Chen Fanghua, Li Yin, Aye Ling, Wu Yingcheng, Dong Liangqing, Yang Zijian, Gao Qiang, Zhang Shu
Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, 200032, China.
Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
Cell Oncol (Dordr). 2023 Feb;46(1):79-91. doi: 10.1007/s13402-022-00736-y. Epub 2022 Nov 8.
Intrahepatic cholangiocarcinoma (iCCA) is the second-most lethal primary liver cancer and its prognosis remains dismal. N-glycosylation, which is biosynthesized by a number of glycosyltransferases, plays an important role in a variety of biological processes and is associated with cancer development and progression.
Based on our previous proteogenomic resources from an iCCA cohort of 262 patients, fucosyltransferases 8 (FUT8) showed significant prognosis relevance in iCCA. Tumor tissues from iCCA patients were used to evaluate the correlation between its expression and clinical information. Gain/loss-of-function experiments in iCCA cell lines were performed to elucidate the biological function of FUT8. In addition, its downstream pathways and post-transcriptional regulators were inferred and verified.
Elevated FUT8 expression was clinically associated with worse overall survival in iCCA patients. Its overexpression promoted migration, invasion and proliferation ability of iCCA cells. In addition, miR-122-5p was found to act as a post-transcriptional regulator of FUT8 and proved to inhibit FUT8 expression and then suppress the proliferation and migration ability of iCCA cell lines. Furthermore, FUT8 was observed to promote iCCA development through PI3K/AKT signaling pathway.
These findings demonstrated that FUT8, regulated by miR-122-5p, could be a tumor promoter of iCCA through PI3K/AKT signaling pathway.
肝内胆管癌（iCCA）是致死率第二高的原发性肝癌，其预后仍然很差。N-糖基化由多种糖基转移酶生物合成，在多种生物学过程中起重要作用，并与癌症的发生和发展相关。
基于我们之前来自262例iCCA患者队列的蛋白质基因组学资源，岩藻糖基转移酶8（FUT8）在iCCA中显示出显著的预后相关性。使用iCCA患者的肿瘤组织评估其表达与临床信息之间的相关性。在iCCA细胞系中进行功能获得/丧失实验，以阐明FUT8的生物学功能。此外，对其下游途径和转录后调节因子进行了推断和验证。
FUT8表达升高在临床上与iCCA患者较差的总生存期相关。其过表达促进了iCCA细胞的迁移、侵袭和增殖能力。此外，发现miR-122-5p作为FUT8的转录后调节因子，可抑制FUT8表达，进而抑制iCCA细胞系的增殖和迁移能力。此外，观察到FUT8通过PI3K/AKT信号通路促进iCCA的发展。
这些发现表明，受miR-122-5p调控的FUT8可能通过PI3K/AKT信号通路成为iCCA的肿瘤促进因子。
