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

Chengwen Zhao, Lu Zheng, Yuting Ma, Yue Zhang, Chanjuan Yue, Feng Gu, Guoping Niu, Yongqiang Chen
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Abstract

Background and objectivesMetformin, 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 methodsThe 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.ResultsIL-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.ConclusionThe 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.
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小剂量二甲双胍通过 AMPK/JNK/IL-8 通路抑制肝细胞癌转移
背景和目的二甲双胍是一种口服降糖药,被认为对多种癌症具有抗肿瘤活性。此外,有报道称白细胞介素-8(IL-8)参与了多种癌症的发展和转移。然而,二甲双胍对肝细胞癌(HCC)中 IL-8 表达的影响仍不清楚。因此,本研究旨在探讨二甲双胍是否能抑制 IL-8 的表达,从而对 HCC 的进展产生抑制作用。材料和方法 使用流式细胞术检测了 159 例 HCC 患者(86 例男性,73 例女性;平均年龄 56 岁)血浆中的 IL-8 水平以及 HCC 细胞(Hep3B 和 HuH7)培养上清液中的 IL-8 水平。此外,人类蛋白质图谱(HPA)数据库也验证了 IL-8 的蛋白质表达水平。使用 Kaplan-Meier Plotter 数据库评估了 IL-8 的预后价值。IL-8的表达与免疫检查点之间的关联则通过TIMER和癌症基因组图谱(TCGA)数据库进行了评估。此外,研究人员还进行了生物信息学分析、Western 印迹和跨孔实验,以说明二甲双胍(≤1 mM)对 HCC 中 IL-8 的分子机制。结果发现,HCC 患者血浆中 IL-8 表达增加,这与 HCC 细胞和组织中 IL-8 的表达一致。IL-8 的高表达与预后不良明显相关。此外,IL-8 与 HCC 中的免疫检查点呈正相关。值得注意的是,我们发现小剂量二甲双胍可抑制HCC细胞分泌IL-8,并抑制HCC细胞的迁移。从机理上讲,小剂量二甲双胍主要通过AMPK/JNK/IL-8/MMP9途径显著抑制HCC转移。针对AMPK/JNK/IL-8轴可能是治疗HCC转移患者的一种有前景的策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
4.00
自引率
0.00%
发文量
88
审稿时长
15 weeks
期刊介绍: International Journal of Immunopathology and Pharmacology is an Open Access peer-reviewed journal publishing original papers describing research in the fields of immunology, pathology and pharmacology. The intention is that the journal should reflect both the experimental and clinical aspects of immunology as well as advances in the understanding of the pathology and pharmacology of the immune system.
期刊最新文献
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