Zhang Chunyan, Yang Huan, Pan Liwei, Zhao Guangfu, Zhang Ruofei, Zhang Tianci, Xiao Zhixiong, Tong Ying, Zhang Yi, Hu Richard, Pandol Stephen J, Han Yuan-Ping
The Center for Growth, Metabolism and Aging, College of Life Sciences, Sichuan University, Chengdu 610065, China.
West China Hospital, Sichuan University, Chengdu 610065, China.
Cancers (Basel). 2021 Mar 9;13(5):1181. doi: 10.3390/cancers13051181.
Hepatitis B virus (HBV) infection is a major etiological risk for the incidence of hepatocellular carcinoma (HCC), and HBV X protein (HBx) is essential for oncogenic transformation. It is not known that if HBx can sabotage the lysosomal system for transformation and tumorigenesis, or its mechanism if it does have an effect. Examining clinical data, we observed that the downregulation of lysosomal components and transcription factor EB (TFEB) was associated with a poor prognosis of HCC patients. In HCC cells, we found that expression of HBx suppressed TFEB, impaired biogenesis of autophagic-lysosome, and promoted cellular dissemination. HBx mediated downregulation of TFEB led to impairment of autophagic/lysosomal biogenesis and flux, and consequently, accumulation of integrin beta 1 (ITGB1) for motility of HCC cells. Conversely, TFEB, in a steady-state condition, through induction of lysosomal biogenesis restrained ITGB1 levels and limited mobility of HCC cells. Specifically, overexpression of TFEB upregulated and activated the cysteine proteases including cathepsin L (CTSL) to degrade ITGB1. Conversely, expression of cystatin A (CSTA) or cystatin B (CSTB), the cellular inhibitors of lysosomal cysteine proteinases, spared ITGB1 from degradation and promoted dissemination of HCC cells. Taken together, this study suggests a potential mechanism for HBV-mediated malignancy, showing that HBx mediated downregulation of TFEB leads to accumulation of ITGB1 for HCC cell migration.
乙型肝炎病毒（HBV）感染是肝细胞癌（HCC）发病的主要病因风险，而HBV X蛋白（HBx）对于致癌转化至关重要。目前尚不清楚HBx是否会破坏溶酶体系统以促进转化和肿瘤发生，或者其作用机制（如果确实有作用的话）。通过检查临床数据，我们观察到溶酶体成分和转录因子EB（TFEB）的下调与HCC患者的不良预后相关。在HCC细胞中，我们发现HBx的表达抑制了TFEB，损害了自噬溶酶体的生物发生，并促进了细胞扩散。HBx介导的TFEB下调导致自噬/溶酶体生物发生和通量受损，从而导致整合素β1（ITGB1）积累以促进HCC细胞的运动。相反，在稳态条件下，TFEB通过诱导溶酶体生物发生来抑制ITGB1水平并限制HCC细胞的迁移。具体而言，TFEB的过表达上调并激活了包括组织蛋白酶L（CTSL）在内的半胱氨酸蛋白酶以降解ITGB1。相反，溶酶体半胱氨酸蛋白酶的细胞抑制剂胱抑素A（CSTA）或胱抑素B（CSTB）的表达使ITGB1免于降解并促进了HCC细胞的扩散。综上所述，本研究揭示了HBV介导恶性肿瘤的潜在机制，表明HBx介导的TFEB下调导致ITGB1积累以促进HCC细胞迁移。
