Zhang Jie, Wang Wenjing, Qian Lin, Zhang Qiuwan, Lai Dongmei, Qi Cong
Department of Gynecology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, P.R. China.
The International Peace Maternity and Child Health Hospital, Shanghai Jiaotong University, Shanghai 200032, P.R. China.
Oncol Rep. 2015 Nov;34(5):2375-84. doi: 10.3892/or.2015.4213. Epub 2015 Aug 20.
Ovarian cancer is the most frequent cause of cancer-related death among all gynecological cancers. Increasing evidence suggests that human ovarian cancer stem-like cells could be enriched under serum-free culture conditions. In the present study, SKOV3 ovarian epithelial cancer cells were cultured for sphere cells. Ursolic acid (UA) with triterpenoid compounds exist widely in food, medicinal herbs and other plants. Evidence shows that UA has anticancer activities in human ovarian cancer cells, but he role of UA in ovarian cancer stem cells (CSCs) remains unknown. The aim of the present study was to investigate the anticancer effects of UA in combination with cisplatin in ovarian CSCs (in vitro and in vivo), along with the molecular mechanism of action. Treatment with UA at various concentrations was examined in combination with cisplatin in human ovarian CSCs. MTT assay and flow cytometry were used for cell viability and apoptosis analysis, and qRT-PCR for stem cell markers and epithelial-mesenchymal transition (EMT) markers for mRNA expression. Transwell assay was employed to observe the migration and invasion of SKOV3 cells and SKOV3 sphere cells after treatment. Moreover, athymic BALB/c-nu nude mice were injected with SKOV3 sphere cells to obtain a xenograft model for in vivo studies. The results showed that CSCs possessed mesenchymal characteristics and EMT ability, and the growth of SKOV3 and sphere cells was significantly inhibited by UA. Transplanted tumors were significantly reduced after injection of UA and UA plus cisplatin. Furthermore, we found that UA could play a role in enhancing the sensitivity of CSCs to cisplatin resistance. Our findings suggested that UA is involved in EMT mechanism to affect the proliferation and apoptosis of human ovarian cancer stem-like cells and it is a potent anti-ovarian cancer agent.
卵巢癌是所有妇科癌症中与癌症相关死亡的最常见原因。越来越多的证据表明，人卵巢癌干细胞样细胞可在无血清培养条件下富集。在本研究中，培养SKOV3卵巢上皮癌细胞以获得球形细胞。熊果酸（UA）与三萜类化合物广泛存在于食物、药草和其他植物中。有证据表明，UA在人卵巢癌细胞中具有抗癌活性，但UA在卵巢癌干细胞（CSCs）中的作用仍不清楚。本研究的目的是研究UA联合顺铂对卵巢CSCs的抗癌作用（体外和体内）及其分子作用机制。在人卵巢CSCs中检测不同浓度的UA与顺铂联合治疗的效果。采用MTT法和流式细胞术分析细胞活力和凋亡情况，采用qRT-PCR检测干细胞标志物和上皮-间质转化（EMT）标志物的mRNA表达。采用Transwell实验观察处理后SKOV3细胞和SKOV3球形细胞的迁移和侵袭情况。此外，将SKOV3球形细胞注射到无胸腺BALB/c-nu裸鼠体内，以获得用于体内研究的异种移植模型。结果表明，CSCs具有间充质特征和EMT能力，UA显著抑制SKOV3细胞和球形细胞的生长。注射UA和UA加顺铂后移植瘤明显缩小。此外，我们发现UA可以增强CSCs对顺铂耐药的敏感性。我们的研究结果表明，UA参与EMT机制，影响人卵巢癌干细胞样细胞的增殖和凋亡，是一种有效的抗卵巢癌药物。
