Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China.
Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, China.
Mol Cell Proteomics. 2024 Sep;23(9):100821. doi: 10.1016/j.mcpro.2024.100821. Epub 2024 Jul 26.
Intrahepatic cholangiocarcinoma (iCCA) has a poor prognosis, and elucidation of the molecular mechanisms underlying iCCA malignancy is of great significance. Glycosylation, an important post-translational modification, is closely associated with tumor progression. Altered glycosylation, including aberrant sialylation resulting from abnormal expression of sialyltransferases (STs) and neuraminidases (NEUs), is a significant feature of cancer cells. However, there is limited information on the roles of STs and NEUs in iCCA malignancy. Here, utilizing our proteogenomic resources from a cohort of 262 patients with iCCA, we identified ST3GAL1 as a prognostically relevant molecule in iCCA. Moreover, overexpression of ST3GAL1 promoted proliferation, migration, and invasion and inhibited apoptosis of iCCA cells in vitro. Through proteomic analyses, we identified the downstream pathway potentially regulated by ST3GAL1, which was the NF-κB signaling pathway, and further demonstrated that this pathway was positively correlated with malignancy in iCCA cells. Notably, glycoproteomics showed that O-glycosylation was changed in iCCA cells with high ST3GAL1 expression. Importantly, the altered O-glycopeptides underscored the potential utility of O-glycosylation profiling as a discriminatory marker for iCCA cells with ST3GAL1 overexpression. Additionally, miR-320b was identified as a post-transcriptional regulator of ST3GAL1, capable of suppressing ST3GAL1 expression and then reducing the proliferation, migration, and invasion abilities of iCCA cell lines. Taken together, these results suggest ST3GAL1 could serve as a promising therapeutic target for iCCA.
肝内胆管癌（iCCA）预后较差，阐明其恶性肿瘤的分子机制具有重要意义。糖基化是一种重要的翻译后修饰，与肿瘤的进展密切相关。糖基化的改变，包括由于唾液酸转移酶（STs）和神经氨酸酶（NEUs）异常表达导致的异常唾液酸化，是癌细胞的一个重要特征。然而，关于 STs 和 NEUs 在 iCCA 恶性肿瘤中的作用的信息有限。在这里，我们利用来自 262 名 iCCA 患者队列的蛋白质基因组资源，鉴定出 ST3GAL1 是 iCCA 中与预后相关的分子。此外，ST3GAL1 的过表达促进了 iCCA 细胞在体外的增殖、迁移和侵袭，并抑制了凋亡。通过蛋白质组学分析，我们鉴定出 ST3GAL1 潜在调节的下游途径是 NF-κB 信号通路，并进一步证明该途径与 iCCA 细胞的恶性程度呈正相关。值得注意的是，糖蛋白质组学显示，高表达 ST3GAL1 的 iCCA 细胞的 O-糖基化发生改变。重要的是，改变的 O-糖肽强调了 O-糖基化谱作为具有 ST3GAL1 过表达的 iCCA 细胞的鉴别标记的潜在用途。此外，miR-320b 被鉴定为 ST3GAL1 的转录后调节因子，能够抑制 ST3GAL1 的表达，从而降低 iCCA 细胞系的增殖、迁移和侵袭能力。总之，这些结果表明 ST3GAL1 可以作为 iCCA 的有前途的治疗靶点。
