Table 2.
List of NRF2 target genes and their effects on HCC development.
| NRF2 Target Genes | Effect of Gene Expression | ARE in Promoter |
|---|---|---|
| NAD(P)H dehydrogenase, quinone 1 (NQO1) and Hemeoxigenase 1 (HO-1) [92] | Constitutive activation of NRF2 by hepatotoxin contributes to the upregulation of NQO1 and HO-1. This promotes liver cancer cell growth. | YES |
| B-cell lymphoma-extra-large (Bcl-xL) [68] | Antioxidant stabilized NRF2 increases the expression of Bcl-xL gene which causes reduction in apoptosis, increase cell survival, and drug resistance in Hepa1-6 cells. | YES |
| Glutathione S-transferase A4 (GSTA4) [93]. Glutamate-cysteine ligase (GCLC) [91], [94] | Constitutive activation of NRF2 in preneoplastic lesions of HCC increases the expression of GSTA4 and GCLC and promotes HCC cell growth. | YES |
| Placental glutathione S-transferase (GST-P) [95,96] | NRF2/MafK heterodimer activates GST-P gene (a prominent tumor marker for hepatocarcinogenesis) through the binding with GPE1 enhancer during hepatocarcinogenesis. | YES |
| Matrix metalloproteinases-9 (MMP-9) [82], [97] | Up-regulation of NRF2 in HepG2 cells increases the MMP-9 expression which promotes the cell invasion ability of HCC. In response to ROS, NRF2 induces MMP-9 expression in HepG2 cells, which contributes to cancer cell migration and invasiveness. |
YES |
| Platelet-Derived Growth Factor-A (PDGFA) [98] | NRF2 promotes PDGFA transcription by interacting with SP1 thus promotes HCC proliferation. | NO (Through interaction with Sp1) |
| Prostaglandin reductase-1 (PTGR1) [99] | PTGR1 expression regulated by NRF2 regulates antioxidant responses to promote cell proliferation in HCC. PTGR1 overexpression in HCC increases cell proliferation and develop resistance to ROS-induced cell death. | YES |
| Peroxisome proliferator-activated receptor γ (PPARγ) [100] | Overexpression of NRF2 in HFD increases the expression of PPARγ and accumulates hepatic triglyceride which initiates NAFLD. | NO (Correlation was tested) |
| 26S proteasome non-ATPase regulatory subunit 10 (PSMD10) or Gankyrin [101] | Increased NRF2 activity up-regulates gankyrin expression in HCC. | YES |
| Mouse double minute 2 homolog (MDM2) [71,102] | During HCV infection, NRF2 translocates into the nucleus and induces MDM2-mediated retinoblastoma protein (Rb) degradation. This induces HCC progression. | YES |