Modulation of MAPK pathways and cell cycle by replicating hepatitis B virus: Factors contributing to hepatocarcinogenesis

Chin, Rey; Earnest-Silveira, Linda; Koeberlein, Bernd; Franz, Susanne; Zentgraf, Hanswalter; Dong, Xuebin; Gowans, Eric J.; Bock, C.‐Thomas; Torresi, Joseph

doi:10.1016/j.jhep.2007.03.025

Cited by 61 publications

(72 citation statements)

References 44 publications

(50 reference statements)

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“…Relationship between MTDH expression and clinicopathological parameters in patients with HBV-related HCC. (34)(35)(36). Additionally, HBx has been shown to activate the transcription factors NF-κB (37) and AP-1 (38).…”

Section: Discussionmentioning

confidence: 99%

Prognostic significance of metadherin overexpression in hepatitis B virus-related hepatocellular carcinoma

et al. 2012

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Abstract. Metadherin (MTDH), which is an HIV-1 or TNF-α-inducible transcript, has a crucial role in several types of cancer by regulating multiple cellular signaling processes. However, to date, the role of MTDH in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) is still unclear. In the present study, we detected MTDH expression in normal liver, chronic hepatitis B and HBV-related HCC tissues. The data showed that MTDH expression levels were elevated in the hepatitis B tissues and especially in the HBV-related HCC tissues compared to normal liver tissues. There was a trend for gradually increased MTDH expression from normal liver tissue to hepatitis B and HBV-related HCC tissues. Furthermore, a statistical analysis revealed that MTDH expression significantly correlated with the American Joint Committee on Cancer (AJCC, 7th edition) stage (P=0.020), T classification (P= 0.007), N classification (P= 0.044), vascular invasion (P=0.006) and histological differentiation (P=0.020) in the HBV-related HCC patients. In addition, patients with high MTDH levels had shorter survival times compared to those with low MTDH expression (P=0.001). Taken together, these results suggest that MTDH could be a potential prognostic marker for overall survival and tumor progression and a chemotherapeutic target in HBV-related HCC patients.

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Section: Discussionmentioning

confidence: 99%

Prognostic significance of metadherin overexpression in hepatitis B virus-related hepatocellular carcinoma

et al. 2012

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“…The results of some studies have shown that cell cycle progression can be altered in cells that contain replicating HBV, and the status of cell proliferation pathways can also affect HBV replication in some experimental systems (reviewed in reference 41). Studies that examined the effect of HBV replication on the cell cycle in Huh7 cells, a human hepatoma cell line, and primary marmoset hepatocytes demonstrated that in the context of HBV replication, these cells stall in G 2 phase (17). The results of a different study demonstrated that entry into S phase was decreased in Huh7 cells and HepG2.2.15 cells, human hepatoblastoma HepG2 cells that contain an integrated HBV genome and can produce infectious HBV (23).…”

mentioning

confidence: 99%

“…Studies of Chang liver cells, HepG2 cells, NIH 3T3 cells, and HL-7702 cells suggested that HBx can induce arrested cells to enter the cell cycle, enter the cell cycle but stall in S phase, or progress through the cell cycle more rapidly (4,5,10,16,34,37,72). HBx can also modulate the levels of p16, p21, p27, cyclin D1, cyclin A, and cyclin B1; activate the p21 promoter; and increase the activity of cyclin-dependent kinase 2 (CDK2) in various cell lines and primary hepatocytes, although the precise effects of HBx varied in different experimental conditions (2,17,25,36,37,45,47,48,50). Andrisani's group has provided direct support for the notion that HBx can have different effects on cell proliferation pathways depending on specific cellular characteristics (37).…”

mentioning

confidence: 99%

The Hepatitis B Virus X Protein Modulates Hepatocyte Proliferation Pathways To Stimulate Viral Replication

