International Session（Workshop）1(JSH・JSGE)
Thu. November 5th   9:40 - 12:00   Room 11: Portopia Hotel South Wing Topaz
IS-W1-4_H
 Genome-wide methylation analysis identified a new intrahepatic vascular endothelial marker associated with induction of tumorigenesis after successful eradication of HCV via ER stress
Masashi Nishikawa1,2, Masao Honda1, Shuichi Kaneko1
1Department of Laboratory Science, Graduate School of Medical Science, Kanazawa University, 2Department of Gastroenterology, National Hospital Organization Kanazawa Medical Center
Purpose
This study aimed to identify new molecular markers associated with HCC after sustained viral response (SVR), using genome-wide methylation analysis.
Methods
We evaluated biopsy specimens of 10 normal livers, 44 chronic hepatitis C liver tissues (before IFN therapy and after achieving SVR), and 28 non-cancerous liver tissues from cases that developed hepatocellular carcinoma (HCC) after achieving SVR.
Results
We selected a methylated gene, TMEM. Kaplan Meier analysis showed that the high expression of TMEM was significantly associated with lower recurrence-free survival in HCV-HCC (p=0.01). TMEM was expressed in vascular endothelial cells in both non-tumor and tumor tissues. TMEM significantly increased tumor growth in xenograft mouse model. TMEM was expressed in cytoplasm and membrane regions and induced by ER stress or mechanical shear stress. Over expression of TMEM substantially induced pro-inflammatory cytokines such as IL6. The suppression of TMEM reduced the expression of the transcriptional factor, ATF6, a key regulator of ER stress signaling. Immunofluorescence staining showed the co-localization of TMEM, ATF6 and BiP. TMEM induced the expression of activated cleaved form of ATF6.
Conclusions
Genome-wide methylation analysis identified a new intrahepatic vascular endothelial marker associated with HCC development after elimination of HCV, through the ATF6 mediated of ER stress signaling.
Index Term 1: HCC
Index Term 2: ER stress signaling
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