Department of Obstetrics and Gynecology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China.
Shanghai Key Laboratory of Gynecologic Oncology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China.
J Zhejiang Univ Sci B. 2019;20(3):219-237. doi: 10.1631/jzus.B1800190.
Bone marrow-derived mesenchymal stem cells (BM-MSCs) play an important role in cancer development and progression. However, the mechanism by which they enhance the chemoresistance of ovarian cancer is unknown.
Conditioned media of BM-MSCs (BM-MSC-CM) were analyzed using a technique based on microRNA arrays. The most highly expressed microRNAs were selected for testing their effects on glycolysis and chemoresistance in SKOV3 and COC1 ovarian cancer cells. The targeted gene and related signaling pathway were investigated using in silico analysis and in vitro cancer cell models. Kaplan-Merier survival analysis was performed on a population of 59 patients enrolled to analyze the clinical significance of microRNA findings in the prognosis of ovarian cancer.
MiR-1180 was the most abundant microRNA detected in BM-MSC-CM, which simultaneously induces glycolysis and chemoresistance (against cisplatin) in ovarian cancer cells. The secreted frizzled-related protein 1 (SFRP1) gene was identified as a major target of miR-1180. The overexpression of miR-1180 led to the activation of Wnt signaling and its downstream components, namely Wnt5a, β-catenin, c-Myc, and CyclinD1, which are responsible for glycolysis-induced chemoresistance. The miR-1180 level was inversely correlated with SFRP1 mRNA expression in ovarian cancer tissue. The overexpressed miR-1180 was associated with a poor prognosis for the long-term (96-month) survival of ovarian cancer patients.
BM-MSCs enhance the chemoresistance of ovarian cancer by releasing miR-1180. The released miR-1180 activates the Wnt signaling pathway in cancer cells by targeting SFRP1. The enhanced Wnt signaling upregulates the glycolytic level (i.e. Warburg effect), which reinforces the chemoresistance property of ovarian cancer cells.
骨髓间充质干细胞（BM-MSCs）在癌症的发生和发展中起着重要作用。然而，它们增强卵巢癌化疗耐药性的机制尚不清楚。
基于 microRNA 阵列的技术分析 BM-MSCs 的条件培养基（BM-MSC-CM）。选择表达水平最高的 microRNAs 用于测试其对 SKOV3 和 COC1 卵巢癌细胞糖酵解和化疗耐药性的影响。使用计算机分析和体外癌细胞模型研究靶向基因和相关信号通路。对 59 例患者进行 Kaplan-Merier 生存分析，以分析 microRNA 检测结果在卵巢癌预后中的临床意义。
BM-MSC-CM 中检测到的最丰富的 microRNA 是 miR-1180，它同时诱导卵巢癌细胞的糖酵解和化疗耐药性（顺铂）。分泌卷曲相关蛋白 1（SFRP1）基因被确定为 miR-1180 的主要靶基因。miR-1180 的过表达导致 Wnt 信号及其下游成分（Wnt5a、β-catenin、c-Myc 和 CyclinD1）的激活，这些成分负责糖酵解诱导的化疗耐药性。miR-1180 水平与卵巢癌组织中 SFRP1 mRNA 表达呈负相关。过表达的 miR-1180 与卵巢癌患者长期（96 个月）生存的预后不良相关。
BM-MSCs 通过释放 miR-1180 增强卵巢癌的化疗耐药性。释放的 miR-1180 通过靶向 SFRP1 激活癌细胞中的 Wnt 信号通路。增强的 Wnt 信号上调糖酵解水平（即 Warburg 效应），从而增强卵巢癌细胞的化疗耐药性。
