Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
Department of General Surgery, The First Affiliated Hospital of Xi'an Medical University, Xi'an, China.
J Cell Mol Med. 2019 Aug;23(8):4945-4954. doi: 10.1111/jcmm.14312. Epub 2019 Jun 14.
MicroRNAs (miRNAs) are powerful regulators in the tumorigenesis of cholangiocarcinoma (CCA). Previous studies report that miR-551b-3p acts as an oncogenic factor in ovarian cancer, but plays a tumour suppressive role in gastric cancer. However, the expression pattern and potential function of miR-551b-3p were still unclear in CCA. Therefore, this study aimed to explore the expression of miR-551b-3p and its role as well as molecular mechanism in CCA. Analysis of TCGA dataset suggested that miR-551b-3p was under-expressed in CCA tissues compared to normal bile duct tissues. Furthermore, our data confirmed the decreased levels of miR-551b-3p in CCA samples and cell lines. Interestingly, TCGA data suggested that low miR-551b-3p level indicated reduced overall survival of CCA patients. Gain- and loss-of-function experiments found that miR-551b-3p inhibited the proliferation, G1-S phase transition and induced apoptosis of CCA cells. In vivo experiments revealed that ectopic expression of miR-551b-3p inhibited tumour growth of CCA in mice. Further investigation demonstrated that miR-551b-3p directly bond to the 3'-UTR of Cyclin D1 (CCND1) mRNA and negatively regulated the abundance of CCND1 in CCA cells. An inverse correlation between miR-551b-3p expression and the level of CCND1 mRNA was detected in CCA tissues from TCGA dataset. Notably, CCND1 knockdown showed similar effects to miR-551b-3p overexpression in HuCCT-1 cells. CCND1 restoration rescued miR-551b-3p-induced inhibition of proliferation, G1 phase arrest and apoptosis in HuCCT-1 cells. In summary, miR-551b-3p inhibits the expression of CCND1 to suppress CCA cell proliferation and induce apoptosis, which may provide a theoretical basis for improving CCA treatment.
微小 RNA（miRNA）是胆管癌（CCA）发生过程中的强大调控因子。既往研究报道 miR-551b-3p 在卵巢癌中作为致癌因子发挥作用，而在胃癌中发挥肿瘤抑制作用。然而，miR-551b-3p 在 CCA 中的表达模式和潜在功能仍不清楚。因此，本研究旨在探讨 miR-551b-3p 的表达及其在 CCA 中的作用和分子机制。TCGA 数据集的分析表明，与正常胆管组织相比，CCA 组织中 miR-551b-3p 表达下调。此外，我们的数据证实了 CCA 样本和细胞系中 miR-551b-3p 水平降低。有趣的是，TCGA 数据表明 miR-551b-3p 水平低提示 CCA 患者总生存率降低。增益和缺失功能实验发现，miR-551b-3p 抑制 CCA 细胞的增殖、G1-S 期转化并诱导细胞凋亡。体内实验表明，CCA 细胞中过表达 miR-551b-3p 可抑制肿瘤生长。进一步研究表明，miR-551b-3p 直接与细胞周期蛋白 D1（CCND1）mRNA 的 3'UTR 结合，并负调控 CCA 细胞中 CCND1 的丰度。在来自 TCGA 数据集的 CCA 组织中检测到 miR-551b-3p 表达与 CCND1 mRNA 水平之间的负相关。值得注意的是，在 HuCCT-1 细胞中，CCND1 敲低与 miR-551b-3p 过表达表现出相似的效果。CCND1 恢复挽救了 miR-551b-3p 诱导的 HuCCT-1 细胞增殖抑制、G1 期阻滞和凋亡。总之，miR-551b-3p 通过抑制 CCND1 的表达来抑制 CCA 细胞的增殖并诱导细胞凋亡，这可能为改善 CCA 治疗提供理论依据。
