Abstract
It has been documented that Helicobacter hepaticus (H. hepaticus) infection is linked to chronic hepatitis and fibrosis in male BALB/c mice. However, the mechanism underlying the mice model of H. hepaticus–induced hepatocellular carcinoma is not fully known. In this study, male BALB/c mice were infected with H. hepaticus for 3, 6, 12, and 18 months. H. hepaticus colonization, histopathology, expression of proinflammatory cytokines, key signaling pathways, and protein downstream high-mobility group box-1 (HMGB1) in the liver were examined. Our data suggested that the H. hepaticus colonization level in the colon and liver progressively increased over the duration of the infection. H. hepaticus–induced hepatic inflammation and fibrosis were aggravated during the infection, and hepatic preneoplasia developed in the liver of infected mice at 12 and 18 months post-inoculation (MPI). H. hepaticus infection increased the levels of alanine aminotransferase and aspartate aminotransferase in the infected mice. In addition, the mRNA levels of IL-6, Tnf-α, Tgf-β, and HMGB1 were significantly elevated in the liver of H. hepaticus–infected mice from 3 to 18 MPI as compared to the controls. In addition, Ki67 was increased throughout the duration of the infection. Furthermore, HMGB1 protein was activated and translocated from the nucleus to the cytoplasm in the hepatocytes and activated the proteins of signal transducers and activators of transcription 3 (Stat3) and mitogen-activated protein kinase (MAPK) [extracellular regulated protein kinases 1/2 (Erk1/2) and mitogen-activated protein kinase p38 (p38)] upon H. hepaticus infection. In conclusions, these data demonstrated that male BALB/c mice infected with H. hepaticus are prone to suffering hepatitis and developing into hepatic preneoplasia. To verify the effect of HMGB1 in the progression of liver preneoplasia, mice were infected by H. hepaticus for 2 months before additional HMGB1 recombinant adenovirus treatment. All mice were sacrificed at 4 MPI, and the sera and liver tissues from all of the mice were collected. Immunology and histopathology evaluation showed that HMGB1 knockdown attenuated the H. hepaticus–induced hepatic and fibrosis at 4 MPI. Therefore, we showed that H. hepaticus–induced liver preneoplasia is closely correlated with the activation and accumulation of HMGB1.
Highlights
Liver cancer, which has displayed consistently in incidence and mortality in the past decades, is one of the main causes of cancer death and a major health problem in both developed and developing countries (Torre et al, 2015; Chen W. et al, 2016)
To better elucidate the relationship between bacterial load and disease development, we determined the level of H. hepaticus colonization in the colon and liver of infected BALB/c mice until 18 months post-inoculation (MPI). qPCR results revealed that H. hepaticus was detected in the colon and liver of H. hepaticus– infected BALB/c mice at all the time points
Our data further demonstrated that H. hepaticus infection induced chronic hepatitis/cirrhosis progressed to hepatic preneoplasia by 18 MPI in this mouse model, whereas no obvious lesions was found in the livers of uninfected aged mice
Summary
Liver cancer, which has displayed consistently in incidence and mortality in the past decades, is one of the main causes of cancer death and a major health problem in both developed and developing countries (Torre et al, 2015; Chen W. et al, 2016). It has been reported that these pathogens are the causes of many chronic liver diseases including hepatocellular carcinoma (HCC), which is the second leading cause of death from malignancy following lung cancer (Ferlay et al, 2015). Because of the close anatomical and physiological connection between the gut and liver, gut microbiota are thought to be one of the triggers of chronic liver diseases and HCC (Milosevic et al, 2019). Several studies have revealed that Helicobacter species, a class of intestinal pathogenic bacteria, were found in the tissue and serum samples among cirrhotic subjects and patients with hepatic carcinoma (Spinzi et al, 2001; Fox et al, 2010), suggesting that animals infected with Helicobacter species may prove to be a new model to investigate the mechanisms of gut microbiota– associated liver carcinogenesis
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