Department of Hepatobiliary Surgery, Shaoxing People's Hospital (Shaoxing Hospital, Zhejiang University School of Medicine), Shaoxing, China; Department of Pharmacology, Toxicology & Neurosciences, LSU Health Sciences Center, Shreveport, LA 71130, USA.
Department of Pharmacology, Toxicology & Neurosciences, LSU Health Sciences Center, Shreveport, LA 71130, USA.
Biochem Pharmacol. 2019 Aug;166:174-184. doi: 10.1016/j.bcp.2019.05.017. Epub 2019 May 11.
Uncoupling protein 2 (UCP2) is upregulated in several human cancers which contributes to tumorigenesis. However, whether UCP2 expression is amplified in cholangiocarcinoma and whether UCP2 promotes cholangiocarcinoma progression are not known. Our results found that in human cholangiocarcinoma tissues, UCP2 was highly expressed in tumors and its levels were negatively associated with prognosis. Importantly, lymph node invasion of cholangiocarcinoma was associated with higher UCP2 expression. In cholangiocarcinoma cells, cell proliferation and migration were suppressed when UCP2 expression was inhibited via gene knockdown. In UCP2 knockdown cells, glycolysis was inhibited, the mesenchymal markers were downregulated whereas AMPK was activated. The increased mitochondrial ROS and AMP/ATP ratio might be responsible for this activation. When the UCP2 inhibitor genipin was applied, tumor cell migration and 3D growth were suppressed via enhancing the mesenchymal-epithelial transition of cholangiocarcinoma cells. Furthermore, cholangiocarcinoma cells became sensitive to cisplatin and gemcitabine treatments when genipin was applied. In conclusion, our results demonstrate that the amplified expression of UCP2 contributes to the progression of cholangiocarcinoma through a glycolysis-mediated mechanism.
解偶联蛋白 2（UCP2）在几种人类癌症中上调，有助于肿瘤发生。然而，UCP2 在胆管癌中的表达是否扩增以及 UCP2 是否促进胆管癌进展尚不清楚。我们的研究结果发现，在人类胆管癌组织中，UCP2 在肿瘤中高表达，其水平与预后呈负相关。重要的是，胆管癌的淋巴结侵犯与 UCP2 表达升高有关。在胆管癌细胞中，通过基因敲低抑制 UCP2 表达可抑制细胞增殖和迁移。在 UCP2 敲低细胞中，糖酵解受到抑制，间充质标志物下调，而 AMPK 被激活。增加的线粒体 ROS 和 AMP/ATP 比值可能是导致这种激活的原因。当应用 UCP2 抑制剂京尼平时，通过增强胆管癌细胞的间质-上皮转化，抑制肿瘤细胞迁移和 3D 生长。此外，当应用京尼平时，胆管癌细胞对顺铂和吉西他滨治疗变得敏感。总之，我们的研究结果表明，UCP2 的扩增表达通过糖酵解介导的机制促进胆管癌的进展。
