Hepatitis B Virus X Protein (HBx) Suppresses Transcription Factor EB (TFEB) Resulting in Stabilization of Integrin Beta 1 (ITGB1) in Hepatocellular Carcinoma Cells.
Chunyan ZhangHuan YangLiwei PanGuangfu ZhaoRuofei ZhangTianci ZhangZhi-Xiong Jim XiaoYing TongYi ZhangRichard HuStephen J PandolYuan-Ping HanPublished in: Cancers (2021)
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.
Keyphrases
- hepatitis b virus
- poor prognosis
- induced apoptosis
- transcription factor
- liver failure
- cell cycle arrest
- signaling pathway
- cell migration
- cell death
- long non coding rna
- cell proliferation
- end stage renal disease
- chronic kidney disease
- endoplasmic reticulum stress
- risk factors
- spinal cord injury
- cystic fibrosis
- escherichia coli
- neuropathic pain
- electronic health record
- spinal cord
- living cells
- small molecule
- candida albicans
- oxidative stress
- staphylococcus aureus
- pi k akt
- deep learning
- pseudomonas aeruginosa
- cell adhesion
- biofilm formation
- patient reported outcomes