间充质干细胞外囊泡中microRNA-4488通过靶向ABHD8抑制卵巢癌进展

microRNA-4488 in extracellular vesicles derived from mesenchymal stem cells suppress ABHD8 to inhibit ovarian cancer progression

目的:研究间充质干细胞(MSC)分泌的细胞外囊泡(EV)中miR-4488通过ABHD8对卵巢癌进展的调控机制。方法:RT-qPCR和Western blot法检测正常卵巢组织和卵巢癌组织中miR-4488和含有α/β-水解酶结构域8(ABHD8)的表达水平,通过双荧光素酶报告基因测定确定miR-4488和ABHD8之间的关系,生物信息学分析miR-4488可能来源于MSC的EV。进一步探究MSC-EV-miR-4488和ABHD8在卵巢癌细胞增殖、凋亡、侵袭和迁移中的调节作用,并通过裸鼠移植瘤体内验证该作用。结果:与正常卵巢细胞和组织相比,卵巢癌细胞和组织中miR-4488低表达,ABHD8高表达。ABHD8是miR-4488的靶基因,MSC-EV包含的miR-4488抑制ABHD8表达。敲低ABHD8会抑制卵巢癌细胞增殖、侵袭和迁移能力,促进癌细胞的凋亡。MSC-EV中过表达的miR-4488通过抑制ABHD8表达抑制细胞增殖、侵袭和迁移。以上体外发现在小鼠体内也得到了证实。结论:MSC-EVs中过表达的miR-4488通过靶向调控ABHD8的表达,抑制卵巢癌细胞的增殖、侵袭和迁移能力,进而发挥抑癌作用。

Objective:To examine the underlying mechanism of mesenchymal stem cell(MSC)-derived extracellular vesicles(EVs)containing miR-4488 in ovarian cancer.Methods:The normal ovarian tissues and ovarian cancer tissues were extracted.RT-qPCR and Western blot analysis were applied to detect miR-4488 andα/β-hydrolase domain-containing(ABHD)8 expressions followed by determination of relationship between miR-4488 and ABHD8 by dual-luciferase reporter assay.After transfection with different plasmids and treatment,the regulatory roles of MSC-EV-miR-4488 in proliferation,apoptosis,invasion and migration of cancer cells were explored.Besides,xenograft tumor in nude mice was conducted to explore the role of miR-4488 and ABHD8 in ovarian cancer in vivo.Results:miR-4488 was poorly expressed and ABHD8 was highly expressed in ovarian cancer cells and tissues.ABHD8 was a target gene of miR-4488 while the knockdown of ABHD8 resulted in the suppression of proliferation,invasion and migration while promoting the apoptosis of cancer cells.Functionally,MSC-EV-derived miR-4488 inhibited the expression of ABHD8.Additionally,miR-4488 over-expressed in MSC-EVs inhibited the cell proliferation,invasion and migration through down-regulation of ABHD8 expression.At last,these in vitro findings were also confirmed in vivo.Conclusion:miR-4488 overexpressed in MSC-EVs suppressed ABHD8 expression to inhibit the cancer cell proliferation,invasion and migration,thus suppressing ovarian cancer.