SYK-targeted Therapy Modulates Inflammatory Liver Microenvironment And Improves The Antitumor Effect Against Hepatocellular Carcinoma

Hepatocellular carcinoma(HCC)symptoms often do not appear in the early stages.Thus,more than 50%of patients are diagnosed with advanced disease.As the approved first-line treatments for advanced HCC,tyrosine kinase inhibitor has a low objective response rate and limited benefits for patient’s survival.Therefore,there is an urgent need to explore the strategy to improve the treatment efficacy for HCC.HCC mainly occurs in the inflammatory environment of fibrotic liver.Studies have shown that organ inflammation is closely associated with the tumor progression.However,the effect of liver inflammation on the HCC growth and metastasis is still unclear.Spleen tyrosine kinase(SYK)involves in a variety of the processes of pathological inflammation and fibrosis.Our previous study suggested that hepatic SYK promotes liver fibrosis and HCC development.Therefore,the current study intends to explore the effect of inflammatory liver microenvironment on the HCC progression and its underlying mechanism,and aim to investigate the regulation mechanism of SYK in the liver inflammation microenvironment on HCC progression and its therapeutic potential.We established a syngeneic orthotopic HCC mouse model with a series of persistent liver injury induced by CCl4 gavage.The results showed that HCC growth and metastasis was positively correlated with the degree of liver inflammation rather than the extent of liver fibrosis.The two inflammatory cytokines,tumor necrosis factor-α(TNF-α)and interleukin-6(IL-6),promoted intrahepatic HCC proliferation and invasion via STAT3-induced epithelial-mesenchymal transition(EMT),In addition,the inflammatory liver microenvironment up-regulated anti-apoptotic protein Mcl-1 and inhibit the apoptosis of HCC induced by sorafenib.In order to explore the effect and regulatory mechanism of SYK on HCC progression,we also established orthotopic HCC mouse model with non-alcoholic steatohepatitis(NASH).It was found that SYK expression was significantly increased both in two mouse model.Analysis of 158 HCC patients showed that patients with high expression of SYK in non-tumor liver tissues had obvious liver inflammation-related pathological features and significantly shortened survival time.The study established hepatic cell-specific SYK knockout mice(SYKfl/fl,Alb-Cre;SYK△Hep)to further verify SYK function:SYK△Hep mice with liver injury or NASH had a more slowly HCC progression than wild type(wild type,WT).The results of in vitro experiments showed SYK promoted the activation of NLRP3 inflammasome in hepatocytes by enhancing the adaptor protein ASC oligomerization,inducing the formation of tumor-promoting liver microenvironment.Currently,there are no studies regarding the treatment strategy of targeting liver microenvironment.Accordingly,we applied SYK inhibitors to treat preclinical HCC mouse models:SYK inhibitors modulated the pathological characteristics of inflammatory liver microenvironment and inhibited the HCC progression.More importantly,SYK inhibitors combined with tyrosine kinase inhibitor(sorafenib and regorafenib)further inhibited the HCC growth and prolonged the survival time of mice.Conclusion:1.Inflammatory liver microenvironment promoted epithelial-mesenchymal transition and anti-apoptotic protein expression,leading to HCC progression and drug resistance;2.Under the effect of injury factors,hepatocyte’s SYK promoted the adaptor protein ASC oligomerization and NLRP3 inflammasome activation,causing pyroptosis of hepatic cell and inducing the formation of tumor-promoting inflammatory liver microenvironment;3.SYK inhibitors modulated the inflammatory liver microenvironment,alleviated the HCC progression,and improved the efficacy of tyrosine kinase inhibitor on HCC within the inflammatory liver microenvironment.