Zhang Juan, Xu Yingyu, Ni Xiaojian, Mao Zhiyi, Xiao Haitao, Chen Maopei, Lin Youpei, Pan Jiaomeng, Zhang Boheng, Zhang Lan, Zheng Xueying, Song Guohe, Ge Ningling
Department of Hepatobiliary Oncology, Liver Cancer Institute, Zhongshan Hospital; Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, People's Republic of China.
Department of Biliary Surgery, Zhongshan Hospital, Fudan University; Biliary Tract Disease Center of Zhongshan Hospital, Fudan University; Biliary Tract Disease Institute, Fudan University; Cancer Center, Zhongshan Hospital, Fudan University; Shanghai Biliary Tract Minimal Invasive Surgery and Materials Engineering Research Center, Shanghai, People's Republic of China.
J Hepatocell Carcinoma. 2025 Jul 17;12:1453-1469. doi: 10.2147/JHC.S493907. eCollection 2025.
Hepatocellular carcinoma (HCC) necessitates novel immunotherapeutic targets. PBK, a cancer/testis antigen (CTA), was identified as a pivotal hub gene influencing prognosis, tumor mutation burden (TMB), and immune microenvironment remodeling.
PBK was prioritized using weighted gene co-expression network analysis (WGCNA) and differential expression screening in the TCGA-LIHC cohort, intersected with curated CTAs. Analyses assessed correlations with clinicopathological features (TNM stage, survival), genomic characterization (mutation frequencies), and functional validation via siRNA-mediated PBK knockdown in Huh7 cells (migration assay). Single-cell RNA sequencing (scRNA-seq) profiled of the tumor immune microenvironment.
PBK overexpression was significantly correlated with advanced TNM stage ( < 0.05) and poor survival (log-rank = 0.003). Genomic analysis revealed distinct mutation profiles: high-PBK tumors exhibited increased mutation frequency (39% vs 17%) but decreased mutations (20% vs 31%). Patients exhibiting with combined PBK overexpression and high TMB demonstrated the poorest prognosis. Functional validation confirmed that PBK knockdown significantly inhibited Huh7 cell migration capacity ( < 0.05). scRNA-seq analysis showed PBK-enriched tumors contained elevated proportions of immunosuppressive SPP1(+) macrophages (22.33% vs 6.6%, FDR corrected < 0.001) and CD8(+) SLC4A10(+) MAIT cells (9.82% vs 4.7%, FDR corrected < 0.001).
PBK synergistically drives HCC progression through three synergistic mechanisms: (1) promoting oncogenic mutation accumulation (eg, ), (2) increasing metastatic potential, and (3) reprogramming an immune-suppressive microenvironment enriched for SPP1(+) macrophages and CD8(+)SLC4A10(+) MAIT cells. This establishes PBK as a dual-purpose biomarker for prognostic stratification and immunotherapy resistance prediction, providing a mechanistic rationale for developing PBK-targeted therapies in HCC.
肝细胞癌（HCC）需要新的免疫治疗靶点。PBK是一种癌胚抗原（CTA），被确定为影响预后、肿瘤突变负荷（TMB）和免疫微环境重塑的关键枢纽基因。
在TCGA-LIHC队列中，使用加权基因共表达网络分析（WGCNA）和差异表达筛选对PBK进行优先级排序，并与经过整理的CTA进行交叉分析。分析评估了与临床病理特征（TNM分期、生存率）、基因组特征（突变频率）的相关性，以及通过在Huh7细胞中进行siRNA介导的PBK敲低进行功能验证（迁移试验）。对肿瘤免疫微环境进行单细胞RNA测序（scRNA-seq）分析。
PBK过表达与晚期TNM分期（<0.05）和较差的生存率（对数秩检验=0.003）显著相关。基因组分析揭示了不同的突变谱：高PBK肿瘤显示出更高的 突变频率（39%对17%），但 突变减少（20%对31%）。同时表现出PBK过表达和高TMB的患者预后最差。功能验证证实，PBK敲低显著抑制Huh7细胞迁移能力（<0.05）。scRNA-seq分析显示，富含PBK的肿瘤中免疫抑制性SPP1（+）巨噬细胞（22.33%对6.6%，FDR校正<0.001）和CD8（+）SLC4A10（+）MAIT细胞（9.82%对4.7%，FDR校正<0.
