小剂量二甲双胍通过 AMPK/JNK/IL-8 通路抑制肝癌转移。

Low-dose metformin suppresses hepatocellular carcinoma metastasis via the AMPK/JNK/IL-8 pathway.

机构信息

Department of Clinical Laboratory, Xuzhou Institute of Medical Science, Xuzhou Central Hospital, Xuzhou, China.

Xuzhou Clinical School of Xuzhou Medical University, Xuzhou, China.

出版信息

Int J Immunopathol Pharmacol. 2024 Jan-Dec;38:3946320241249445. doi: 10.1177/03946320241249445.

DOI:10.1177/03946320241249445

PMID:38679570

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11057349/

Abstract

BACKGROUND AND OBJECTIVES

Metformin, an oral hypoglycemic drug, has been suggested to possess antitumour activity in several types of cancers. Additionally, interleukin-8 (IL-8) has been reported to be involved in the development and metastasis of many cancers. However, the effect of metformin on IL-8 expression in hepatocellular carcinoma (HCC) remains unclear. Therefore, this study aimed to investigate whether metformin could inhibit IL-8 expression to exert an inhibitory effect on HCC progression.

MATERIALS AND METHODS

The IL-8 levels were measured in the plasma of 159 HCC patients (86 men, 73 women; average age 56 years) and in the culture supernatant of HCC cells (Hep3B and HuH7) using flow cytometry. In addition, the protein expression levels of IL-8 were also validated by the Human Protein Atlas (HPA) database. The prognostic value of IL-8 was evaluated using the Kaplan-Meier Plotter database. The association between IL-8 expression and immune checkpoints was estimated using the TIMER and The Cancer Genome Atlas (TCGA) databases. What's more, bioinformatics analysis, western blotting, and transwell assays were conducted to illustrate the molecular mechanism of metformin (≤1 mM) on IL-8 in HCC.

RESULTS

IL-8 expression was found to be increased in the plasma of HCC patients, which is consistent with the expression of IL-8 in HCC cells and tissues. High expression of IL-8 was significantly related to poor prognosis. In addition, IL-8 was positively correlated with immune checkpoints in HCC. Notably, we found that low-dose metformin could inhibit the secretion of IL-8 by HCC cells and the migration of HCC cells. Mechanistically, low-dose metformin significantly suppresses HCC metastasis mainly through the AMPK/JNK/IL-8/MMP9 pathway.

CONCLUSION

The results indicate that low-dose metformin can inhibit HCC metastasis by suppressing IL-8 expression. Targeting the AMPK/JNK/IL-8 axis may be a promising treatment strategy for patients with HCC metastasis.

摘要

背景与目的

二甲双胍是一种口服降糖药，已被证实对多种类型的癌症具有抗肿瘤活性。此外，白细胞介素-8（IL-8）已被报道参与许多癌症的发展和转移。然而，二甲双胍对肝细胞癌（HCC）中 IL-8 表达的影响尚不清楚。因此，本研究旨在探讨二甲双胍是否可以通过抑制 IL-8 表达来抑制 HCC 的进展。

材料与方法

采用流式细胞术检测 159 例 HCC 患者（男 86 例，女 73 例；平均年龄 56 岁）和 HCC 细胞（Hep3B 和 HuH7）培养上清液中的 IL-8 水平。此外，还通过人类蛋白质图谱（HPA）数据库验证了 IL-8 的蛋白表达水平。采用 Kaplan-Meier Plotter 数据库评估 IL-8 的预后价值。通过 TIMER 和癌症基因组图谱（TCGA）数据库评估 IL-8 表达与免疫检查点之间的关系。此外，还进行了生物信息学分析、Western blot 和 Transwell 实验，以阐明二甲双胍（≤1mM）对 HCC 中 IL-8 的分子机制。

结果

研究发现 HCC 患者的血浆中 IL-8 表达增加，与 HCC 细胞和组织中的 IL-8 表达一致。高表达的 IL-8 与预后不良显著相关。此外，IL-8 在 HCC 中与免疫检查点呈正相关。值得注意的是，我们发现低剂量的二甲双胍可以抑制 HCC 细胞分泌 IL-8 和 HCC 细胞的迁移。机制上，低剂量的二甲双胍主要通过 AMPK/JNK/IL-8/MMP9 通路显著抑制 HCC 转移。