Viral expression and molecular profiling in liver tissue versus microdissected hepatocytes in hepatitis B virus - associated hepatocellular carcinoma

Melis, Marta; Diaz, Giacomo; Kleiner, David E.; Zamboni, Fausto; Kabát, Juraj; Lai, Jinping; Mogavero, Giulia; Tice, Ashley; Engle, Ronald E.; Becker, Steven M.; Brown, Charles R.; Hanson, Jeffrey C.; Rodriguez‐Canales, Jaime; Emmert‐Buck, Michael R.; Govindarajan, Sugantha; Kew, Michael C.; Farci, Patrizia

doi:10.1186/s12967-014-0230-1

Cited by 54 publications

(67 citation statements)

References 47 publications

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“…Because STING is an IFN‐inducible protein, it is possible that STING is induced in the liver upon infection of, e.g., liver macrophages or dendritic cells and that this leads to restoration of the pathway . However, data mining of published data sets did not indicate increased expression of STING upon liver inflammation . In vivo transfection of murine hepatocytes resulted in STING expression in about one third of the cells.…”

Section: Discussionmentioning

confidence: 99%

Lack of immunological DNA sensing in hepatocytes facilitates hepatitis B virus infection

et al. 2016

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Hepatitis B virus (HBV) is a major human pathogen, and about one third of the global population will be exposed to the virus in their lifetime. HBV infects hepatocytes, where it replicates its DNA and infection can lead to acute and chronic hepatitis with a high risk of liver cirrhosis and hepatocellular carcinoma. Despite this, there is limited understanding of how HBV establishes chronic infections. In recent years it has emerged that foreign DNA potently stimulates the innate immune response, particularly type 1 interferon (IFN) production; and this occurs through a pathway dependent on the DNA sensor cyclic guanosine monophosphate-adenosine monophosphate synthase and the downstream adaptor protein stimulator of IFN genes (STING). In this work we describe that human and murine hepatocytes do not express STING. Consequently, hepatocytes do not produce type 1 IFN in response to foreign DNA or HBV infection and mice lacking STING or cyclic guanosine monophosphate-adenosine monophosphate synthase exhibit unaltered ability to control infection in an adenovirus-HBV model. Stimulation of IFN production in the murine liver by administration of synthetic RNA decreases virus infection, thus demonstrating that IFN possesses anti-HBV activity in the liver. Importantly, introduction of STING expression specifically in hepatocytes reconstitutes the DNA sensing pathway, which leads to improved control of HBV in vivo. Conclusion: The lack of a functional innate DNA-sensing pathway in hepatocytes hampers efficient innate control of HBV infection; this may explain why HBV has adapted to specifically replicate in hepatocytes and could contribute to the weak capacity of this cell type to clear HBV infection. (HEPATOLOGY 2016;64:746-759) H epatitis B virus (HBV) is a human pathogenic virus that specifically infects hepatocytes, causes chronic hepatitis, and is a major cause of hepatocellular carcinoma. HBV is a DNA virus, and it is estimated that more than 2 billion people are or have been infected worldwide (1) and that 240 million are chronic carriers. Immune responses are detectable only weeks after HBV infection when adaptive immune responses become activated, (2,3) but there are data to support that an earlier response would benefit virus clearance by the host. (4) Chronic HBV infection is a strong risk factor for development of liver

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Section: Discussionmentioning

confidence: 99%

Lack of immunological DNA sensing in hepatocytes facilitates hepatitis B virus infection

et al. 2016

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“…The application of genomic technologies has provided valuable tools to investigate the pathogenesis of complex diseases using a global approach (6), and many studies of gene expression on HCC-associated with hepatitis B virus (HBV; ref. 7) or hepatitis C virus (HCV; refs. 8,9) have been reported.…”

Section: Introductionmentioning

confidence: 99%

“…Additional WLT specimens were obtained from livers with non-HCC HDV cirrhosis. Because HDV is invariably associated with HBV, we have also compared the gene expression profiles of patients with HDV-associated HCC with those from patients with HCC associated with HBV alone (7), as well as with those from patients with HCC associated with HCV, to identify distinct molecular signatures for each hepatitis virus-associated HCC, which may shed new light on pathogenesis and facilitate the discovery of new biomarkers for the early detection of these deadly tumors.…”

Section: Introductionmentioning

confidence: 99%

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

Diaz

Engle

Tice

et al. 2018

Molecular Cancer Research

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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 ( = 5) and with non-HCC HDV cirrhosis ( = 7) were studied using an integrated genomic approach. Transcriptomic profiling was performed using laser capture-microdissected (LCM) malignant and nonmalignant hepatocytes, tumorous and nontumorous 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 cell-cycle/DNA replication, damage, and repair (Sonic Hedgehog, GADD45, DNA-damage-induced 14-3-3σ, cyclins and cell-cycle regulation, cell cycle: G-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. This study identifies a molecular signature of HDV-associated hepatocellular carcinoma and suggests the potential for new biomarkers for early diagnostics. .

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“…The gene expression series matrix of normal and cancerous liver tissues was downloaded from the Gene Expression Omnibus (GEO) website (www.ncbi.nlm.nih.gov/geo), and included the GEO datasets GSE45436 (26) and GSE55092 (27). The gene expression series matrix of normal and cancerous lung tissues were downloaded from the GSE18442 (28), GSE19188 (29), GSE19804 (30) and GSE27262 (31) datasets.…”

Section: Methodsmentioning

confidence: 99%

“…The GSE45436 and GSE55092 datasets included the expression profiles derived from normal liver and malignant liver tissues (27). The expression levels of the E2F family genes varied significantly between normal liver or malignant tissues.…”

Section: E2f Family Genes Exhibit Hyper-dna Methylation Patterns In Pmentioning

confidence: 99%

Integrated analysis of the E2F transcription factors across cancer types

Wang

et al. 2020

Oncol Rep

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E2F transcription factors are associated with the development of cancer. However, the E2F family genes have not yet been studied in a comprehensive manner. Using The Cancer Genome Atlas, the present study analyzed the functions of the E2F family genes across different types of tumor. It was revealed that compared with normal tissues, the E2F family genes are highly expressed in several types of tumor tissue. Furthermore, E2F transcription factors were significantly enriched in tumor samples across different types of tumor. The high expression levels of E2F family genes were associated with an unfavorable prognosis in liver hepatocellular carcinoma (LIHC) and lung adenocarcinoma (LUAD). Furthermore, patients with pathological T1 stage and iCluster2 molecular subtype of LIHC expressed particularly low levels of E2F family genes. The present study demonstrated that hypo-DNA methylation, DNA amplification and TP53 mutation contributed to the high expression levels of E2F family genes in cancer cells. Finally, the present study revealed that, compared with other types of tumor, the E2F family genes were specifically downregulated in patients with LIHC. The expression levels and prognostic effects of the E2F family genes were validated using the Gene Expression Omnibus database. The results of the present study revealed the biological functions of E2F family genes in the development of cancer and provided potential biomarkers for further therapeutic studies, particularly for patients with LIHC and LUAD.

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Viral expression and molecular profiling in liver tissue versus microdissected hepatocytes in hepatitis B virus - associated hepatocellular carcinoma

Cited by 54 publications

References 47 publications

Lack of immunological DNA sensing in hepatocytes facilitates hepatitis B virus infection

Lack of immunological DNA sensing in hepatocytes facilitates hepatitis B virus infection

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

Integrated analysis of the E2F transcription factors across cancer types

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