Gearhart¹,

Bouchard

2010

J Virol

101

121

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Worldwide, there are over 350 million people who are chronically infected with the human hepatitis B virus (HBV); chronic HBV infections are associated with the development of hepatocellular carcinoma (HCC). The results of various studies suggest that the HBV X protein (HBx) has a role in the development of HBVassociated HCC. HBx can regulate numerous cellular signal transduction pathways, including those that modulate cell proliferation. Many previous studies that analyzed the impact of HBx on cell proliferation pathways were conducted using established or immortalized cell lines, and when HBx was expressed in the absence of HBV replication, and the precise effect of HBx on these pathways has often differed depending on experimental conditions. We have studied the effect of HBx on cell proliferation in cultured primary rat hepatocytes, a biologically relevant system. We demonstrate that HBx, both by itself and in the context of HBV replication, affected the levels and activities of various cell cycle-regulatory proteins to induce normally quiescent hepatocytes to enter the G 1 phase of the cell cycle but not to proceed to S phase. We linked HBx regulation of cell proliferation to cytosolic calcium signaling and HBx stimulation of HBV replication. Cumulatively, our studies suggest that HBx induces normally quiescent hepatocytes to enter the G 1 phase of the cell cycle and that this calcium-dependent HBx activity is required for HBV replication. These studies identify an essential function of HBx during HBV replication and a mechanism that may connect HBV infections to the development of HCC.Viruses often encode proteins that modulate normal cellular processes to create an environment that facilitates viral replication. A potential consequence of the activities of viral proteins that alter normal cellular signaling pathways is that they can stimulate cell transformation and cancer progression. Included among confirmed oncogenic viruses is the hepatitis B virus (HBV); HBV is the prototype member of the Hepadnaviridae, a family of hepatotropic viruses (57). The HBV genome is a partially double-stranded, circular DNA that contains four overlapping open reading frames (ORFs) that encode the viral envelope, capsid, reverse transcriptase, and X (HBx) proteins (57). Worldwide, there are over 350 million people who are chronically infected with HBV; approximately 25% of these chronically HBV-infected individuals develop hepatocellular carcinoma (HCC) (3, 57). While there is evidence of a strong link between chronic HBV infections and HCC development, exactly how chronic HBV infections can lead to the development of HCC has not been defined. The results of numerous studies suggest that the development of HBV-associated HCC involves a combination of the activities of HBV proteins that modulate cell signal transduction pathways, such as HBx, and the consequences of the host immune response to infection, including immune-mediated destruction of HBV-infected hepatocytes that induces repeated liver regeneration cycles.HBx is a...

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“…However, Ras mutations that could account for sustained pathway activation are rare in human HCCs (Min et al, 2010). One explanation for constistutive ERK activation in HCCs can be that HBV or HCV viral infection interferes and activates the ERK signaling cascade facilitating thus hepatocarcinogenesis (Chin et al, 2007;Zhao et al, 2005). Another reason may lie with the fact that there is global suppression of negative regulators that control the ERK signaling cascade in HCC cell lines.…”

Section: Erk Pathway and Hccmentioning

confidence: 99%

The Involvement of the ERK-Hypoxia-Angiogenesis Signaling Axis and HIF-1 in Hepatocellular Carcinoma

Mylonis¹,

Simos²

2012

Hepatocellular Carcinoma - Basic Research

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Modulation of MAPK pathways and cell cycle by replicating hepatitis B virus: Factors contributing to hepatocarcinogenesis

Cited by 61 publications

References 44 publications

Prognostic significance of metadherin overexpression in hepatitis B virus-related hepatocellular carcinoma

Prognostic significance of metadherin overexpression in hepatitis B virus-related hepatocellular carcinoma

The Hepatitis B Virus X Protein Modulates Hepatocyte Proliferation Pathways To Stimulate Viral Replication

The Involvement of the ERK-Hypoxia-Angiogenesis Signaling Axis and HIF-1 in Hepatocellular Carcinoma

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