肿瘤相关巨噬细胞通过介导CCAT1/Let-7b/HMGA2信号通路促进肝癌发展。
Tumor-Linked Macrophages Promote HCC Development by Mediating the CCAT1/Let-7b/HMGA2 Signaling Pathway.
作者信息
Deng Liang, Huang Shan, Chen Bin, Tang Yajun, Huang Fei, Li Dong, Tang Di
机构信息
Department of General Surgery, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, Guangdong 518107, People's Republic of China.
Department of Oncology, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, Guangdong 518107, People's Republic of China.
出版信息
Onco Targets Ther. 2020 Dec 14;13:12829-12843. doi: 10.2147/OTT.S283786. eCollection 2020.
BACKGROUND
The role of high mobility group A2 (HMGA2) in the progression of hepatocellular carcinoma (HCC) is yet to be investigated, though tumor-associated macrophages (TAMs) are known to mediate the process.
METHODS
Immunohistochemistry (IHC), Western blot, and real-time PCR assays were performed to identify HMGA2 and TAMs markers. The TAMs-like macrophages (TAMs-Mφs) were triggered with the help of 25 ng/mL hM-CSF and 50% NBCM. EdU assay wound healing assay, transwell assay, and TUNEL assay, as well as flow cytometry, were carried out to study the effect of HMGA2 or TAMs on the functioning of HCC cells.
RESULTS
HCC tumor tissues were detected with upregulated HMGA2 and TAMs markers (CD68, CD163, and CD204); in addition, HMGA2 was positively correlated with TAMs markers. The proliferation, migration, and invasion of HepG2 cells were also observed to be stimulated by HMGA2. Remarkably, cell apoptosis was not affected by upregulated HMGA2, but HMAG2 inhibition was observed to intensify it. Also, the release of CSF1 was observed to be amplified by HMGA2. HMGA2-overexpressed-HepG2 cells promoted the migrating abilities of both M0-Mφs and TAMs-Mφs but were suppressed by HMGA2 down-regulated HepG2 cells. In addition, TAMs-Mφs supernatant regulated the CCAT1/let-7b/HMGA2 signaling pathway by intensifying the malignant biological behaviors.
CONCLUSION
HMGA2 stimulated TAMs-induced HCC progression, mediated by the CCAT1/let-7b/HMGA2 signaling pathway, TAMs aggravated HCC development.
背景
尽管已知肿瘤相关巨噬细胞（TAM）介导肝细胞癌（HCC）进展过程，但高迁移率族蛋白A2（HMGA2）在HCC进展中的作用尚待研究。
方法
采用免疫组织化学（IHC）、蛋白质免疫印迹法和实时荧光定量PCR检测HMGA2和TAM标志物。在25 ng/mL人巨噬细胞集落刺激因子（hM-CSF）和50%正常人支气管肺泡灌洗上清（NBCM）的作用下诱导出TAM样巨噬细胞（TAMs-Mφs）。采用EdU检测、伤口愈合试验、Transwell试验、TUNEL检测以及流式细胞术研究HMGA2或TAM对HCC细胞功能的影响。
结果
HCC肿瘤组织中HMGA2和TAM标志物（CD68、CD163和CD204）表达上调；此外，HMGA2与TAM标志物呈正相关。还观察到HMGA2可刺激HepG2细胞的增殖、迁移和侵袭。值得注意的是，上调HMGA2对细胞凋亡无影响，但抑制HMAG2可增强细胞凋亡。此外，观察到HMGA2可放大集落刺激因子1（CSF1）的释放。过表达HMGA2的HepG2细胞可促进M0-Mφs和TAMs-Mφs的迁移能力，但下调HMGA2的HepG2细胞则抑制其迁移能力。此外，TAMs-Mφs上清液通过强化恶性生物学行为来调节CCAT1/let-7b/HMGA2信号通路。
结论
HMGA2通过CCAT1/let-7b/HMGA2信号通路刺激TAM诱导的HCC进展，TAM加剧HCC发展。
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