Table 2.
Carcinogenic mechanisms of HBx.
| Mechanisms | Function | Source of evidence | Reference |
|---|---|---|---|
| Activating a variety of transcription factors | Promoting NF-κB to inhibit TNF-α and Fas-mediated apoptosis | Cell experiments (hepatoma cell lines: HepG2 and Huh7) | 75 |
| Stimulating the transcription factors CREB and ATF-2 | Cell experiments (hepatoma cell line: HepG2) | 76 | |
| Disrupting the Smc5/6 complex and relieving transcriptional repression | Cell experiments (hepatoma cell lines: HepG2 and HepAD38) | 77 | |
| + animal experiments (human liver chimeric uPA-SCID mice) | |||
| Interacting with oncogenes and tumor suppressor genes | Inhibiting tumor suppressive genes (inhibiting p53 and inactivating the RB gene) | Cell experiments (hepatocyte cell line: THLE-5b; hepatoma cell lines: Hep3B, SK-Hep-1, HepG2, Huh7, 97L, PLC/PRF/5, and SMMC7721) | 78, 79, 80 |
| + animal experiments (HBx-transgenic mice and Balb/c nude mice) | |||
| + clinical samples (paired HCC samples, n = 51) | |||
| Activating oncogenes: the Ras-GTP complex | Cell experiments | 81 | |
| Stimulating cytoplasmic signaling pathways | Activating the mTOR signaling pathway | Cell experiments (hepatoma cell lines: HepG2, Hep3B, Huh7, and Hep2.2.15) | 82 |
| + animal experiments (DEN-induced HCC mouse model and spontaneous HCC mouse model) | |||
| + clinical samples (paired HCC samples, n = 80) | |||
| Affecting the Fas/FasL signaling pathway | Cell experiments (hepatoma cell lines: HepG2, SNU-354, SNU-368, SNU-387, SNU-398, and SNU-423) | 83,84 | |
| + animal experiments (HBx homozygote transgenic mice) | |||
| + clinical samples (paired HCC samples, n = 15) | |||
| Interacting with noncoding RNAs | Affecting miRNAs, such as miR-122 and miR-152 | Cell experiments (hepatocyte cell line: LO2; hepatoma cell lines: Hepa1-6, HepG2, HepG2.2.15, and Huh7) | 85,86 |
| + animal experiments (HBx-transgenic mice) | |||
| + clinical samples (chronic hepatitis B samples, n = 22; severe chronic hepatitis B samples, n = 19; normal liver tissues, n = 10; paired HCC samples, n = 20) | |||
| Affecting lncRNA, such as lncRNA DLEU2 and LINC01431X | Cell experiments (hepatoma cell lines: HepG2, HLCZ01, HepAD38, Huh7, and HepG2.2.15) | 87 | |
| + animal experiments (hydrodynamic injection mouse model) | |||
| + clinical samples (para-tumor tissues, n = 41) |
Abbreviations: ATF-2, activating transcription factor-2; CREB, cAMP response element binding protein; DEN, diethylnitrosamine; HBx, hepatitis B virus X; HCC, hepatocellular carcinoma; lncRNA, long-stranded noncoding RNA; miRNA, microRNA; mTOR, mammalian target of rapamycin; NF-κB, nuclear factor-kappa B; RB, retinoblastoma; Smc5/6, structural maintenance of chromosomes 5/6; TNF-α, tumor necrosis factor-alpha.