Hepatitis B Virus Infection Promotes Hepatocellular Carcinoma Progression Through LPC/ENPP2/LPA Axis

Abstract

Background: Hepatitis B virus (HBV) infection is considered as an independent risk factor for poor prognosis in hepatocellular carcinoma (HCC) patients, but the molecular mechanisms have not been fully elucidated. Ectonucleotide pyrophosphatase-phosphodiesterase 2 (ENPP2) hydrolyzes lysophosphatidylcholine (LPC) to produce lysophosphatidic acid (LPA) and participates in virus replication and tumor progress. This study aimed to elucidate whether HBV infection inducing HCC progression via LPC/ENPP2/LPA axis. Methods: The clinical data for HCC patients were collected and prognosis was analyzed. The in vitro and in vivo experiments were used to investigate the influences of HBV, ENPP2 and activated hepatic stellate cell (HSC) on HCC progression. Findings: We found that ENPP2 expression was positively related to HBV infection and poor prognosis. HBV-induced HCC progression via ENPP2 was enhanced by LPC which was secreted by activated HSC. HCC patients with high ENPP2 combined with cirrhosis had worse prognosis than non-cirrhotic patients. In cirrhotic HCC patients, high ENPP2 expression cohort also had worse prognosis than low expression cohort. Interpretation: In HBV positive cirrhotic HCC patients, HBV enhanced host cell secretion of ENPP2, combined with LPC secreted by fibroblast to promote tumor progression via LPC/ENPP2/LPA. These findings may provide insights into novel approaches to HBV associated HCC therapy. Funding Statement: This study was supported by the National Natural Science Foundation of China (81801999, 81772597, 81672412, 81972255), the Guangdong Science and Technology Foundation (2017A030311002), the Science Foundation of Jiangxi (20181BAB214002), the Education Department Science and Technology Foundation of Jiangxi (GJJ170936) and grant from Guangdong Science and Technology Department (2017B030314026). Declaration of Interests: The authors declare no conflict of interest. Ethics Approval Statement: The clinicopathologic information of HCC patient (n = 774) and tumor tissues (n = 158) were obtained from Sun Yat-sen Memorial Hospital after approval by the hospital Ethical Committee. Animal studies were carried out in the South China University of Technology and approved by the Laboratory Animal Welfare and Ethics Committee of the South China University of Technology. All animal experiments conformed to the approved guidelines of Animal Care and Use Committee of South China University of Technology.