[High-mobility group protein 1 promotes diethylnitrosamine-induced liver cancer formation in mice by activating...

Objective: To study the role of high-mobility group protein 1 (HMGB1) in the promotion of diethylnitrosamine-induced liver cancer formation in C57BL/6 mice and its mechanism. Methods: HMGB1(loxp/loxp)/Alb-Cre(+/-) were used as a liver-specific knockout (KO) of HMGB1 gene in mice. HMGB1(loxp/loxp)/Alb-Cre(-/-), HMGB1(loxp/WT)/Alb-Cre(+/-) and HMGB1(loxp/WT)/Alb-Cre(-/-) born in the same litter were wild-type mice. Six 12-day-old male WT and KO mice were separated and given a single intraperitoneal injection of diethylnitrosamine (25 mg/kg). Six months later, HE staining was used to evaluate the histopathological changes and then the incidence of liver cancer in each mice group was calculated. Serum samples were taken from each mice group to determine alanine aminotransferase levels. Immunohistochemical staining was used to detect the expression and intracellular localizations of HMGB1 protein status in tumor tissue of the two groups of mice. Western blot was used to detect the expressional condition of mitochondrial biogenesis in tumor tissue of the two groups of mice. RT-PCR was used to detect mitochondrial DNA copy number of tumor tissue and normal liver tissue in the two groups of mice. Intra and inter group data comparison was compared using t-tests and one one-way analysis of variance. Results: Compared with WT mice, the liver/body weight ratio of KO mice was decreased significantly (t = 2.634, P = 0.0225). Serum alanine aminotransferase levels in both groups of mice were increased, and the difference was not statistically significant (t = 0.4062, P = 0.6932). There were many visible gray-white nodules of different sizes on the liver surface of WT mice, and the histological type was hepatocellular carcinoma. There was no statistically significant difference in the incidence of liver cancer among different genotypes of WT mice (P > 0.05). The incidence rate of liver cancer in KO mice was significantly reduced (t = 8.521, P < 0.001). Compared with WT mice, the expression levels of HMGB1 and mitochondrial biogenesis (PGC-1α and NRF1) was significantly reduced (t = 6.238, 4.852, P = 0.0335, 0.041) in tumor tissue of KO mice. Mitochondrial DNA copy number was decreased significantly (t = 9.211, P < 0.01). Mitochondrial DNA copy number in tumor tissue of WT mice was significantly higher than that in normal liver tissue (t = 8.305, P = 0.0142). Conclusion: HMGB1 promotes the formation of diethylnitrosamine-induced liver cancer by inducing mitochondrial biogenesis.