癌症研究
基因敲除
索拉非尼
肝细胞癌
体内
下调和上调
CD8型
化学
转移
微泡
细胞凋亡
医学
免疫系统
生物
癌症
内科学
小RNA
免疫学
基因
生物化学
生物技术
作者
Ao Chen,Xin Zhang,Qingyang Zhang,Karen Man‐Fong Sze,Lü Tian,Hongyang Huang,Xia Wang,Eva Lee,Jingyi Lu,Xueying Lyu,M. Lee,Chun‐Ming Wong,Daniel Wai‐Hung Ho,Irene Oi‐Lin Ng
出处
期刊:Gut
[BMJ]
日期:2024-06-05
卷期号:: gutjnl-331903
被引量:1
标识
DOI:10.1136/gutjnl-2024-331903
摘要
Objective Fat mass and obesity-associated protein (FTO), an eraser of N 6 -methyadenosine (m6A), plays oncogenic roles in various cancers. However, its role in hepatocellular carcinoma (HCC) is unclear. Furthermore, small extracellular vesicles (sEVs, or exosomes) are critical mediators of tumourigenesis and metastasis, but the relationship between FTO-mediated m6A modification and sEVs in HCC is unknown. Design The functions and mechanisms of FTO and glycoprotein non-metastatic melanoma protein B (GPNMB) in HCC progression were investigated in vitro and in vivo. Neutralising antibody of syndecan-4 (SDC4) was used to assess the significance of sEV-GPNMB. FTO inhibitor CS2 was used to examine the effects on anti-PD-1 and sorafenib treatment. Results FTO expression was upregulated in patient HCC tumours. Functionally, FTO promoted HCC cell proliferation, migration and invasion in vitro, and tumour growth and metastasis in vivo. FTO knockdown enhanced the activation and recruitment of tumour-infiltrating CD8 + T cells. Furthermore, we identified GPNMB to be a downstream target of FTO, which reduced the m6A abundance of GPNMB, hence, stabilising it from degradation by YTH N 6 -methyladenosine RNA binding protein F2. Of note, GPNMB was packaged into sEVs derived from HCC cells and bound to the surface receptor SDC4 of CD8 + T cells, resulting in the inhibition of CD8 + T cell activation. A potential FTO inhibitor, CS2, suppresses the oncogenic functions of HCC cells and enhances the sensitivity of anti-PD-1 and sorafenib treatment. Conclusion Targeting the FTO/m6A/GPNMB axis could significantly suppress tumour growth and metastasis, and enhance immune activation, highlighting the potential of targeting FTO signalling with effective inhibitors for HCC therapy.
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