X相互作用蛋白对人卵巢癌细胞系顺铂耐药性的影响及其机制。采用RT-PCR和蛋白质印迹法检测顺铂耐药和敏感组织、顺铂耐药细胞系A2780/CP和SKOV3/CP以及顺铂敏感细胞系A2780和SKOV3中乙型肝炎X相互作用蛋白的mRNA和蛋白水平。检测细胞活力和凋亡情况以评估A2780/CP细胞对顺铂的细胞敏感性。采用荧光素酶报告基因检测法确定乙型肝炎X相互作用蛋白与CD147之间的关系。在顺铂耐药异种移植模型中评估乙型肝炎X相互作用蛋白对肿瘤负荷的体内功能。结果显示，乙型肝炎X相互作用蛋白在顺铂耐药组织和细胞的卵巢癌中高表达。值得注意的是，与单独使用顺铂治疗相比，敲低乙型肝炎X相互作用蛋白显著降低了A2780/CP细胞的活力。乙型肝炎X相互作用蛋白与顺铂协同诱导凋亡，并增加c-半胱天冬酶3的表达以及Bax/Bcl-2比值。我们证实在蛋白表达和转录水平上乙型肝炎X相互作用蛋白上调CD147。此外，我们发现乙型肝炎X相互作用蛋白能够通过Sp1激活CD147启动子。在体内，敲低乙型肝炎X相互作用蛋白可减小顺铂诱导的肿瘤体积和重量。综上所述，这些结果表明乙型肝炎X相互作用蛋白在卵巢癌细胞系中促进顺铂耐药并通过Sp1调节CD147。影响声明我们发现乙型肝炎X相互作用蛋白（HBXIP）能够通过Sp1激活CD147启动子。在体内，敲低HBXIP可减小CP诱导的肿瘤体积和重量。综上所述，这些结果表明HBXIP在卵巢癌细胞系中促进顺铂耐药并通过Sp1调节CD147。
