METTL3/16-mediated m6A modification of ZNNT1 promotes hepatocellular carcinoma progression by activating ZNNT1/osteopontin/S100A9 positive feedback loop-mediated crosstalk between macrophages and tumour cells

• Published in: Clinical immunology (Orlando, Fla.) Vol. 261; p. 109924
• Main Authors: Wei, Huamei, Li, Wenchuan, Yang, Meng, Fang, Quan, Nian, Jiahui, Huang, Youguan, Wei, Qing, Huang, Zihua, Liu, Guoman, Xu, Zuoming, Hu, Anbin, Pu, Jian
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 01.04.2024
• Subjects: Crosstalk; Hepatocellular carcinoma; N6-methyladenosine; Positive feedback loop; Tumour-associated macrophage; TAM; lncRNA; IHC; Crosstalk; Hepatocellular carcinoma; OPN; ChIP; ATCC; TUNEL; Positive feedback loop; FBS; CCK-8; cDNA; LIHC; IF; PMA; qRT-PCR; BCLC; HCC; CM; Tumour-associated macrophage; TME; MeRIP; TCGA; NC; EdU; FISH; RIP; N6-methyladenosine; S100A9; ELISA
• ISSN: 1521-6616; 1521-7035
• DOI: 10.1016/j.clim.2024.109924

Macrophages are the major components of tumour microenvironment, which play critical roles in tumour development. N6-methyladenosine (m6A) also contributes to tumour progression. However, the potential roles of m6A in modulating macrophages in hepatocellular carcinoma (HCC) are poorly understood. Here, we identified ZNNT1 as an HCC-related m6A modification target, which was upregulated and associated with poor prognosis of HCC. METTL3 and METTL16-mediated m6A modification contributed to ZNNT1 upregulation through stabilizing ZNNT1 transcript. ZNNT1 exerted oncogenic roles in HCC. Furthermore, ZNNT1 recruited and induced M2 polarization of macrophages via up-regulating osteopontin (OPN) expression and secretion. M2 Macrophages-recruited by ZNNT1-overexpressed HCC cells secreted S100A9, which further upregulated ZNNT1 expression in HCC cells via AGER/NF-κB signaling. Thus, this study demonstrates that m6A modification activated the ZNNT1/OPN/S100A9 positive feedback loop, which promoted macrophages recruitment and M2 polarization, and enhanced malignant features of HCC cells. m6A modification-triggered ZNNT1/OPN/S100A9 feedback loop represents potential therapeutic target for HCC. [Display omitted] •ZNNT1 was an m6A modification target, whose expression level and m6A modification level were both increased in HCC.•METTL3 and METTL16-mediated m6A modification contributed to ZNNT1 upregulation through increasing ZNNT1 transcript stability.•ZNNT1 recruited and induced M2 polarization of macrophages via up-regulating OPN expression and secretion.•M2 Macrophages secreted S100A9, which further upregulated ZNNT1 expression in HCC cells via AGER/NF-κB signaling.