肝细胞癌中ADH1A表达与微血管侵犯及患者预后的关联性分析

doi:10.3969/j.issn.1004-616x.2025.06.006

摘要/Abstract

摘要： 目的：探讨醇脱氢酶1A(ADH1A)在肝细胞癌(HCC)中的表达变化及其与微血管侵犯(MVI)、患者预后和肿瘤免疫微环境的关系，进一步揭示其潜在的分子机制。方法：基于公开的101例HCC患者蛋白质组数据，比较其肿瘤组织和癌旁组织的ADH1A表达差异。根据ADH1A蛋白表达的中位数将101例患者分为ADH1A高、低表达组，绘制生存曲线，并分析ADH1A蛋白表达与临床病理指标的关系。通过GO生物过程富集分析，识别与ADH1A表达相关的蛋白主要富集的通路及其显著性，并检验其在ADH1A高、低表达组间的丰度差异。应用CIBERSORT算法进行免疫浸润分析，比较ADH1A高、低表达组间各免疫细胞亚群的丰度差异。合并公开的空间转录组数据集，分析ADH1A的空间表达特征。最后，通过Western blot和免疫组织化学技术检测HCC患者组织样本中ADH1A的表达，并评估其与MVI状态的相关性。结果：ADH1A在HCC肿瘤组织中的表达显著低于癌旁组织(P<0.01)，ADH1A的表达水平与患者微血管侵犯(MVI)显著相关(P<0.05)，且ADH1A的低表达与患者不良预后显著相关。GO富集分析显示，与ADH1A表达呈正相关的蛋白主要参与有机酸代谢等代谢相关过程，而与ADH1A表达呈负相关的蛋白主要参与细胞-基质黏附、细胞铺展等过程。针对负相关条目中“细胞黏附”类生物过程中的7个关键黏附相关蛋白在ADH1A低表达组中均显著上调(均为P<0.05)。免疫浸润分析显示，ADH1A低表达组中初始CD4 T细胞和静息型肥大细胞均显著降低(均为P<0.05)。空间转录组分析、Western blot和免疫组织化学检测结果均显示ADH1A在肿瘤区域的表达较癌旁区域下降，且在MVI阳性样本的表达较MVI阴性样本下降(P<0.05)。结论：ADH1A在肝细胞癌中表达下调，与微血管侵犯及不良预后显著相关。ADH1A可能通过调控细胞黏附通路和免疫微环境发挥抗肿瘤作用，具有作为预后生物标志物和治疗靶点的潜力。

关键词: 醇脱氢酶1A, 肝细胞癌, 微血管侵犯, 肿瘤免疫微环境, 细胞黏附通路

Abstract: OBJECTIVE：To investigate changes in expression of alcohol dehydrogenase 1A (ADH1A) and association with microvascular invasion (MVI)，the tumor immune microenvironment and prognosis as molecular mechanisms for hepatocellular carcinoma (HCC). METHODS：Using publicly available proteomic data from 101 HCC patients，ADH1A expression between tumor tissues and adjacent non-tumor tissues was compared. Based on the median ADH1A protein expression level，patients were divided into high and low expression groups. Survival curves were plotted，and associations between ADH1A expression and clinicopathological features were analyzed. Gene Ontology (GO) biological process enrichment analysis was performed to identify pathways enriched among proteins positively or negatively correlated with ADH1A expression and to evaluate their abundance differences between high and low ADH1A expression groups. Immune infiltration was analyzed using the CIBERSORT algorithm to assess differences in immune cell subsets between groups. Spatial transcriptomics data were analyzed to explore the spatial expression pattern of ADH1A. Finally，Western blot and immunohistochemistry (IHC) were performed on clinical HCC tissue samples to examine ADH1A expression and its relationship with MVI status. RESULTS：ADH1A expression was significantly lower in tumor tissues compared to adjacent non-tumor tissues (P<0.01). Its expression was significantly associated with MVI (P<0.05)，and low ADH1A expression was strongly correlated with poor prognosis. GO enrichment analysis revealed that proteins positively correlated with ADH1A were mainly involved in metabolic processes such as organic acid metabolism，while negatively correlated proteins were enriched in cell-matrix adhesion and cell spreading pathways. Notably，seven key adhesion-related proteins within the “cell adhesion” biological process were significantly upregulated in the low ADH1A expression group (all P<0.05). Immune infiltration analysis showed that na-ve CD4 T cells and resting mast cells were significantly decreased in the low ADH1A group (both P<0.05). Spatial transcriptomics，Western blot，and IHC consistently demonstrated reduced ADH1A expression in tumor regions compared to non-tumor regions，and lower expression in MVI-positive samples than in MVI-negative ones. CONCLUSION：ADH1A was downregulated in hepatocellular carcinoma and was significantly associated with microvascular invasion and poor prognosis. ADH1A may exert anti-tumor effects by modulating cell adhesion pathways and the immune microenvironment，suggesting its potential as a prognostic biomarker and therapeutic target.

