自噬相关基因预后模型对肝细胞癌患者生存预测的临床价值

The clinical value of autophagy-related gene prognostic models for predicting survival in patients with hepatocellular carcinoma

摘要

目的 对自噬相关基因与肝癌患者预后关系及潜在机制进行探索。方法 基于TCGA及GEO(GSE76427)肝癌转录组数据集,利用R软件进行数据预处理,通过Wilcoxon检验筛选差异表达基因,运用单变量Cox比例风险回归模型鉴定预后相关自噬基因。利用Lasso回归构建预后风险模型,CCK8实验检测细胞增殖情况,RT-qPCR检测基因表达,利用GSEA进行基因富集分析。结果 本研究基于8个预后相关自噬差异基因(BIRC5、PRKCD、ITGB1、CTSD、SQSTM1、ATIC、RHEB和HDAC1)构建了一个与肝癌总生存期相关的预后特征模型,其AUC值为0.790。外部验证进一步证实了该模型的预后价值。核苷酸切除修复、细胞周期、泛素调节的蛋白质降解、碱基切除修复及磷脂酰肌醇信号通路在高风险组中明显富集。结论 由BIRC5、PRKCD、ITGB1、CTSD、SQSTM1、ATIC、RHEB和HDAC1组成的预后风险预测模型展现出优异的独立预测效能。

Abstract

Objective To investigate the relationship between autophagy-related genes and the prognosis of hepatocellular carcinoma (HCC) patients, as well as the underlying mechanisms. Methods This study processed transcriptomic datasets of HCC from TCGA and GEO (GSE76427) using R software. Differentially expressed genes were screened via Wilcoxon test, followed by identification of prognosis-related autophagy genes using a univariate Cox proportional hazards regression model. A prognostic risk model was constructed employing Lasso regression. In vitro functional validation included detecting cell proliferation through CCK-8 assays and measuring gene expression via reverse transcription quantitative polymerase chain reaction (RT-qPCR). Gene enrichment analysis was performed using Gene Set Enrichment Analysis (GSEA). Results This study constructed a prognostic signature model related to overall survival based on eight prognosis-related differential autophagy genes (BIRC5, PRKCD, ITGB1, CTSD, SQSTM1, ATIC, RHEB, and HDAC1), with an AUC value of 0.790. External validation yielded consistent conclusions. Nucleotide excision repair, cell cycle, ubiquitin-mediated proteolysis, base excision repair, and phosphatidylinositol signaling pathways were significantly enriched in the high-risk group. Conclusion The prognostic risk prediction model composed of BIRC5, PRKCD, ITGB1, CTSD, SQSTM1, ATIC, RHEB, and HDAC1 demonstrates excellent independent predictive performance.

关键词

肝细胞癌(HCC) / 自噬相关基因 / 预后特征 / TCGA / GEO / GSEA

Key words

hepatocellular carcinoma(HCC) / autophagy-related gene / prognostic signature / TCGA / GEO / GSEA

参考文献

[1] BRAY F, LAVERSANNE M, SUNG H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin, 2024, 74(3): 229-263.

[2] ZHANG Y J, CHEN J B, ZHOU Z G, et al. Transarterial chemoembolization with radiofrequency ablation versus surgical resection for small late—recurrence hepatocellular carcinoma[J]. Radiology, 2025, 314(2): e241096.

[3] ZHONG B Y, FAN W, GUAN J J, et al. Combination locoregional and systemic therapies in hepatocellular carcinoma[J]. Lancet Gastroenterol Hepatol, 2025, 10(4): 369-386.

[4] MAGYAR C T J, RAJENDRAN L, LI Z, et al. Precision surgery for hepatocellular carcinoma[J]. Lancet Gastroenterol Hepatol, 2025, 10(4): 350-368.

[5] LI J H, LIU Y N, QIU Y Q, et al. Comparison of adjuvant treatment regimens for high—risk hepatocellular carcinoma: a Bayesian network meta analysis and systematic review[J]. Front Immunol, 2024, 15: 1487353.

[6] COMITO T, LOI M, FRANZESE C, et al. Stereotactic radiotherapy after incomplete transarterial (chemo—) embolization (TAE\TACE) versus exclusive TAE or TACE for treatment of inoperable HCC: a phase Ⅲ trial (NCT02323360)[J]. Curr Oncol, 2022, 29(11): 8802-8813.

[7] SOLHI R, POURHAMZEH M, ZARRABI A, et al. Novel biomarkers for monitoring and management of hepatocellular carcinoma[J]. Cancer Cell Int, 2024, 24(1): 428.

[8] HASENLEITHNER S O, SPEICHER M R. A clinician's handbook for using ctDNA throughout the patient journey[J]. Mol Cancer, 2022, 21(1): 81.

