Guo Yan, Li Qi, Ren Wei, Wu Hongyan, Wang Chengzhi, Li Xinyu, Xue Bin, Qiu Yudong, Zhang Jingzi, Chen Jun, Fang Lei
Department of Pathology, The Affiliated Drum Tower Hospital of Nanjing University, Jiangsu Key Laboratory of Molecular Medicine, Chemistry and Biomedicine Innovation Center, Medical School of Nanjing University, Nanjing 210093, China.
The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University & Clinical Cancer Institute of Nanjing University, Nanjing 210008, China.
J Proteome Res. 2022 Oct 7;21(10):2504-2514. doi: 10.1021/acs.jproteome.2c00472. Epub 2022 Sep 6.
Intrahepatic cholangiocarcinoma (iCCA) is a lethal hepatobiliary malignancy that arises from the epithelial cells of the intrahepatic bile ducts, accounting for approximately 10% of cholangiocarcinoma (CCA). According to the 2019 World Health Organization (WHO) classification of tumors of the digestive system, iCCA is divided into small-duct type (SD-type) and large-duct type (LD-type). However, it remains unknown which molecular events contribute to the disparity. To explore the proteomic characteristics of iCCA, we used an isobaric tag for relative and absolute quantitation (iTRAQ) based quantitative proteomics strategy to investigate stably dysregulated proteins in the SD-type and LD-type of iCCA tissues. Importantly, we found three glycolysis/gluconeogenesis-related enzymes, triosephosphate isomerize 1 (TPI1), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), and phosphoglycerate kinase 1 (PGK1), were significantly down-regulated in the LD-type iCCA, which were further confirmed by immunohistochemistry using tissue microarray. Moreover, we demonstrated that the knockdown of these three candidate proteins by siRNAs notably increased the ability of proliferation in two CCA cell lines (HuH28 and RBE), suggesting that effective down-regulation of the glycolysis/gluconeogenesis pathway might be an underlying novel mechanism contributing to the LD-type iCCA.
肝内胆管癌（iCCA）是一种致命的肝胆恶性肿瘤，起源于肝内胆管上皮细胞，约占胆管癌（CCA）的10%。根据2019年世界卫生组织（WHO）消化系统肿瘤分类，iCCA分为小胆管型（SD型）和大胆管型（LD型）。然而，尚不清楚哪些分子事件导致了这种差异。为了探索iCCA的蛋白质组学特征，我们使用基于相对和绝对定量的等压标签（iTRAQ）定量蛋白质组学策略，研究iCCA组织SD型和LD型中稳定失调的蛋白质。重要的是，我们发现三种糖酵解/糖异生相关酶，磷酸丙糖异构酶1（TPI1）、甘油醛-3-磷酸脱氢酶（GAPDH）和磷酸甘油酸激酶1（PGK1），在LD型iCCA中显著下调，使用组织芯片的免疫组织化学进一步证实了这一点。此外，我们证明，通过小干扰RNA（siRNA）敲低这三种候选蛋白显著增加了两种CCA细胞系（HuH28和RBE）的增殖能力，表明糖酵解/糖异生途径的有效下调可能是导致LD型iCCA的一种潜在新机制。
