FGF19/FGFR4-mediated elevation of ETV4 facilitates hepatocellular carcinoma metastasis by upregulating PD-L1 and CCL2

下调和上调 肝细胞癌 转移 医学 癌症研究 内科学 免疫学 生物 癌症 生物化学 基因
作者
Meng Xie,Zhuoying Lin,Xiaoyu Ji,Xiangyuan Luo,Zerui Zhang,Mengyu Sun,Xiaoping Chen,Bixiang Zhang,Huifang Liang,Danfei Liu,Yangyang Feng,Yijun Wang,Yiwei Li,Bi‐Feng Liu,Wenjie Huang,Limin Xia
出处
期刊:Journal of Hepatology [Elsevier BV]
卷期号:79 (1): 109-125 被引量:103
标识
DOI:10.1016/j.jhep.2023.02.036
摘要

•ETV4 is upregulated and indicates poor prognosis in human HCC.•ETV4 increases TAM and MDSC infiltration and inhibits CD8+ T-cell accumulation, facilitating HCC metastasis.•FGF19/FGFR4 and HGF/c-MET upregulate ETV4 expression in HCC cells.•Anti-PD-L1 combined with BLU-554 or trametinib inhibit FGF19-ETV4 signalling-mediated HCC metastasis. Background & AimsMetastasis remains the major reason for the high mortality of patients with hepatocellular carcinoma (HCC). This study was designed to investigate the role of E-twenty-six-specific sequence variant 4 (ETV4) in promoting HCC metastasis and to explore a new combination therapy strategy for ETV4-mediated HCC metastasis.MethodsPLC/PRF/5, MHCC97H, Hepa1-6, and H22 cells were used to establish orthotopic HCC models. Clodronate liposomes were used to clear macrophages in C57BL/6 mice. Gr-1 monoclonal antibody was used to clear myeloid-derived suppressor cells (MDSCs) in C57BL/6 mice. Flow cytometry and immunofluorescence were used to detect the changes of key immune cells in the tumour microenvironment.ResultsETV4 expression was positively related to higher tumour–node–metastasis (TNM) stage, poor tumour differentiation, microvascular invasion, and poor prognosis in human HCC. Overexpression of ETV4 in HCC cells transactivated PD-L1 and CCL2 expression, which increased tumour-associated macrophage (TAM) and MDSC infiltration and inhibited CD8+ T-cell accumulation. Knockdown of CCL2 by lentivirus or CCR2 inhibitor CCX872 treatment impaired ETV4-induced TAM and MDSC infiltration and HCC metastasis. Furthermore, FGF19/FGFR4 and HGF/c-MET jointly upregulated ETV4 expression through the ERK1/2 pathway. Additionally, ETV4 upregulated FGFR4 expression, and downregulation of FGFR4 decreased ETV4-enhanced HCC metastasis, which created a FGF19–ETV4–FGFR4 positive feedback loop. Finally, anti-PD-L1 combined with FGFR4 inhibitor BLU-554 or MAPK inhibitor trametinib prominently inhibited FGF19–ETV4 signalling-induced HCC metastasis.ConclusionsETV4 is a prognostic biomarker, and anti-PD-L1 combined with FGFR4 inhibitor BLU-554 or MAPK inhibitor trametinib may be effective strategies to inhibit HCC metastasis.Impact and implicationsHere, we reported that ETV4 increased PD-L1 and chemokine CCL2 expression in HCC cells, which resulted in TAM and MDSC accumulation and CD8+ T-cell inhibition to facilitate HCC metastasis. More importantly, we found that anti-PD-L1 combined with FGFR4 inhibitor BLU-554 or MAPK inhibitor trametinib markedly inhibited FGF19–ETV4 signalling-mediated HCC metastasis. This preclinical study will provide a theoretical basis for the development of new combination immunotherapy strategies for patients with HCC. Metastasis remains the major reason for the high mortality of patients with hepatocellular carcinoma (HCC). This study was designed to investigate the role of E-twenty-six-specific sequence variant 4 (ETV4) in promoting HCC metastasis and to explore a new combination therapy strategy for ETV4-mediated HCC metastasis. PLC/PRF/5, MHCC97H, Hepa1-6, and H22 cells were used to establish orthotopic HCC models. Clodronate liposomes were used to clear macrophages in C57BL/6 mice. Gr-1 monoclonal antibody was used to clear myeloid-derived suppressor cells (MDSCs) in C57BL/6 mice. Flow cytometry and immunofluorescence were used to detect the changes of key immune cells in the tumour microenvironment. ETV4 expression was positively related to higher tumour–node–metastasis (TNM) stage, poor tumour differentiation, microvascular invasion, and poor prognosis in human HCC. Overexpression of ETV4 in HCC cells transactivated PD-L1 and CCL2 expression, which increased tumour-associated macrophage (TAM) and MDSC infiltration and inhibited CD8+ T-cell accumulation. Knockdown of CCL2 by lentivirus or CCR2 inhibitor CCX872 treatment impaired ETV4-induced TAM and MDSC infiltration and HCC metastasis. Furthermore, FGF19/FGFR4 and HGF/c-MET jointly upregulated ETV4 expression through the ERK1/2 pathway. Additionally, ETV4 upregulated FGFR4 expression, and downregulation of FGFR4 decreased ETV4-enhanced HCC metastasis, which created a FGF19–ETV4–FGFR4 positive feedback loop. Finally, anti-PD-L1 combined with FGFR4 inhibitor BLU-554 or MAPK inhibitor trametinib prominently inhibited FGF19–ETV4 signalling-induced HCC metastasis. ETV4 is a prognostic biomarker, and anti-PD-L1 combined with FGFR4 inhibitor BLU-554 or MAPK inhibitor trametinib may be effective strategies to inhibit HCC metastasis.
最长约 10秒,即可获得该文献文件