[9] YAMAMOTO Y, KONDO S, MATSUZAKI J, et al. Highly sensitive circulating MicroRNA panel for accurate detection of hepatocellular carcinoma in patients with liver disease[J]. Hepatol Commun, 2020, 4(2): 284-297.

[10] YIN H, ZHANG M J, ZHANG Y, et al. Liquid biopsies in cancer[J]. Mol Biomed, 2025, 6(1): 18.

[11] ALIX—PANABIÈRES C, PANTEL K. Liquid biopsy: from discovery to clinical application[J]. Cancer Discov, 2021, 11(4): 858-873.

[12] WANG Y H, LIU J W, WANG H, et al. Multiple regulatory mechanisms, functions and therapeutic potential of chaperone—mediated autophagy[J]. Theranostics, 2025, 15(7): 2778-2793.

[13] CHEN R, HU X, HUANG Y, et al. Regulated cell death in lenvatinib resistance of hepatocellular carcinoma: from molecular mechanisms to therapeutic strategies[J]. Int J Biol Sci, 2025, 21(5): 2012-2026.

[14] SABERIYAN M, GHOLAMI S, EJLALIDIZ M, et al. The dual role of chaperone—mediated autophagy in the response and resistance to cancer immunotherapy[J]. Crit Rev Oncol Hematol, 2025, 210: 104700.

[15] LI Z, CHEN W, YAO S, et al. Single—cell mitophagy patterns within the tumor microenvironment modulate intercellular communication, impacting the progression and prognosis of hepatocellular carcinoma[J]. Front Immunol, 2024, 15: 1448878.

[16] ALHAMAD D W, ELGENDY S M, HERSI F, et al. The inhibition of autophagy by spautin boosts the anticancer activity of fingolimod in multidrug—resistant hepatocellular carcinoma[J]. Life Sci, 2022, 304: 120699.

[17] SHAN Y, LU C, WANG J, et al. IGF—1 contributes to liver cancer development in diabetes patients by promoting autophagy[J]. Ann Hepatol, 2022, 27(4): 100697.

[18] CHI Y, MA G, LIU Q, et al. Multi—omics analysis reveals glutathione metabolism—related immune suppression and constructs a prognostic model in lung adenocarcinoma[J]. Front Immunol, 2025, 16: 1608407.

[19] GUO W, WANG X, ZHANG Y, et al. Construction and validation of a novel prognostic signature for cutaneous melanoma based on ferroptosis—related genes[J]. Heliyon, 2023, 9(5): e15725.

[20] WU H, LV S, ZHANG R, et al. Next—generation flexible embolic systems: targeted transarterial chemoembolization strategies for hepatocellular carcinoma[J]. Advanced Materials, 2025, 37(24): e2503971.

[21] ZHANG W, HONG X, XIAO Y, et al. Sorafenib resistance and therapeutic strategies in hepatocellular carcinoma[J]. Biochim Biophys Acta Rev Cancer, 2025, 1880(3): 189310.

[22] STOJANOVIC N, HASSAN Z, WIRTH M, et al. HDAC1 and HDAC2 integrate the expression of p53 mutants in pancreatic cancer[J]. Oncogene, 2017, 36(13): 1804-1815.

[23] CAMPOS T, ZIEHE J, PALMA M, et al. Rheb promotes cancer cell survival through p27Kip1—dependent activation of autophagy[J]. Mol Carcinog, 2016, 55(2): 220-229.

[24] YANG L, YOU J, YANG X, et al. ACSS2 drives senescence—associated secretory phenotype by limiting purine biosynthesis through PAICS acetylation[J]. Nat Commun, 2025, 16(1): 2071.

[25] YANG X, CAO X, ZHU Q. p62/SQSTM1 in cancer: phenomena, mechanisms, and regulation in DNA damage repair[J]. Cancer and Metastasis Reviews, 2025, 44(1): 33.

[26] FENG Y, KLIONSKY D J. Autophagy regulates DNA repair through SQSTM1/p62[J]. Autophagy, 2017, 13(6): 995-996.

[27] QIANG L, ZHAO B, SHAH P, et al. Autophagy positively regulates DNA damage recognition by nucleotide excision repair[J]. Autophagy, 2016, 12(2): 357-368.

[28] WANG B J, ZHENG W L, FENG N N, et al. The effects of autophagy and PI3K/AKT/m—TOR signaling pathway on the cell—cycle arrest of rats primary sertoli cells induced by zearalenone[J]. Toxins (Basel), 2018, 10(10): 398.

[29] WANG S J, CHAO D, WEI W, et al. CD147 promotes collective invasion through cathepsin B in hepatocellular carcinoma[J]. J Exp Clin Cancer Res, 2020, 39(1): 145.

基金资助

陕西省自然科学基础研究计划资助项目(2024JC-YBQN-0783)

西安交通大学第一附属医院科研发展基金项目(2025QN-15)