Abstract
Background
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.
Methods
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. Results: 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. Conclusions: 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.
概要
目的
已知骨髓间充质干细胞在癌症的发生发展中起有 重要作用, 本研究分析它们在增强卵巢癌化疗耐 药能力中的具体作用。
创新点
发现骨髓间充质干细胞可以通过释放微小RNA (microRNA)影响卵巢癌化疗耐药能力, 并确定 了介导此作用的microRNA 分子和相关作用机制。
方法
收集骨髓间充质干细胞条件培养基, 以微阵列方 法分析其中microRNA 表达谱。 针对所获高表达 microRNA, 分析它(们)对细胞内糖酵解及相关 化疗耐药行为的影响。 通过生物信息学方法查找 所获microRNA 的靶基因, 分析信号作用机制。 纳入59 名卵巢癌患者, 以Kaplan-Merier 生存分 析方法考察所获microRNA 分子表达程度的临床 预后意义。
结论
迁移至卵巢癌组织内的骨髓间充质干细胞可释放 miR-1180 分子。 MiR-1180 分子进入癌细胞后, 识别并下调SFRP1 蛋白(分泌型Wnt 受体, 起 信号抑制作用), 由此提高Wnt 通路活性。 活化 后的Wnt 信号通路可增强癌细胞内糖酵解水平 (即Warburg 效应), 从而引起糖酵解依赖性化 疗耐药行为。
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Project supported by the National Key Research and Development Program of China (No. 2016YFC1303100), the Science and Technology Commission of Shanghai Municipality (Nos. 15441905700, 15DZ1940502, and 12411950200), the Shanghai Municipal Commission of Health and Family Planning (No. 2013ZYJB0202), and the National Natural Science Foundation of China (Nos. 81572548, 81772770, 81272882, and 81072137)
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Gu, ZW., He, YF., Wang, WJ. et al. MiR-1180 from bone marrow-derived mesenchymal stem cells induces glycolysis and chemoresistance in ovarian cancer cells by upregulating the Wnt signaling pathway. J. Zhejiang Univ. Sci. B 20, 219–237 (2019). https://doi.org/10.1631/jzus.B1800190
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DOI: https://doi.org/10.1631/jzus.B1800190
Key words
- Chemoresistant ovarian cancer
- Mesenchymal stem cell
- MiR-1180
- Secreted frizzled-related protein 1 (SFRP1)
- Wnt
- Glycolysis