Molecular Signature and Mechanisms of Hepatitis D Virus-Associated Hepatocellular Carcinoma

被引：52

作者：

Diaz, Giacomo ^{[1
]}

Engle, Ronald E. ^{[2
]}

Tice, Ashley ^{[2
]}

Melis, Marta ^{[2
]}

Montenegro, Stephanie ^{[2
]}

Rodriguez-Canales, Jaime ^{[3
]}

Hanson, Jeffrey ^{[3
]}

Emmert-Buck, Michael R. ^{[3
]}

Bock, Kevin W. ^{[4
]}

Moore, Ian N. ^{[4
]}

Zamboni, Fausto ^{[5
]}

Govindarajan, Sugantha ^{[6
]}

Kleiner, David E. ^{[7
]}

Farci, Patrizia ^{[2
]}

机构：

[1] Univ Cagliari, Dept Biomed Sci, Cagliari, Italy

[2] NIAID, Hepat Pathogenesis Section, Lab Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA

[3] NCI, Laser Capture Microdissect Core Facil, Pathol Lab, NIH, Bethesda, MD 20892 USA

[4] NIAID, Infect Dis Pathogenesis Sect, Comparat Med Branch, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA

[5] Brotzu Hosp, Liver Transplantat Ctr, Cagliari, Italy

[6] Univ Southern Calif, Rancho Los Amigos Hosp, Dept Pathol, Downey, CA 90242 USA

[7] NCI, Lab Pathol, NIH, Bethesda, MD 20892 USA

来源：

MOLECULAR CANCER RESEARCH | 2018年 / 16卷 / 09期

关键词：

CHROMOSOMAL INSTABILITY; C VIRUS; LIVER; EXPRESSION; ANTIGEN; SURFACE;

D O I：

10.1158/1541-7786.MCR-18-0012

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

There is limited data on the molecular mechanisms whereby hepatitis D virus (HDV) promotes liver cancer. Therefore, serum and liver specimens obtained at the time of liver transplantation from well-characterized patients with HDV-HCC (n = 5) and with non-HCCHDV cirrhosis (n = 7) were studied using an integrated genomic approach. Transcriptomic profiling was performed using laser capture-microdissected (LCM) malignant and nonmalignant hepatocytes, tumorous and non-tumorous liver tissue from patients with HDV-HCC, and liver tissue from patients with non-HCC HDV cirrhosis. HDV-HCC was also compared with hepatitis B virus (HBV) HBV-HCC alone, and hepatitis C virus (HCV) HCV-HCC. HDV malignant hepatocytes were characterized by an enrichment of upregulated transcripts associated with pathways involved in cellcycle/DNA replication, damage, and repair (Sonic Hedgehog, GADD45, DNA-damage-induced 14-3-3s, cyclins and cell-cycle regulation, cell cycle: G2-M DNA-damage checkpoint regulation, and hereditary breast cancer). Moreover, a large network of genes identified functionally relate to DNA repair, cell cycle, mitotic apparatus, and cell division, including 4 cancer testis antigen genes, attesting to the critical role of genetic instability in this tumor. Besides being overexpressed, these genes were also strongly coregulated. Gene coregulation was high not only when compared with nonmalignant hepatocytes, but also to malignant hepatocytes from HBV-HCC alone or HCV-HCC. Activation and coregulation of genes critically associated with DNA replication, damage, and repair point to genetic instability as an important mechanism of HDV hepatocarcinogenesis. This specific HDV-HCC trait emerged also from the comparison of the molecular pathways identified for each hepatitis virus-associated HCC. Despite the dependence of HDV on HBV, these findings suggest that HDV and HBV promote carcinogenesis by distinct molecular mechanisms. Implications: This study identifies a molecular signature of HDV-associated hepatocellular carcinoma and suggests the potential for new biomarkers for early diagnostics. (C) 2018 AACR.

引用

页码：1406 / 1419

页数：14

共 41 条

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