Wu Liyan, Weng Zelin, Yang Xia, Huang Yuhua, Lin Yansong, Li Shuo, Fu Lingyi, Yun Jingping
State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, PR China.
Department of Pathology, Sun Yat-sen University Cancer Center, Dongfeng East Road, Guangzhou, 510060, Guangdong, PR China.
Sci Rep. 2025 Apr 10;15(1):12278. doi: 10.1038/s41598-025-97616-w.
Adenosine 5'-diphosphate ribosylation factor-like 8B (ARL8B), a small GTPase, is involved in lysosome motility. Our study investigates the role of ARL8B in hepatocellular carcinoma (HCC) using in vitro and in vivo experiments, bioinformatics, and clinical data. We found that ARL8B expression is abnormally elevated in HCC and correlates with poor prognosis. ARL8B knockdown triggered lysosomal dysfunction-manifesting as abnormal morphology, decreased pH, reduced hydrolase activity, and impaired autophagic degradation-which subsequently led to cell cycle arrest and reduced cell viability. Additionally, tumors with high ARL8B expression (ARL8B) exhibited notable differences in tumor microenvironment composition compared to those with low ARL8B expression (ARL8B). ARL8B HCCs had significantly increased infiltration of NFKBIZ/HIF1A and VEGFA/SPP1 neutrophils. EcoTyper analysis indicated that ARL8B HCCs had a lower proportion of carcinoma ecotype 6, a cellular ecosystem common in normal tissues but rare in tumors. Bioinformatics and real-world analysis showed a positive correlation between ARL8B and PD-L1 expression. Patients with high ARL8B expression exhibited increased sensitivity to sorafenib and immune checkpoint blockade therapy. In conclusion, our findings identify ARL8B as a key lysosomal regulator associated with tumor microenvironment composition in HCC, suggesting its potential as both a therapeutic target and a biomarker for predicting treatment response.
5'-二磷酸腺苷核糖基化因子样蛋白8B（ARL8B）是一种小GTP酶，参与溶酶体运动。我们的研究使用体外和体内实验、生物信息学和临床数据，探究了ARL8B在肝细胞癌（HCC）中的作用。我们发现，ARL8B在HCC中的表达异常升高，且与预后不良相关。敲低ARL8B会引发溶酶体功能障碍，表现为形态异常、pH值降低、水解酶活性降低以及自噬降解受损，随后导致细胞周期停滞和细胞活力降低。此外，与低ARL8B表达（ARL8B）的肿瘤相比，高ARL8B表达的肿瘤在肿瘤微环境组成上表现出显著差异。高ARL8B表达的HCC中NFKBIZ/HIF1A和VEGFA/SPP1中性粒细胞的浸润显著增加。EcoTyper分析表明，高ARL8B表达的HCC中癌生态型6的比例较低，癌生态型6是一种在正常组织中常见但在肿瘤中罕见的细胞生态系统。生物信息学和实际数据分析表明，ARL8B与PD-L1表达呈正相关。高ARL8B表达的患者对索拉非尼和免疫检查点阻断治疗的敏感性增加。总之，我们的研究结果确定ARL8B是一种与HCC肿瘤微环境组成相关的关键溶酶体调节因子，表明其作为治疗靶点和预测治疗反应生物标志物的潜力。
