Identification of a Transmembrane Protein Involved in Shear Stress Signaling and Hepatocarcinogenesis After a Sustained Virological Response to Hepatitis C Virus

The mechanism by which hepatocellular carcinoma develops after the eradication of hepatitis C virus remains unclear. We identified an epigenetically regulated new transmembrane protein, shear stress-induced transmembrane protein associated with endoplasmic reticulum stress signaling (SHERMER). SHERMER is induced by shear stress in liver endothelial cells mediating endoplasmic reticulum stress signaling and inflammatory responses. Thus, SHERMER is a novel endothelial marker associated with liver fibrosis, hepatocarcinogenesis, and progression of hepatocellular carcinoma. BACKGROUND & AIMS: The risk of hepatocellular carcinoma (HCC) remains after achieving a sustained virological response (SVR) in patients with chronic hepatitis C (CHC). Epigenetic abnormalities might be key regulators in the development of HCC. This study aimed to identify the genes involved in hepatocarcinogenesis after an SVR. METHODS: DNA methylation in liver tissue was compared between 21 CHC patients without HCC and 28 CHC patients with HCC, all of whom had achieved an SVR. Additional comparisons with 23 CHC patients before treatment and 10 normal livers were performed. The characteristics of a newly identified gene were explored in vitro and in vivo. RESULTS: We found that the transmembrane protein no. 164 (TMEM164) gene was demethylated by hepatitis C virus infection and HCC development after achieving an SVR. TMEM164 was expressed mainly in endothelial cells, alpha smooth muscle actin-positive cells, and some capillarized liver sinusoidal endothelial cells. TMEM164 expression was significantly correlated with liver fibrosis and relapse-free survival in HCC patients. TMEM164 was induced by shear stress, interacted with GRP78/BiP, accelerated ATF6 (activating transcription factor 6)-mediated endoplasmic reticulum (ER) stress signaling, and activated interleukin-6/STAT3 (signal transducer and activator of transcription 3) signaling in the TMNK1 liver endothelial cell line. Therefore, we termed TMEM164 "shear stress-induced transmembrane protein associated with ER stress signaling" (SHERMER). SHERMER knockout mice were protected against CCL4-induced liver fibrosis. SHERMER overexpression in TMNK1 cells accelerated HCC growth in a xenograft model. CONCLUSIONS: We identified a new transmembrane protein, SHERMER, in CHC patients with HCC after achieving an SVR. SHERMER was induced by shear stress and accelerated ATF6mediated ER stress signaling in endothelial cells. Thus, SHERMER is a novel endothelial marker associated with liver fibrosis, hepatocarcinogenesis, and progression of HCC.