ALKBH5在肝癌中的表达及其对抗肿瘤免疫的影响-东南大学学报医学版

ALKBH5在肝癌中的表达及其对抗肿瘤免疫的影响

单位：1. 南京大学医学院附属鼓楼医院 Ⅰ期临床试验研究中心, 江苏南京 210008;
2. 南京中医药大学鼓楼临床医学院, 江苏南京 210023

分类号：R735.7;R657.3

出版年·卷·期（页码）：2024·43·第四期（508-515）

摘要：

目的: 探讨N6-甲基腺苷(m⁶A)去甲基化酶ALKBH5在人肝癌中的表达及其对抗肿瘤免疫的影响。方法: 采用免疫组织化学染色(IHC)检测50例肝细胞癌(HCC)样本中ALKBH5的表达;采用 χ²检验分析其与临床特征之间的关系;采用Kaplan-Meier法分析其与患者生存之间的关系;采用GSEA、GO、KEGG和Reactome通路富集分析预测ALKBH5潜在的作用机制;利用TIMER、TISIDB数据库分析ALKBH5 mRNA与免疫细胞浸润及免疫检查点分子之间的关系。结果: ALKBH5在HCC组织中低表达,并且在肿瘤直径>5 cm、有包膜浸润、ES分级Ⅲ/Ⅳ级的HCC组织中的表达更低,ALKBH5低表达组患者总生存(OS)和无进展生存(PFS)较差;基因富集分析显示ALKBH5可能参与免疫相关通路,ALKBH5与CD4⁺ T、CD8⁺ T、DC、NK等免疫细胞的浸润相关,与PD-1/L1和CTLA4的表达呈正相关。结论: ALKBH5可能通过影响抗肿瘤免疫促进肝癌恶性进展,导致患者预后不良。

Objective: To investigate the expression of ALKBH5 and its effect on antitumor immunity in liver cancer. Methods: The expression of ALKBH5 in 50 patients of HCC and corresponding adjacent nontumor tissues was detected by immunohistochemical staining(IHC), and the correlations between ALKBH5 and clinical features were analyzed by χ² test. The relationships between ALKBH5 and the survival of HCC patients was evaluated by Kaplan-Meier method. GSEA, GO, KEGG, and Reactome pathway enrichment analysis were applied to predict the potential mechanism of ALKBH5 involved. The relationship between ALKBH5 mRNA and immune cell infiltration and immune checkpoint molecules was analyzed in TIMER and TISIDB databases. Results: ALKBH5 was downregulated in HCC tissue, and the expression level of ALKBH5 were lower in HCC tissues with tumor size >5 cm, or with infiltration of tumor encapsulation, or ES grade Ⅲ/Ⅳ. Patients with lower ALKBH5 showed poor overall survival(OS) and progression free survival(PFS). Moreover, gene enrichment analysis showed that ALKBH5 might participate in immune related pathways. ALKBH5 was correlated with the infiltration of immune cells, such as CD4⁺ T, CD8⁺ T, DC, NK, and the expression of PD-1/L1 and CTLA4. Conclusion: ALKBH5 can promote malignant progression of HCC by affecting its antitumor immunity, resulting in patient poor prognosis.