Key words: ADH1A, hepatocellular carcinoma, microvascular invasion, tumor immune microenvironment, cell adhesion pathways

中图分类号:

R730.2

王宏伟, 李海洋, 胡楠, 吴凡, 荣维淇, 吴健雄. 肝细胞癌中ADH1A表达与微血管侵犯及患者预后的关联性分析[J]. 癌变·畸变·突变, 2025, 37(6): 458-466,493.

WANG Hongwei, LI Haiyang, HU Nan, WU Fan, RONG Weiqi, WU Jianxiong. Association analysis of ADH1A expression with microvascular invasion and patients prognosis in hepatocellular carcinoma[J]. Carcinogenesis, Teratogenesis & Mutagenesis, 2025, 37(6): 458-466,493.

参考文献

[1] NG C K Y, DAZERT E, BOLDANOVA T, et al. Integrative proteogenomic characterization of hepatocellular carcinoma across etiologies and stages[J]. Nat Commun, 2022, 13(1): 2436.
[2] GAN W J, WANG J R, ZHU X L, et al. RARγ-induced E-cadherin downregulation promotes hepatocellular carcinoma invasion and metastasis[J]. J Exp Clin Cancer Res, 2016, 35(1): 164.
[3] LU J P, FENG J K, ZHAO Y, et al. Grading risk of microvascular invasion impacts survival in hepatocellular carcinoma patients undergoing adjuvant transarterial chemoembolization: a multicenter study[J]. Eur J Surg Oncol, 2025, 51(8): 110102.
[4] SHENG X, JI Y, REN G P, et al. A standardized pathological proposal for evaluating microvascular invasion of hepatocellular carcinoma: a multicenter study by LCPGC[J]. Hepatol Int, 2020, 14(6): 1034-1047.
[5] WANG W T, GUO Y X, ZHONG J T, et al. The clinical significance of microvascular invasion in the surgical planning and postoperative sequential treatment in hepatocellular carcinoma[J]. Sci Rep, 2021, 11(1): 2415.
[6] 中华人民共和国国家卫生健康委员会. 原发性肝癌诊疗指南(2024年版)[J]. 临床肝胆病杂志, 2024, 40(5): 893-918.
[7] 李雪梅, 康萌, 万静之, 等. 酒精性肝病中的铁死亡机制研究进展[J]. 癌变·畸变·突变, 2024, 36(1): 66-69, 76.
[8] SEITZ H K, STICKEL F. Acetaldehyde as an underestimated risk factor for cancer development: role of genetics in ethanol metabolism[J]. Genes Nutr, 2010, 5(2): 121-128.
[9] LIU X Y, LI T T, KONG D L, et al. Prognostic implications of alcohol dehydrogenases in hepatocellular carcinoma[J]. BMC Cancer, 2020, 20(1): 1204.
[10] CUI Q H, PENG L N, WEI L X, et al. Genetic variant repressing ADH1A expression confers susceptibility to esophageal squamous-cell carcinoma[J]. Cancer Lett, 2018, 421: 43-50.
[11] WANG P, ZHANG L B, HUANG C X, et al. Distinct prognostic values of alcohol dehydrogenase family members for non-small cell lung cancer[J]. Med Sci Monit, 2018, 24: 3578-3590.
[12] WILHELM S M, CARTER C, TANG L Y, et al. BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis[J]. Cancer Res, 2004, 64(19): 7099-7109.
[13] LLOVET J M, RICCI S, MAZZAFERRO V, et al. Sorafenib in advanced hepatocellular carcinoma[J]. N Engl J Med, 2008, 359(4): 378-390.
[14] CHENG A L, KANG Y K, CHEN Z D, et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial[J]. Lancet Oncol, 2009, 10(1): 25-34.
[15] ZHENG R Q, WENG S, XU J P, et al. Autophagy and biotransformation affect sorafenib resistance in hepatocellular carcinoma[J]. Comput Struct Biotechnol J, 2023, 21: 3564-3574.
[16] JIANG Y, SUN A H, ZHAO Y, et al. Proteomics identifies new therapeutic targets of early-stage hepatocellular carcinoma[J]. Nature, 2019, 567(7747): 257-261.
