Induction of Huh‑7 cell apoptosis by HCV core proteins via CK1α‑p53‑Bid signaling pathway.

Hepatitis C virus (HCV)‑infected liver cells sensitize host cells to tumor necrosis factor (TNF)‑related apoptosis‑inducing ligand (TRAIL)‑induced cell apoptosis; however, the precise mechanisms are unknown. In the present study, flow cytometry demonstrated that the Annexin V‑positive Huh‑7 cell number was higher in groups transfected with core proteins when compared with the pcDNA3.1 group. The mRNA and protein expression levels of B‑cell lymphoma 2 (Bcl‑2) were negatively associated, while Bcl‑2‑associated X protein (Bax) were positively correlated, with cell apoptotic rate, which, were verified by reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) and western blotting. There were no significant differences in the expressions of casein kinase 1 (CK1)‑ε, CK1γ or CK1δ; however, the mRNA and protein levels of CK1α were markedly higher in groups transfected with the T (those derived from the HCV‑J6 strain), NT (those derived from non‑tumor tissues) and C191 (those derived from tumor tissues) HCV core proteins than in mock group. When compared with the Mock and Negative Control (control known‑down) groups, the mRNA and protein levels of CK1α were lower in the CK1α known‑down group, and there were no marked Huh‑7 cell morphological changes among the 3 groups. There was more sensitivity to cell apoptosis in CK1α‑silenced, however, not in non‑CK1α‑silenced, Huh‑7 cells. BH3 interacting‑domain death agonist (Bid) protein levels in CK1α‑silenced Huh‑7 cells were higher when compared with non‑CK1α‑silenced Huh‑7 cells, and the level of p53 that translocated to the nucleus increased. Chromatin immunoprecipitation‑PCR demonstrated that p53 bound to human Bid gene promoter. The level of the Bid promoter in CK1α‑silenced Huh‑7 cells was significantly higher than in the non‑CK1α‑silenced Huh‑7 cells. Electron microscopy indicated that p53 knockdown decreased HCV core protein and TRAIL‑induced cell apoptosis. Bid/caspase‑8 protein levels in CK1α‑silenced Huh‑7 cells that were transfected with p53 siRNA were lower than in the control group. The present study demonstrated that HCV core proteins sensitize host cells to TRAIL‑induced cell apoptosis by activating the CK1α‑p53‑Bid dependent pathway.