Promotion of epithelial-mesenchymal transformation by hepatocellular carcinoma-educated macrophages through Wnt2b/β-catenin/c-Myc signaling and reprogramming glycolysis.
Promotion of epithelial-mesenchymal transformation by hepatocellular carcinoma-educated macrophages through Wnt2b/β-catenin/c-Myc signaling and reprogramming glycolysis.
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DOI：
10.1186/s13046-020-01808-3
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发表时间：
2021-01-06
期刊：
影响因子：
--
通讯作者：
Zhang J
中科院分区：
文献类型：
--
作者：
Jiang Y;Han Q;Zhao H;Zhang J
肿瘤微环境（TME）中的肿瘤相关巨噬细胞（TAM）可促进肝细胞癌（HCC）的进展。一些肿瘤可以通过靶向肿瘤细胞中的Wnt 2b来抑制。然而，Wnt 2b在HCC中的作用仍然未知。特别是，Wnt 2b介导的信号激活在HCC微环境中巨噬细胞极化中的作用，以及Wnt和TAM中糖酵解之间的调节作用尚未描述。通过qPCR和免疫荧光检测TAM中Wnt 2b的表达。通过携带靶向shRNA或TLR 9激动剂的慢病毒进行HCC-TAM中的Wnt 2b/β-catenin干扰。流式细胞术和qPCR检测巨噬细胞极化相关标志物和关键糖酵解酶表达的变化。用Seahorse分析仪分析ECAR。采用MTT法、创伤愈合实验、Western blotting法观察不同HCC-TAM对体外培养的肝癌细胞增殖、迁移及EMT的影响。将肿瘤细胞和不同的HCC-TAM通过皮下注射到免疫缺陷小鼠中，以评估CpG ODN、Wnt 2b或β-连环蛋白在体内肿瘤生长中对HCC-TAM的影响。肝癌细胞来源的极化促进因子上调巨噬细胞Wnt 2b的表达，通过激活Wnt 2b/β-catenin/c-Myc信号通路促进TAM向M2样巨噬细胞极化。此外，这一过程与HCC-TAM中糖酵解的活化有关。这些HCC-TAM可促进HCC的EMT、增殖和迁移。TLR 9激动剂CpG ODN除了沉默Wnt 2b或β-catenin的表达外，还下调了HCC-TAMs的糖酵解水平，抑制了TAMs的M2极化，逆转了TAMs在体外和体内的促肿瘤作用。Wnt 2b作为HCC治疗的潜在靶点，可能对TME中TAM的功能发挥重要的调节作用。此外，TLR 9激动剂CpG ODN可能作为Wnt 2b信号抑制剂，并可能通过干扰Wnt 2b/β-catenin/c-Myc和抑制HCC-TAM中的糖酵解而用于HCC治疗。
Tumour-associated macrophages (TAMs) in the tumour microenvironment (TME) can promote the progression of hepatocellular carcinoma (HCC). Some tumours can be suppressed by targeting Wnt2b in tumour cells. However, the role of Wnt2b in HCC is still unknown. In particular, the role of Wnt2b-mediated signal activation in macrophage polarization in the HCC microenvironment, and the regulatory effect between Wnt and glycolysis in TAMs has not been described. The expression of Wnt2b in TAMs was detected by qPCR and immunofluorescence. Wnt2b/β-catenin interference in HCC-TAMs was performed by lentivirus carrying targeted shRNA or TLR9 agonist. Markers related to macrophage polarization and the changes of key glycolytic enzymes expression were detected by flow cytometry and qPCR. ECAR was analysed by Seahorse analyser. MTT assay, wound healing assay, western blotting were used to evaluate the promoting effect of different HCC-TAMs on the proliferation, migration and EMT of HCC in vitro. Tumour cells and different HCC-TAMs were injected via subcutaneously into immunodeficient mice to assess the effects of CpG ODN, Wnt2b, or β-catenin on HCC-TAMs in tumour growth in vivo. Polarization-promoting factors derived from HCC cells upregulated the expression of Wnt2b in macrophages, which promoted the polarization of TAMs to M2-like macrophages by activating Wnt2b/β-catenin/c-Myc signalling. Furthermore, this process was associated with the activation of glycolysis in HCC-TAMs. These HCC-TAMs could promote the development of EMT, proliferation, and migration of HCC. In addition to silencing Wnt2b or β-catenin expression, TLR9 agonist CpG ODN downregulated the level of glycolysis and inhibited the M2 polarization of HCC-TAMs, reversing the tumour-promoting effects of TAMs in vitro and vivo. As a potential target for HCC therapy, Wnt2b may play an important regulatory role for the functions of TAMs in the TME. Moreover, the TLR9 agonist CpG ODN might act as a Wnt2b signal inhibitor and can potentially be employed for HCC therapy by disturbing Wnt2b/β-catenin/c-Myc and inhibiting glycolysis in HCC-TAMs.
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影响因子：
11.2
作者：
Hong Y;Manoharan I;Suryawanshi A;Majumdar T;Angus-Hill ML;Koni PA;Manicassamy B;Mellor AL;Munn DH;Manicassamy S
通讯作者：
Manicassamy S
影响因子：
4.8
作者：
Osthus, RC;Shim, H;Dang, CV
通讯作者：
Dang, CV
DOI：
10.1186/s12964-018-0262-x
发表时间：
2018-09-04
期刊：
Cell communication and signaling : CCS
影响因子：
--
作者：
Feng R;Morine Y;Ikemoto T;Imura S;Iwahashi S;Saito Y;Shimada M
通讯作者：
Shimada M
miR-324-3p 通过靶向 WNT2B 抑制鼻咽癌的迁移和侵袭。
影响因子：
5.8
作者：
Liu C;Li G;Yang N;Su Z;Zhang S;Deng T;Ren S;Lu S;Tian Y;Liu Y;Qiu Y
通讯作者：
Qiu Y
HBx突变通过Wnt/-catenin信号通路促进肝癌细胞迁移
影响因子：
5.7
作者：
Chen Z;Tang J;Cai X;Huang Y;Gao Q;Liang L;Tian L;Yang Y;Zheng Y;Hu Y;Tang N
通讯作者：
Tang N