MiR-31 regulates the cisplatin resistance by targeting Src in gallbladder cancer.
MiR-31 regulates the cisplatin resistance by targeting Src in gallbladder cancer.
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MiR-31 通过靶向 Src 调节胆囊癌的顺铂耐药
DOI：
10.18632/oncotarget.13067
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发表时间：
2016-12-13
期刊：
影响因子：
--
通讯作者：
Gong W
中科院分区：
文献类型：
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作者：
Li M;Chen W;Zhang H;Zhang Y;Ke F;Wu X;Zhang Y;Weng M;Liu Y;Gong W
背景胆囊癌（GBC）是一种对化疗高度耐药的恶性肿瘤.发现微小RNA（miRNA）广泛参与致癌作用和化疗耐药性的调节。本研究旨在探讨GBC中由miRNA表达调控的顺铂（DDP）敏感性及其相关通路。结果微阵列筛选出DDP耐药细胞与亲本细胞差异倍数最大的microRNA-31（miR-31）。在DDP耐药细胞和异种移植肿瘤模型中，miR-31的异位过表达降低了细胞增殖、活力和侵袭能力，但促进了细胞凋亡。通过敲低Src原癌基因（Src）表达，细胞凋亡和DDP化疗敏感性显著增加，随后通过在miR-31表达细胞中拯救Src表达而逆转。方法应用基因芯片技术筛选2株DDP耐药GBC细胞中的候选miRNA。分别通过伤口愈合、transwell实验、CCK-8实验、集落形成和流式细胞术实验来检测调节表达的miRNA对细胞迁移、侵袭、增殖和凋亡的影响。异种移植肿瘤模型用于验证下游靶标的功能。结论miR-31在GBC耐药细胞中的表达显著降低，上调miR-31表达可增强GBC的化疗敏感性，有望克服GBC的耐药。
Background Gallbladder cancer (GBC) is a malignant tumor highly resistant to chemotherapy. MicroRNAs (miRNAs) are found extensively involved in modulation of carcinogenesis and chemoresistance. This study aimed to investigate cisplatin (DDP)-susceptibility regulated by expression of the miRNAs and underlying pathways in GBC. Results The microRNA-31 (miR-31) was selected by microarray due to the biggest fold change between DDP-resistant and parental cells. Ectopic overexpression of miR-31 decreased cell proliferation, viability and invasion capacity, but promoted apoptosis in DDP-resistant cells and in xenograft tumor models. Cell apoptosis and DDP-chemosensitivity was remarkably increased by knockdown of Src proto-oncogene (Src) expression, which was subsequently reversed by rescue of Src expression in miR-31-expressing cells. Methods The microarray was used to select the candidate miRNA in two DDP-resistant GBC cell lines. The effect of regulated expression of the miRNA on cell migration, invasion, proliferation and apoptosis was examined by wound healing, transwell assays, CCK-8 assays, colony formation and flow cytometry assays, respectively. Xenograft tumor models were used to validate the function of the downstream target. Conclusion Our results demonstrated that miR-31reduced significantly in GBC cells rendering resistance to cisplatin, and upregulated expression of miR-31 augmented chemosensitivity, presenting a therapeutic potential to overcome drug resistance in GBC.