Li Xin, Yang Zhou-Sheng, Cai Wen-Wu, Deng Yang, Chen Lei, Tan Sheng-Lan
Department of Vascular Surgery, the Second Xiangya Hospital, Central South University, Changsha, Hunan, China, 410011.
The Institute of Vascular Diseases, Central South University, Changsha, Hunan, China, 410011.
J Cancer. 2021 Aug 22;12(20):6058-6070. doi: 10.7150/jca.61311. eCollection 2021.
Cholangiocarcinoma (CCA) leads to poor prognosis due to high aggressiveness and common chemoresistance. Dihydromyricetin (DMY), the main bioactive compound isolated from Ampelopsis grossedentata, exhibits broad anti-tumor effects. This study aimed to investigate the inhibitory effect of DMY on CCA tumor growth and epithelial-mesenchymal transition (EMT) and its underlying mechanism in CCA. DMY treatment significantly inhibited cell proliferation and EMT in CCA cell lines. The expression of ZEB1 and vimentin were down-regulated, while the level of E-cadherin was increased after DMY treatment. By analyzing the TCGA dataset, we found that miR-455 expression was significantly downregulated, while the level of ZEB1 was up-regulated in human CCA tumor tissues compared to normal samples. Mechanistic studies showed that ZEB1 was a direct target of miR-455-3p in CCA. Moreover, DMY treatment potently increased miR-455-3p expression and inhibited ZEB1 expression. Inhibition of miR-455-3p expression abolished DMY's inhibitory effects on tumor growth and EMT in both CCA cells and cell-engrafted nude mice. Finally, DMY significantly suppressed the expressions of p-PI3K and p-AKT, while silencing miR-455-3p remarkably abrogated the inhibitory effect. In conclusion, DMY suppresses tumor growth and EMT through regulating miR-455-3p in human cholangiocarcinoma, suggesting a potential option for CCA treatment.
胆管癌（CCA）因其高侵袭性和常见的化疗耐药性导致预后不良。二氢杨梅素（DMY）是从显齿蛇葡萄中分离出的主要生物活性化合物，具有广泛的抗肿瘤作用。本研究旨在探讨DMY对CCA肿瘤生长和上皮-间质转化（EMT）的抑制作用及其潜在机制。DMY处理显著抑制了CCA细胞系中的细胞增殖和EMT。DMY处理后，ZEB1和波形蛋白的表达下调，而E-钙黏蛋白水平升高。通过分析TCGA数据集，我们发现与正常样本相比，人CCA肿瘤组织中miR-455表达显著下调，而ZEB1水平上调。机制研究表明，ZEB1是CCA中miR-455-3p的直接靶点。此外，DMY处理显著增加了miR-455-3p表达并抑制了ZEB1表达。抑制miR-455-3p表达消除了DMY对CCA细胞和细胞移植裸鼠肿瘤生长和EMT的抑制作用。最后，DMY显著抑制p-PI3K和p-AKT的表达，而沉默miR-455-3p显著消除了这种抑制作用。总之，DMY通过调节人胆管癌中的miR-455-3p抑制肿瘤生长和EMT，提示其可能是CCA治疗的一个潜在选择。
