Department of Clinical Laboratory, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116011, China.
College of Laboratory Medicine, Dalian Medical University, Dalian, Liaoning 116044, China.
Dig Liver Dis. 2023 Jan;55(1):113-122. doi: 10.1016/j.dld.2022.04.009. Epub 2022 Apr 30.
Glycosylation exhibits crucial effect on hepatocellular carcinoma (HCC) progression. Long non-coding RNAs (lncRNAs) are involved in multilevel regulation of gene transcription during tumor development. The purpose of this study is to clarify the potential mechanism that HOTAIR modulates hepatocellular carcinoma progression by activating FUT8/core-fucosylated Hsp90/MUC1/STAT3 feedback loop via JAK1/STAT3 cascade.
qRT-PCR was used to show the differential expression of genes. Functional experiments were used to measure the malignancy of HCC cells. ChIP and co-IP assays showed the directly interaction of the key molecules. Xenografts was conducted to show the in vivo effects.
Upregulation of FUT8 showed closely correlation with HCC progression. Core-fucosylation of Hsp90 stabilized MUC1 binding to the downstream p-STAT3, which involved in the activation of JAK1/STAT3 cascade. STAT3 was identified as the regulator of FUT8 and MUC1 transcription, while FUT8 and MUC1 impacted STAT3 level both in nuclear and cytoplasm. HOTAIR recruited P300 to efficiently bind with STAT3. The transcript complex co-modulated the transcrption of FUT8 and MUC1. Moreover, highly HOTAIR expression also exhibited closely correlation with HCC progression.
FUT8 triggered core-fucosylated-Hsp90/MUC1/P300-HOTAIR-STAT3 cascade via JAK1/STAT3 pathway, which exhibited as positive feedback loop during HCC progression.
糖基化对肝细胞癌（HCC）的进展具有至关重要的影响。长链非编码 RNA（lncRNA）参与肿瘤发展过程中基因转录的多层次调控。本研究旨在阐明 HOTAIR 通过 JAK1/STAT3 级联激活 FUT8/核心岩藻糖基化 HSP90/MUC1/STAT3 反馈环来调节肝细胞癌进展的潜在机制。
使用 qRT-PCR 显示基因的差异表达。功能实验用于测量 HCC 细胞的恶性程度。ChIP 和 co-IP 测定显示关键分子的直接相互作用。异种移植用于显示体内效应。
FUT8 的上调与 HCC 的进展密切相关。Hsp90 的核心岩藻糖基化稳定了 MUC1 与下游 p-STAT3 的结合，这涉及 JAK1/STAT3 级联的激活。STAT3 被鉴定为 FUT8 和 MUC1 转录的调节剂，而 FUT8 和 MUC1 均在核和细胞质中影响 STAT3 水平。HOTAIR 招募 P300 与 STAT3 有效结合。转录复合物共同调节 FUT8 和 MUC1 的转录。此外，高表达 HOTAIR 也与 HCC 的进展密切相关。
FUT8 通过 JAK1/STAT3 途径触发核心岩藻糖基化-Hsp90/MUC1/P300-HOTAIR-STAT3 级联，在 HCC 进展过程中表现为正反馈环。
