Hepatocyte proliferation and cell cycle phase fractions in chronic viral hepatitis C by image analysis method

Werling, Klára; Szentirmay, Zoltán; Szepesi, Ágota; Schaff, Zsuzsa; Szalay, Ferenç; Szabó, Z.; Telegdy, László; Dávid, K; Stotz, G; Tulassay, Zsolt

doi:10.1097/00042737-200105000-00005

Cited by 10 publications

(10 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Thus, low expression of these mitotic checkpoint regulators in advanced HCV might reflect loss of mitotic checkpoint control that could render cells to chromosomal instability. This hypothesis is also supported by a previous study which showed presence of near-aneuploidy DNA content in liver specimens from chronic hepatitis C patients [11]. …”

Section: Discussionsupporting

confidence: 84%

See 1 more Smart Citation

Modulations of cell cycle checkpoints during HCV associated disease

et al. 2009

View full text Add to dashboard Cite

BackgroundImpaired proliferation of hepatocytes has been reported in chronic Hepatitis C virus infection. Considering the fundamental role played by cell cycle proteins in controlling cell proliferation, altered regulation of these proteins could significantly contribute to HCV disease progression and subsequent hepatocellular carcinoma (HCC). This study aimed to identify the alterations in cell cycle genes expression with respect to early and advanced disease of chronic HCV infection.MethodsUsing freshly frozen liver biopsies, mRNA levels of 84 cell cycle genes in pooled RNA samples from patients with early or advanced fibrosis of chronic HCV infection were studied. To associate mRNA levels with respective protein levels, four genes (p27, p15, KNTC1 and MAD2L1) with significant changes in mRNA levels (> 2-fold, p-value < 0.05) were selected, and their protein expressions were examined in the liver biopsies of 38 chronic hepatitis C patients.ResultsIn the early fibrosis group, increased mRNA levels of cell proliferation genes as well as cell cycle inhibitor genes were observed. In the advanced fibrosis group, DNA damage response genes were up-regulated while those associated with chromosomal stability were down-regulated. Increased expression of CDK inhibitor protein p27 was consistent with its mRNA level detected in early group while the same was found to be negatively associated with liver fibrosis. CDK inhibitor protein p15 was highly expressed in both early and advanced group, but showed no correlation with fibrosis. Among the mitotic checkpoint regulators, expression of KNTC1 was significantly reduced in advanced group while MAD2L1 showed a non-significant decrease.ConclusionCollectively these results are suggestive of a disrupted cell cycle regulation in HCV-infected liver. The information presented here highlights the potential of identified proteins as predictive factors to identify patients with high risk of cell transformation and HCC development.

show abstract

Section: Discussionsupporting

confidence: 84%

“…Studies performed on hepatic biopsies from chronic hepatitis C patients have shown an imbalance at G1/S checkpoint of cell cycle [11,12]. In fact, the report from Marshal et al showed a G1 arrest in hepatocytes characterized by over expression of CDK inhibitor p21.…”

Section: Introductionmentioning

confidence: 99%

Modulations of cell cycle checkpoints during HCV associated disease

et al. 2009

View full text Add to dashboard Cite

show abstract

“…The hepatitis C virus (HCV) 3 infection is a rapidly increasing public health problem, with millions of chronically infected patients to date. It is well known that patients with chronic disease have an increased risk of developing hepatocellular carcinoma (HCC) (1).…”

mentioning

confidence: 99%

“…Clinical observations indicate that the increased proliferation rate of hepatocytes is a major risk factor for the development of HCC (2). Several in vivo studies on hepatic biopsies reported an imbalance between the G 1 and the S phases of the cell cycle in liver cells obtained from chronic hepatitis C patients (3). Moreover, some studies revealed a G 2 /M dysfunction in hepatocarcinoma-derived cells (4).…”

mentioning

confidence: 99%

Role of p38 MAPK and RNA-dependent Protein Kinase (PKR) in Hepatitis C Virus Core-dependent Nuclear Delocalization of Cyclin B1

Spaziani

Alisi

Sanna

et al. 2006

Journal of Biological Chemistry

View full text Add to dashboard Cite

Some hepatitis C virus (HCV) proteins, including core protein, deregulate the cell cycle of infected cells, thereby playing an important role in the viral pathogenesis of HCC. Thus far, there are only few studies that have deeply investigated in depth the effects of the HCV core protein expression on the progression through the G 1 /S and G 2 /M phases of the cell cycle. To shed light on the molecular mechanisms by which the HCV core protein modulates cell proliferation, we have examined its effects on cell cycle in hepatocarcinoma cells. We show here that HCV core protein perturbs progression through both the G 1 /S and the G 2 /M phases, by modulating the expression and the activity of several cell cycle regulatory proteins. In particular, our data provided evidence that core-dependent deregulation of the G 1 /S phase and its related cyclin-CDK complexes depends upon the ERK1/2 pathway. On the other hand, the viral protein also increases the activity of the cyclin B1-CDK1 complex via the p38 MAPK and JNK pathways. Moreover, we show that HCV core protein promotes nuclear import of cyclin B1, which is affected by the inhibition of both the p38 and the RNA-dependent protein kinase (PKR) activities. The important role of p38 MAPK in regulating G 2 /M phase transition has been previously documented. It is becoming clear that PKR has an important role in regulating both the G 1 /S and the G 2 /M phase, in which it induces M phase arrest. Based on our model, we now show, for the first time, that HCV core expression leads to deregulation of the mitotic checkpoint via a p38/PKR-dependent pathway. The hepatitis C virus (HCV)3 infection is a rapidly increasing public health problem, with millions of chronically infected patients to date. It is well known that patients with chronic disease have an increased risk of developing hepatocellular carcinoma (HCC) (1). Despite the research already done in this field, HCV-related mechanisms inducing cell transformation are still incompletely understood. Clinical observations indicate that the increased proliferation rate of hepatocytes is a major risk factor for the development of HCC (2). Several in vivo studies on hepatic biopsies reported an imbalance between the G 1 and the S phases of the cell cycle in liver cells obtained from chronic hepatitis C patients (3). Moreover, some studies revealed a G 2 /M dysfunction in hepatocarcinoma-derived cells (4). A large body of evidence has pointed to the possibility that HCV pathogenesis is due to virus-mediated disruption of several signal transduction pathways that normally regulate cell proliferation (5-7). However, the lack of appropriate cell culture systems and of suitable animal models that mimic viral propagation in humans has hampered the full understanding of HCV-dependent pathogenic mechanisms. The analysis of HCV gene product(s), responsible for the impairment of cell cycle regulation, has already suggested a main role of HCV core protein in regulating hepatocyte proliferation, making cells susceptible to cellular transforma...

show abstract

“…• Cell cycle analysis can add valuable information, and viral antigens including hepatitis C antigen can be detected in liver tissue by immunohistochemistry [66,67].…”

Section: Functional Liver Tissue Analysis In Lbmentioning

confidence: 99%