Promotion of epithelial-mesenchymal transformation by hepatocellular carcinoma-educated macrophages through Wnt2b/β-catenin/c-Myc signaling and reprogramming glycolysis

Abstract

Background 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. Methods 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. Results 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. Conclusions 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.

Environmentally relevant perinatal exposure to DBP accelerated spermatogenesis by promoting the glycolipid metabolism of Sertoli cells in male mice

“…1E). A large number of studies have con rmed that β-catenin promotes glycolysis by regulating the expression of glycolysis related genes (Fan et al 2018;Jiang et al 2021). In this study, MBP increased the expression of β-catenin (Fig.…”

Identification of a Three-Glycolysis-Related lncRNA Signature Correlated With Prognosis and Metastasis in Clear Cell Renal Cell Carcinoma

“…As a result, the gene sets about metastasis and Wnt-related pathway regulators attracted our attention. Wnt/β-catenin signaling pathway was shown to be mainly involved in the Warburg effect and malignant progression of cancer cells ( 30 , 31 ). It was reported that Wnt/β-catenin signaling induced an increase in glucose uptake and suppressed mitochondrial respiration, mechanically activating pyruvate carboxylase to support cancer cells proliferation ( 32 ).…”

ENO3 Inhibits Growth and Metastasis of Hepatocellular Carcinoma via Wnt/β-Catenin Signaling Pathway

“…Furthermore, the translocation of PKM2 into the nucleus could elevate β-catenin accumulation, afterward causing the expression of C-Myc ( David et al, 2010 ; Yang et al, 2011 ). Interestingly, the activation of Wnt/β-catenin signaling has been demonstrated to augment glycolysis via C-Myc in tumors ( David et al, 2010 ; Jiang et al, 2021 ). Hence, there may be a positive feedback loop between C-Myc and PKM2 to drive glycolysis and EMT.…”