科研通智能强力驱动
Strongly Powered by AbleSci AI
更新
PDF的下载单位、IP信息已删除 (2025-6-4)

科研通是完全免费的文献互助平台,具备全网最快的应助速度,最高的求助完成率。 对每一个文献求助,科研通都将尽心尽力,给求助人一个满意的交代。
实时播报
隐形曼青应助able采纳,获得10
4秒前
咸鱼已躺平完成签到,获得积分10
6秒前
诡异的饭团完成签到,获得积分10
7秒前
anan完成签到 ,获得积分10
8秒前
常绝山完成签到 ,获得积分10
8秒前
幽默皮皮虾完成签到,获得积分10
8秒前
易止完成签到 ,获得积分10
8秒前
just完成签到,获得积分10
9秒前
11秒前
Disguise完成签到,获得积分10
11秒前
Young4399完成签到 ,获得积分10
11秒前
火星上宛秋完成签到 ,获得积分10
12秒前
12秒前
12秒前
量子星尘发布了新的文献求助10
12秒前
szh123完成签到 ,获得积分10
13秒前
Luke发布了新的文献求助10
15秒前
mauve完成签到 ,获得积分10
15秒前
丽丽完成签到,获得积分10
19秒前
敏感笑槐完成签到 ,获得积分10
20秒前
Luke完成签到,获得积分10
20秒前
得鹿梦鱼完成签到,获得积分10
21秒前
嗝嗝完成签到,获得积分10
23秒前
Perry应助科研通管家采纳,获得30
23秒前
23秒前
今后应助水晶茶杯采纳,获得10
23秒前
peterlzb1234567完成签到,获得积分10
25秒前
natsu401完成签到 ,获得积分10
28秒前
mmddlj完成签到 ,获得积分10
28秒前
健康的雁凡完成签到,获得积分10
28秒前
稳重完成签到 ,获得积分10
30秒前
33秒前
haiqi完成签到,获得积分20
37秒前
白智妍发布了新的文献求助10
38秒前
王叮叮完成签到,获得积分10
39秒前
jeronimo完成签到,获得积分10
40秒前
40秒前
pcr163应助大橙子采纳,获得150
43秒前
李燕发布了新的文献求助10
45秒前
道友等等我完成签到,获得积分0
45秒前
高分求助中
【提示信息,请勿应助】关于scihub 10000
Les Mantodea de Guyane: Insecta, Polyneoptera [The Mantids of French Guiana] 3000
徐淮辽南地区新元古代叠层石及生物地层 3000
The Mother of All Tableaux: Order, Equivalence, and Geometry in the Large-scale Structure of Optimality Theory 3000
Handbook of Industrial Diamonds.Vol2 1100
Global Eyelash Assessment scale (GEA) 1000
Picture Books with Same-sex Parented Families: Unintentional Censorship 550
热门求助领域 (近24小时)
化学 材料科学 医学 生物 工程类 有机化学 生物化学 物理 内科学 纳米技术 计算机科学 化学工程 复合材料 遗传学 基因 物理化学 催化作用 冶金 细胞生物学 免疫学
热门帖子
关注 科研通微信公众号,转发送积分 4038184
求助须知:如何正确求助?哪些是违规求助? 3575908
关于积分的说明 11373872
捐赠科研通 3305715
什么是DOI,文献DOI怎么找? 1819255
邀请新用户注册赠送积分活动 892662
科研通“疑难数据库(出版商)”最低求助积分说明 815022