[17] XING X H, HU E, OUYANG J H, et al. Integrated omics landscape of hepatocellular carcinoma suggests proteomic subtypes for precision therapy[J]. Cell Rep Med, 2023, 4(12): 101315.
[18] WU R, GUO W B, QIU X Y, et al. Comprehensive analysis of spatial architecture in primary liver cancer[J]. Sci Adv, 2021, 7(51): eabg3750.
[19] KUECKELHAUS J, FRERICH S, KADA-BENOTMANE J, et al. Inferring histology-associated gene expression gradients in spatial transcriptomic studies[J]. Nat Commun, 2024, 15: 7280.
[20] DUESTER G. Families of retinoid dehydrogenases regulating vitamin A function: production of visual pigment and retinoic acid[J]. Eur J Biochem, 2000, 267(14): 4315-4324.
[21] GAO Q, ZHU H W, DONG L Q, et al. Integrated proteogenomic characterization of HBV-related hepatocellular carcinoma[J]. Cell, 2019, 179(5): 1240.
[22] ZHAO N, ZHANG Y H, CHENG R F, et al. Spatial maps of hepatocellular carcinoma transcriptomes highlight an unexplored landscape of heterogeneity and a novel gene signature for survival[J]. Cancer Cell Int, 2022, 22(1): 57.
[23] üNAL E, İDILMAN İ S, AKATA D, et al. Microvascular invasion in hepatocellular carcinoma[J]. Diagn Interv Radiol, 2016, 22(2): 125-132.
[24] ZAHID K R, YAO S, KHAN A R R, et al. mTOR/HDAC1 crosstalk mediated suppression of ADH1A and ALDH2 links alcohol metabolism to hepatocellular carcinoma onset and progression in silico[J]. Front Oncol, 2019, 9: 1000.
[25] CHRISTOU C, STYLIANOU A, GKRETSI V. Midkine (MDK) in hepatocellular carcinoma: more than a biomarker[J]. Cells, 2024, 13(2): 136.
[26] OMRAN M M, FARID K, OMAR M A, et al. A combination of α-fetoprotein, midkine, thioredoxin and a metabolite for predicting hepatocellular carcinoma[J]. Ann Hepatol, 2020, 19(2): 179-185.
[27] ZHAO S, LI H D, WANG Q J, et al. The role of c-Src in the invasion and metastasis of hepatocellular carcinoma cells induced by association of cell surface GRP78 with activated α2M[J]. BMC Cancer, 2015, 15: 389.
[28] GNANI D, ROMITO I, ARTUSO S, et al. Focal adhesion kinase depletion reduces human hepatocellular carcinoma growth by repressing enhancer of zeste homolog 2[J]. Cell Death Differ, 2017, 24(5): 889-902.
[29] YOON J W, KIM K M, CHO S, et al. Th1-poised naive CD4 T cell subpopulation reflects anti-tumor immunity and autoimmune disease[J]. Nat Commun, 2025, 16(1): 1962.
[30] ALI E, -ERVENKOVÁ L, PÁLEK R, et al. Prognostic role of macrophages and mast cells in the microenvironment of hepatocellular carcinoma after resection[J]. BMC Cancer, 2024, 24(1): 142.
[31] PINTO M L, RIOS E, DUR-ES C, et al. The two faces of tumor-associated macrophages and their clinical significance in colorectal cancer[J]. Front Immunol, 2019, 10: 1875.
[32] GRIZZI F. Mast cells and human hepatocellular carcinoma[J]. World J Gastroenterol, 2003, 9(7): 1469.
[33] ROHR-UDILOVA N, TSUCHIYA K, TIMELTHALER G, et al. Morphometric analysis of mast cells in tumor predicts recurrence of hepatocellular carcinoma after liver transplantation[J]. Hepatol Commun, 2021, 5(11): 1939-1952.