Xiang Daimin, Yang Zhao, Gu Mingye, Xu Midie, Liu Chunliang, Liu Erdong, Liu Junyu, Wang Yichuang, Wang Hongyang, Fu Jing
International Cooperation Laboratory on Signal Transduction, National Center for Liver Cancer, Third Affiliated Hospital of Naval Medical University, Shanghai 200438, China.
Medical Innovation Center, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai 200120, China.
Sci Adv. 2025 Aug 8;11(32):eadv6723. doi: 10.1126/sciadv.adv6723.
Gallbladder cancer (GBC) is the most common malignancy in the biliary system and lacks biomarkers for personalized therapy. Here, we reported that hepatic leukemia factor (HLF) was highly expressed in gallbladder cancer stem cells (CSCs) and patients with gemcitabine-resistant GBC. Mechanistic study revealed that interleukin-6 receptor (IL-6R) and transcription factor EB (TFEB) are direct target genes of HLF. The IL-6/IL-6R/signal transducer and activator of transcription 3 axis transactivates HLF expression in GBC, forming a positive feedback loop. Functional studies revealed that HLF promoted gallbladder CSCs' expansion and gemcitabine resistance via TFEB-induced autophagy. In addition, HLF drives TFEB-induced programmed death ligand 1 expression in human tumors and governs tumor immune evasion in a CD8 T cell-dependent manner. Patient cohorts' analysis suggested that HLF levels in GBCs might determine the distinct responses to chemotherapy and immunotherapy. In conclusion, our findings demonstrated that HLF could act as a driver for gallbladder CSCs' self-renewal and drug resistance and a biomarker for individualized therapy.
胆囊癌（GBC）是胆道系统中最常见的恶性肿瘤，且缺乏用于个性化治疗的生物标志物。在此，我们报告肝白血病因子（HLF）在胆囊癌干细胞（CSC）和吉西他滨耐药的GBC患者中高表达。机制研究表明，白细胞介素6受体（IL-6R）和转录因子EB（TFEB）是HLF的直接靶基因。IL-6/IL-6R/信号转导子和转录激活子3轴在GBC中反式激活HLF表达，形成正反馈回路。功能研究表明，HLF通过TFEB诱导的自噬促进胆囊CSC的扩增和吉西他滨耐药。此外，HLF在人类肿瘤中驱动TFEB诱导的程序性死亡配体1表达，并以CD8 T细胞依赖的方式控制肿瘤免疫逃逸。患者队列分析表明，GBC中HLF水平可能决定对化疗和免疫治疗的不同反应。总之，我们的研究结果表明，HLF可作为胆囊CSC自我更新和耐药的驱动因子以及个体化治疗的生物标志物。
