School of Biomedical Sciences, The Chinese University of Hong Kong, Faculty of Medicine, the Chinese University of Hong Kong, Hong Kong SAR, China.
CUHK-SDU Joint Laboratory on Reproductive Genetics, School of Biomedical Sciences, the Chinese University of Hong Kong, Hong Kong, China.
Cell Death Dis. 2018 Oct 22;9(11):1076. doi: 10.1038/s41419-018-1117-5.
We have previously reported that microRNA-10 family could disturb normal development of granulosa cells (GC) during follicle formation. In the current study, the effect of miR-10a on granulosa cell tumor (GCT), a subtype of ovarian cancer, was examined. Strong miR-10a signal was detected in tissues from malignant GCT patients. Forced expression of miR-10a significantly promoted cell proliferation, migration, invasion, ovarian hormone production, and repressed anticancer drug-induced apoptosis in vitro. The oncogenic role of miR-10a was further validated in an orthotopic GCT model in vivo. In addition, by using CRISPR-Cas9 system, the aggressive phenotype was repressed in miR-10a knockout cancer GC. By using a heterotopic mice model, the oncogenic role of miR-10a was confirmed in vivo. RNA-seq, FISH, western blot, luciferase reporter assay were used to identified PTEN, a well-known anti-GCT gene, as direct functional target of miR-10a in cancer GC; Akt and Wnt were also found as two associated oncogenic pathways of miR-10a in cancer GC. Taken together, our results demonstrate that the miR-10a could promote GCT development via synergistically regulating PTEN, Akt, and Wnt pathways.
我们之前曾报道过，miRNA-10 家族可能会干扰滤泡形成过程中颗粒细胞（GC）的正常发育。在本研究中，我们研究了 miR-10a 对卵巢癌亚型——颗粒细胞瘤（GCT）的影响。在恶性 GCT 患者的组织中检测到强烈的 miR-10a 信号。过表达 miR-10a 可显著促进细胞增殖、迁移、侵袭、卵巢激素产生，并抑制抗癌药物诱导的细胞凋亡。miR-10a 的致癌作用在体内同源性 GCT 模型中得到进一步验证。此外，通过使用 CRISPR-Cas9 系统，miR-10a 敲除的 GC 中抑制了侵袭表型。通过使用异位小鼠模型，在体内证实了 miR-10a 的致癌作用。RNA-seq、FISH、western blot、荧光素酶报告基因检测用于鉴定 PTEN，作为 miR-10a 在癌症 GC 中的直接功能靶基因；还发现 Akt 和 Wnt 是 miR-10a 在癌症 GC 中的两个相关致癌途径。总之，我们的研究结果表明，miR-10a 可能通过协同调节 PTEN、Akt 和 Wnt 途径促进 GCT 的发展。
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