miR-210 promotes hepatocellular carcinoma progression by modulating macrophage autophagy through PI3K/AKT/mTOR signaling
miR-210 promotes hepatocellular carcinoma progression by modulating macrophage autophagy through PI3K/AKT/mTOR signaling
复制标题
DOI：
10.1016/j.bbrc.2023.04.055
复制
发表时间：
2023-04-24
影响因子：
3.1
通讯作者：
Ren, Chunxia
中科院分区：
文献类型：
--
作者：
Bi, Shumin;Zhang, Yidan;Ren, Chunxia
背景：肿瘤相关巨噬细胞（tumor associated macrophages, tam）在肿瘤发生发展中起着重要作用。越来越多的研究表明，miR-210可能促进肿瘤毒力的进展，但其在原发性肝细胞癌（HCC）中的促癌作用是否通过对M2巨噬细胞的作用尚未得到证实。方法：用肉豆酸酯phorbol acetate （PMA）和IL-4、IL-13诱导THP-1单核细胞向m2极化巨噬细胞分化。用miR-210模拟物或miR-210抑制剂转染M2巨噬细胞。流式细胞术检测巨噬细胞相关标志物及细胞凋亡水平。采用qRT-PCR和Western blot检测M2巨噬细胞的自噬水平、PI3K/AKT/mTOR信号通路相关mrna及蛋白的表达。采用M2巨噬细胞条件培养基培养HepG2和MHCC-97H肝癌细胞系，探讨M2巨噬细胞源性miR-210对肝癌细胞增殖、迁移、侵袭和凋亡的影响。结果：qRT-PCR显示M2巨噬细胞中miR-210表达升高。转染miR-210模拟物的M2巨噬细胞中，自噬相关基因和蛋白表达增强，而凋亡相关蛋白表达降低。MDC染色和透射电镜观察到miR-210模拟组M2巨噬细胞中MDC标记的囊泡和自噬体的积累。miR-210 mimic组M2巨噬细胞中PI3K/AKT/mTOR信号通路表达降低。与转染miR-210模拟物的M2巨噬细胞共培养的HCC细胞，与对照组相比，增殖和侵袭能力增强，而凋亡水平降低。此外，促进或抑制自噬可分别增强或消除上述观察到的生物学效应。结论：miR-210可通过PI3K/AKT/mTOR信号通路促进M2巨噬细胞自噬。M2巨噬细胞来源的miR-210通过自噬促进HCC的恶性进展，提示巨噬细胞自噬可能成为HCC新的治疗靶点，靶向miR-210可能重置M2巨噬细胞对HCC的作用。(c) 2023作者。Elsevier Inc.出版。这是一篇基于CC BY-NC许可（http://creativecommons.org/licenses/by-nc/4.0/）的开放获取文章。
Background: Tumor-associated macrophages (TAMs) play an important role in tumor development. Increasing research suggests that miR-210 may promote the progression of tumor virulence, but whether its pro-carcinogenic effect in primary hepatocellular carcinoma (HCC) is via an action on M2 macro-phages has not been examined.Methods: Differentiation of THP-1 monocytes into M2-polarized macrophages was induced with phorbol myristate acetate (PMA) and IL-4, IL-13. M2 macrophages were transfected with miR-210 mimics or miR-210 inhibitors. Flow cytometry was used to identify macrophage-related markers and apoptosis levels. The autophagy level of M2 macrophages, expression of PI3K/AKT/mTOR signaling pathway-related mRNAs and protein were detected by qRT-PCR and Western blot. HepG2 and MHCC-97H HCC cell lines were cultured with M2 macrophages conditioned medium to explore the effects of M2 macrophage-derived miR-210 on the proliferation, migration, invasion and apoptosis of HCC cells.Results: qRT-PCR showed increased expression of miR-210 in M2 macrophages. Autophagy-related gene and protein expression was enhanced in M2 macrophages transfected with miR-210 mimics, while apoptosis-related proteins were decreased. MDC staining and transmission electron microscopy observed the accumulation of MDC-labeled vesicles and autophagosomes in M2 macrophages in the miR-210 mimic group. The expression of PI3K/AKT/mTOR signaling pathway in M2 macrophages was reduced in miR-210 mimic group. HCC cells co-cultured with M2 macrophages transfected with miR-210 mimics exhibited enhanced proliferation and invasive ability as compared to the control group, while apoptosis levels were reduced. Moreover, promoting or inhibiting autophagy could enhance or abolish the above observed biological effects, respectively.Conclusions: miR-210 can promote autophagy of M2 macrophages via PI3K/AKT/mTOR signaling pathway. M2 macrophage-derived miR-210 promotes the malignant progression of HCC via autophagy, suggesting that macrophage autophagy may serve as a new therapeutic target for HCC, and targeting miR-210 may reset the effect of M2 macrophages on HCC.(c) 2023 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC license (http://creativecommons.org/licenses/by-nc/4.0/).