The effect of inhibiting the cGAS-STING pathway in a chronic liver disease mouse model
Hepatocellular carcinoma (HCC) mostly develops on the background of a chronic liver disease (CLD). The hallmarks of CLD includes increased hepatocyte apoptosis, compensatory proliferation and DNA damage. Mice with MCL-1 deficiency in hepatocytes (Mcl-1Dhep mice ) recapitulated these key features of CLD and developed HCC later in life. However, it is unclear how MCL-1 deficiency drives tumorigenesis. We analysed replication stress and the activation the cGAS-STING pathway in Mcl-1Dhep mice. 2-month-old Mcl-1Dhep mice showed increased replication stress, micronucleated hepatocytes and increased cytosolic DNA sensing. We found that an increase in extrachromosomal circular DNA in Mcl-1Dhep liver promoted a crosstalk between hepatocytes and immune cells to drive the immune response which was dependent on the canonical cGAS-STING pathway. We then generated Mcl-1Dhep/STING-/- double knockout mice to study the effects of inhibiting the cGAS-STING pathway in liver homeostasis and tumorigenesis. In fact, deletion of STING in Mcl-1Dhep mice reduced immune cell chemotaxis, as well as tumor incidence. Our findings indicate that the cytosolic DNA sensing pathway may play an important role in inflammation-driven liver carcinogenesis. Overall design: Knockout mice were generated by crossing transgenic mice with different genetic background.