参考文献：

[1] SUNG H,FERLAY J,SIEGEL R L,et al.Global cancer statistics 2020:GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J].CA Cancer J Clin,2021,71(3):209-249.
[2] FERLAY J,COLOMBET M,SOERJOMATARAM I,et al.Estimating the global cancer incidence and mortality in 2018:GLOBOCAN sources and methods[J].Int J Cancer,2019,144(8):1941-1953.
[3] LAN Q,LIU P Y,HAASE J,et al.The critical role of RNA m (6) A methylation in cancer[J].Cancer Res,2019,79(7):1285-1292.
[4] CHEN M,WONG C M.The emerging roles of N6-methyladenosine (m6A) deregulation in liver carcinogenesis[J].Mol Cancer,2020,19(1):44.
[5] ZHENG G,DAHL J A,NIU Y,et al.ALKBH5 is a mammalian RNA demethylase that impacts RNA metabolism and mouse fertility[J].Mol Cell,2013,49(1):18-29.
[6] JIN S,LI M,CHANG H,et al.The m6A demethylase ALKBH5 promotes tumor progression by inhibiting RIG-I expression and interferon alpha production through the IKKepsilon/TBK1/IRF3 pathway in head and neck squamous cell carcinoma[J].Mol Cancer,2022,21(1):97.
[7] LI N,KANG Y,WANG L,et al.ALKBH5 regulates anti-PD-1 therapy response by modulating lactate and suppressive immune cell accumulation in tumor microenvironment[J].Proc Natl Acad Sci U S A,2020,117(33):20159-20170.
[8] SONG W,FEI F,QIAO F,et al.ALKBH5-mediated N (6)-methyladenosine modification of TRERNA1 promotes DLBCL proliferation via p21 downregulation[J].Cell Death Discov,2022,8(1):25.
[9] YANG C,ZHANG H,ZHANG L,et al.Evolving therapeutic landscape of advanced hepatocellular carcinoma[J].Nat Rev Gastroenterol Hepatol,2023,20(4):203-222.
[10] YANG C,HU Y,ZHOU B,et al.The role of m (6) A modification in physiology and disease[J].Cell Death Dis,2020,11(11):960.
[11] WANG J,YU H,DONG W,et al.N6-methyladenosine-mediated up-regulation of FZD10 regulates liver cancer stem cells'properties and lenvatinib resistance through WNT/beta-catenin and hippo signaling pathways[J].Gastroenterology,2023,164(6):990-1005.
[12] ZHANG L,LI Y,ZHOU L,et al.The m6A reader YTHDF2 promotes bladder cancer progression by suppressing RIG-I-mediated immune response[J].Cancer Res,2023,83(11):1834-1850.
[13] NIU Y,LIN Z,WAN A,et al.RNA N6-methyladenosine demethylase FTO promotes breast tumor progression through inhibiting BNIP3[J].Mol Cancer,2019,18(1):46.
[14] QU J,YAN H,HOU Y,et al.RNA demethylase ALKBH5 in cancer:from mechanisms to therapeutic potential[J].J Hematol Oncol,2022,15(1):8.
[15] ZHANG S,ZHAO B S,ZHOU A,et al.m (6) A demethylase aLKBH5 maintains tumorigenicity of glioblastoma stem-like cells by sustaining FOXM1 expression and cell proliferation program[J].Cancer Cell,2017,31(4):591-606 e596.
[16] CHEN Y,ZHAO Y,CHEN J,et al.ALKBH5 suppresses malignancy of hepatocellular carcinoma via m (6) A-guided epigenetic inhibition of LYPD1[J].Mol Cancer,2020,19(1):123.
[17] QIU X,YANG S,WANG S,et al.M (6) A demethylase ALKBH5 regulates PD-L1 expression and tumor immunoenvironment in intrahepatic cholangiocarcinoma[J].Cancer Res,2021,81(18):4778-4793.
[18] BAO Y,ZHAI J,CHEN H,et al.Targeting m (6) A reader YTHDF1 augments antitumour immunity and boosts anti-PD-1 efficacy in colorectal cancer[J].Gut,2023,72(8):1497-1509.
[19] YOU Y,WEN D,ZENG L,et al.ALKBH5/MAP3K8 axis regulates PD-L1+macrophage infiltration and promotes hepatocellular carcinoma progression[J].Int J Biol Sci,2022,18(13):5001-5018.
[20] MENG Y,SHU Z,WANG X,et al.Hepatitis B virus-mediated m6A demethylation increases hepatocellular carcinoma stemness and immune escape[J].Mol Cancer Res,2024,22(7):642-655.
[21] DONNE R,LUJAMBIO A.The liver cancer immune microenvironment:therapeutic implications for hepatocellular carcinoma[J].Hepatology,2023,77(5):1773-1796.
[22] XING R,GAO J,CUI Q,et al.Strategies to improve the antitumor effect of immunotherapy for hepatocellular carcinoma[J].Front Immunol,2021,12:783236.
[23] HOOS A.Development of immuno-oncology drugs-from CTLA4 to PD1 to the next generations[J].Nat Rev Drug Discov,2016,15(4):235-247.
[24] 陈琴,曾李华,金晓灵.肝胆肿瘤患者免疫检查点抑制剂治疗致不良反应分析与护理[J].现代医学,2021,49(12):1463-1466.

服务与反馈：

【文章下载】【发表评论】【查看评论】【加入收藏】

提示：您还未登录，请登录！点此登录