Wang Xuehong, Li Lanyu, Sun Tian, Qiu Zhidong
Department of Pathology, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
Guangxi Key Laboratory of Molecular Medicine in Liver Injury and Repair, the First Affiliated Hospital of Guilin Medical University, Guilin, China.
J Gastrointest Oncol. 2025 Aug 30;16(4):1635-1647. doi: 10.21037/jgo-2025-567. Epub 2025 Aug 27.
The prognosis and clinical treatment of hepatocellular carcinoma (HCC), one of the most prevalent malignant tumors, remains significantly challenging, underscoring the urgent need for novel biomarkers and therapeutic strategies to improve patient outcomes. Our study investigated the clinical significance and biological functions of glucosylceramidase beta 3 (GBA3) in HCC progression.
GBA3 expression was analyzed in 39 paired HCC and adjacent non-tumor tissues, validated in The Cancer Genome Atlas (TCGA) dataset, and further confirmed via immunohistochemistry (IHC) in 90 additional paired specimens. The connection between GBA3 expression and clinical outcomes was analyzed through use of TCGA data and Kaplan-Meier survival analysis. The functional roles of GBA3 were examined through knockdown experiments in HCC cells, with proliferation, migration, and invasion being evaluated. Mechanistic studies were conducted to clarify the link between GBA3 downregulation and ceramide metabolism via ceramide synthase 3 (CerS3).
The expression of GBA3 messenger RNA (mRNA) and protein were significantly downregulated in HCC tissues as compared to non-tumor tissues. Low GBA3 expression correlated with advanced HCC and shorter patient survival. Functional assays demonstrated that GBA3 knockdown enhanced HCC cell proliferation, migration, and invasion. Mechanistically, GBA3 downregulation reduced CerS3 expression, disrupting ceramide metabolism and promoting HCC progression.
GBA3 downregulation in HCC is related to the aggressive behavior and poor prognosis, indicating its potential as a sphingolipid metabolism-related prognostic biomarker and therapeutic target for HCC.
肝细胞癌（HCC）是最常见的恶性肿瘤之一，其预后和临床治疗仍然极具挑战性，这凸显了迫切需要新的生物标志物和治疗策略来改善患者预后。我们的研究调查了葡萄糖神经酰胺酶β3（GBA3）在HCC进展中的临床意义和生物学功能。
分析了39对HCC及其相邻非肿瘤组织中GBA3的表达，并在癌症基因组图谱（TCGA）数据集中进行了验证，还通过免疫组织化学（IHC）在另外90对样本中进一步证实。利用TCGA数据和Kaplan-Meier生存分析来分析GBA3表达与临床结果之间的关联。通过在HCC细胞中进行敲低实验来研究GBA3的功能作用，并评估其增殖、迁移和侵袭能力。进行机制研究以阐明GBA3下调与通过神经酰胺合酶3（CerS3）的神经酰胺代谢之间的联系。
与非肿瘤组织相比，HCC组织中GBA3信使核糖核酸（mRNA）和蛋白质的表达显著下调。低GBA3表达与晚期HCC和患者较短生存期相关。功能分析表明，敲低GBA3可增强HCC细胞的增殖、迁移和侵袭能力。从机制上讲，GBA3下调会降低CerS3表达，破坏神经酰胺代谢并促进HCC进展。
HCC中GBA3下调与侵袭性行为和不良预后相关，表明其作为HCC中与鞘脂代谢相关的预后生物标志物和治疗靶点的潜力。
