L-岩藻糖通过引起 microRNA-200b 的过表达来抑制胆管癌的进展。

L-Fucose inhibits the progression of cholangiocarcinoma by causing microRNA-200b overexpression.

机构信息

Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China.

Department of Diagnostic Medical Sonography, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430014, China.

出版信息

Chin Med J (Engl). 2022 Dec 20;135(24):2956-2967. doi: 10.1097/CM9.0000000000002368.

DOI:10.1097/CM9.0000000000002368

PMID:36728287

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10106127/

Abstract

BACKGROUND

Cholangiocarcinoma (CCA) is a malignant biliary tract tumor with an extremely poor prognosis. There is an urgent demand to explore novel therapeutic strategies. L-fucose has been confirmed to participate in anti-inflammation and antitumor activities. However, the effect of L-fucose on the progression of CCA has not been well investigated. This study aimed to determine whether L-fucose induced the inhibition of CCA and its possible mechanism.

METHODS

The anti-growth activity was determined using Cell Counting Kit-8 assay, colony formation assays, Annexin V-fluorescein isothiocyanate/propidium iodide (FITC/PI) assay, and cell cycle analysis. The anti-metastasis activity was determined by wound healing, transwell, and invasion assays. The anti-angiogenesis activity was determined by tube formation and transwell assays. MicroRNAs that may be involved in the L-fucose-induced CCA inhibition was analyzed using bioinformatics methods. The preclinical therapeutic efficacy was mainly estimated by ultrasound in xenograft nude mouse models. Differences were analyzed via Student's t test or one-way analysis of variance.

RESULTS

L-Fucose induced apoptosis and G0/G1 cell cycle arrest, inhibited cell epithelial-mesenchymal transition of CCA cells, and additionally inhibited tube formation of human umbilical vein endothelial cells (HUVECs) in a dose-dependent manner, leading to a decrease in cell proliferation, metastasis, and angiogenesis. Mechanistically, L-fucose induced microRNA-200b (miR-200b) upregulation, and mitogen-activated protein kinase 7 (MAPK7) downregulation was found to be targeted by miR-200b, with decreased cell proliferation and metastasis. Additionally, phosphorylated signal transducer and activator of transcription 3 was found to be downregulated after L-fucose treatment. Finally, in vivo experiments in CCA xenograft models also confirmed the antitumor properties of L-fucose.

CONCLUSION

L-Fucose inhibited the progression of CCA via the miR-200b/MAPK7 and signal transducer and activator of transcription 3 signaling pathways.

摘要

背景

胆管癌（CCA）是一种恶性胆道肿瘤，预后极差。因此，迫切需要探索新的治疗策略。L-岩藻糖已被证实参与抗炎和抗肿瘤活性。然而，L-岩藻糖对 CCA 进展的影响尚未得到很好的研究。本研究旨在确定 L-岩藻糖是否诱导 CCA 抑制及其可能的机制。

方法

采用细胞计数试剂盒-8 测定法、集落形成测定法、Annexin V-荧光素异硫氰酸酯/碘化丙啶（FITC/PI）测定法和细胞周期分析测定抗生长活性。通过划痕愈合、Transwell 和侵袭测定法测定抗转移活性。通过管形成和 Transwell 测定法测定抗血管生成活性。使用生物信息学方法分析可能参与 L-岩藻糖诱导的 CCA 抑制的 microRNAs。在异种移植裸鼠模型中，主要通过超声评估临床前治疗效果。通过 Student's t 检验或单向方差分析分析差异。

结果

L-岩藻糖诱导 CCA 细胞凋亡和 G0/G1 细胞周期停滞，抑制细胞上皮-间充质转化，并且以剂量依赖性方式抑制人脐静脉内皮细胞（HUVEC）的管形成，导致细胞增殖、转移和血管生成减少。机制上，L-岩藻糖诱导 microRNA-200b（miR-200b）上调，发现 MAPK7 是 miR-200b 的靶基因，MAPK7 下调导致细胞增殖和转移减少。此外，在 L-岩藻糖处理后发现磷酸化信号转导和转录激活因子 3 下调。最后，CCA 异种移植模型的体内实验也证实了 L-岩藻糖的抗肿瘤特性。