Upregulated PrPC by HBx enhances NF-κB signal via liquid–liquid phase separation to advance liver cancer

• Published in: NPJ precision oncology 2024-09, Vol.8 (1), p.211-21, Article 211
• Main Authors: Liu, Yang, Zhang, Jing, Zhai, Zixu, Liu, Chenyi, Yang, Siqi, Zhou, Ying, Zeng, Xianhuang, Liu, Jiaqi, Zhang, Xiaoyu, Nie, Xinqi, Xu, Jiaqi, Huang, Junsong, Liu, Chaozhi, Liu, Zhepeng, Guo, Mingxiong, Sun, Guihong
• Format: Article
• Language: English
• Subjects: 631/337; 631/67/1504/1610/4029; 631/80/86/2368; Cancer Research; Gene Therapy; Human Genetics; Internal Medicine; Liver cancer; Medicine; Medicine & Public Health; Oncology
• ISSN: 2397-768X; 2397-768X
• DOI: 10.1038/s41698-024-00697-5

Cellular prion protein (PrP C ) has been implicated in carcinogenic through the activation of various signal pathways, however, the precise mechanisms remain elusive. In vitro studies have shown that PrP C is prone to undergo liquid-liquid phase separation (LLPS). However, it remains unknown whether PrP C contributes to LLPS-inducing cancer development. Herein, we observed an upregulation of PrP C expression in hepatitis B virus-positive hepatocellular carcinoma (HCC). Subsequent investigation revealed that HBx of HBV enhances PrP C expression in a dose-dependent manner by binding to CREB1. Furthermore, we demonstrated that PrP C undergoes LLPS and recruits TRAF2/6, TAB2/3, and TAK1 protein, thereby activating the NF-κB signaling pathway and promoting tumor progression. Notably, although unable to undergo LLPS itself, the α3 helix of PrP C is essential for its activation of the NF-κB signaling pathway during the LLPS process. Further analysis unveiled that disulfide bond formation within the C-terminal domain of PrP C is necessary for its LLPS and subsequent activation of the NF-κB signaling pathway. Additionally, our findings indicate that NF-κB activation by PrP C condensates leads to increased IL-8 expression which further promotes tumor development.