M2 巨噬细胞外泌体通过 miR-200c-3p 促进肝癌细胞对索拉非尼的耐药性。
M2 macrophage exosomes promote resistance to sorafenib in hepatocellular carcinoma cells via miR-200c-3p.
机构信息
Shihezi University School of Medicine, Shihezi 832000, China; Key Laboratory for Prevention and Treatment of High Morbidity in Central Asia, National Health and Health Commission, Shihezi 832000, China.
Shihezi University School of Medicine, Shihezi 832000, China; The First Affiliated Hospital, Shihezi University School of Medicine, Shihezi 832000, China; Key Laboratory for Prevention and Treatment of High Morbidity in Central Asia, National Health and Health Commission, Shihezi 832000, China.
出版信息
Int Immunopharmacol. 2024 Sep 30;139:112807. doi: 10.1016/j.intimp.2024.112807. Epub 2024 Jul 27.
OBJECTIVE
Sorafenib is a chemotherapeutic agent used to treat hepatocellular carcinoma (HCC). However, its clinical response rates are often low. Tumour-associated macrophages (TAMs) have been implicated in tumour resistance. The relationship between TAMs-derived exosomes and primary resistance to sorafenib in hepatocellular carcinoma is unclear.
METHODS
The study analysed RNA-SEQ data from TCGA-LIHC to explore the relationship between TAMs and sorafenib IC50. THP-1-induced M2 macrophages were used as a model to investigate the relationship between M2 macrophage exosomes and primary resistance to sorafenib in hepatocellular carcinoma cells using apoptosis, colony generation, cell viability and dual luciferase.
RESULTS
M2 macrophage score and sorafenib IC50 were positively correlated in hepatocellular carcinoma patients, M2 macrophage exosomes promoted sorafenib resistance in hepatocellular carcinoma cells, and M2-exo-miR-200c-3p facilitated the development of sorafenib resistance in hepatocellular carcinoma cells by mediating the activation of PI3K/AKT.
CONCLUSION
We propose and demonstrate for the first time that M2 macrophage exosomes promote sorafenib resistance in hepatocellular carcinoma, providing a new perspective for the clinical treatment of hepatocellular carcinoma patients.
目的
索拉非尼是一种用于治疗肝细胞癌（HCC）的化疗药物。然而，其临床反应率往往较低。肿瘤相关巨噬细胞（TAMs）与肿瘤耐药有关。TAMs 衍生的外泌体与肝细胞癌对索拉非尼原发性耐药之间的关系尚不清楚。
方法
本研究分析了 TCGA-LIHC 的 RNA-SEQ 数据，以探讨 TAMs 与索拉非尼 IC50 之间的关系。使用 THP-1 诱导的 M2 巨噬细胞作为模型，通过凋亡、集落生成、细胞活力和双荧光素酶检测，研究 M2 巨噬细胞外泌体与肝细胞癌细胞对索拉非尼原发性耐药的关系。
结果
肝细胞癌患者中 M2 巨噬细胞评分与索拉非尼 IC50 呈正相关，M2 巨噬细胞外泌体促进肝细胞癌细胞对索拉非尼耐药，M2-exo-miR-200c-3p 通过介导 PI3K/AKT 的激活促进肝细胞癌细胞对索拉非尼耐药的发展。
结论
我们首次提出并证明了 M2 巨噬细胞外泌体促进肝细胞癌对索拉非尼耐药，为肝细胞癌患者的临床治疗提供了新的视角。
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