Cytokines derived from innate lymphoid cells assist to aggravate hepatocellular tumorigenesis in viral transgenic mice.

Background: Recently, intestinal microbiome has been involved in hepatic diseases due to the immunologic and metabolic communication between liver and intestine. Initiation of hepatocellular carcinoma (HCC) frequently attributes to conspiracy between immune cells and infectious carcinogens. Here, the hypothesis that the tumorigenesis of HCC with HBV infection will be aggravated by specific intestinal bacteria was verified in viral transgenic mouse models.

Methods: Comparative 16S rRNA sequencing was adopted to observe the intestinal enrichment of in HCC. Oral administration of was carried out to evaluate its hepatic carcinogenic effect in HBV transgenic mice or wildtype C57BL/6. The livers of experimental mice were collected and examined for the degree of tumorigenesis.

Results: We found that more likely colonized at lower colon of HBV-infected mice with HCC, compared with C57BL/6 and HBV-infected mice without neoplasm. Pretreatment of in transgenic mice aggravated tumor formation, with higher incidence, more tumor nodule and higher serum AFP. Then, a cytokines expression patterns with inclined IFN-γ, IFN-γR1, IL-17 and IL-23 was found in HBV-infected mice with . Furthermore, innate lymphoid cells, especially Th17 and NK cells which can secret IL-17 and IFN-γ respectively, might be recruited by cooperated with HBV. Besides, increased expression of CD69, NKG2D and IFN-γ showed activation of cytokine production in intrahepatic NK cells. Finally, IFN-γ decreased E-cadherin expression through p-STAT1 pathway, resulting in epithelial-mesenchymal transition with inclined expression of Snail2, SIP1 and CXCR4 in vitro. p-STAT1 inhibitor was able to reverse the expression of E-cadherin and EMT resulted from IFN-γ function on HBsAg-positive hepatocytes.

Conclusions: generate a detrimental immune microenvironment by IFN-γ/p-STAT1 axis which can promote the tumorigenesis of hepatitis B via recruiting innate lymphoid cells.