Online citations, reference lists, and bibliographies.
Please confirm you are human
(Sign Up for free to never see this)
← Back to Search

Improved Detection Of Hepatocyte Proliferation Using Antibody To The Pre‐replication Complex: An Association With Hepatic Fibrosis And Viral Replication In Chronic Hepatitis C Virus Infection

A. Freeman, S. Hamid, L. Morris, S. Vowler, S. Rushbrook, D. Wight, N. Coleman, G. Alexander
Published 2003 · Biology, Medicine

Save to my Library
Download PDF
Analyze on Scholarcy
Share
Summary. To test the hypothesis that hepatitis C virus (HCV) might induce hepatocyte proliferation directly, thereby predisposing HCV carriers to cirrhosis and hepatocellular carcinoma, we have used a new method to identify proliferating hepatocytes, employing a novel monoclonal antibody to minichromosome maintenance (Mcm) proteins, essential components of the pre‐replication complex. Antibody to Ki‐67, a conventional marker of cell division, was also studied. Eighty‐seven patients with chronic HCV infection and a broad spectrum of histological change were studied. Proliferation was observed rarely in hepatocytes from normal liver from healthy controls (always less than 0.01%). However, proliferating hepatocytes were detected in all HCV‐infected patients and the proportion of hepatocytes expressing Mcm‐2 (3–40%) always exceeded that expressing Ki‐67 (1–14%) and correlated positively with increasing stage of fibrosis (P = 0.0001) and viral replication (P = 0.0004). There were weaker but significant associations between the proportion of hepatocytes expressing Mcm‐2 and inflammatory indices including interface hepatitis, portal tract inflammation, lobular inflammation and steatosis. There was no association between the proportion of hepatocytes expressing Mcm‐2 and age, gender or past alcohol consumption, but there was a weak association with current consumption of alcohol (P = 0.0067). The proportion of Ki‐67 hepatocytes did not correlate with any clinical, laboratory or histological parameter. Mcm‐2 was also detected in bile duct cells, sinusoidal lining cells and infiltrating lymphocytes, but at low frequency. These data indicate first, that Mcm‐2 is a more sensitive marker of hepatocyte proliferation than Ki‐67, second that many hepatocytes in chronic HCV infection have entered the cell cycle and third, suggest that interference with the hepatocyte cell cycle might be an alternative approach to therapy.
This paper references
10.1016/0960-9822(92)90522-C
Cell proliferation and control
J. Pines (1992)
10.1016/S0168-8278(00)80401-8
Control of cyclins, cyclin-dependent kinase inhibitors, p21 and p27, and cell cycle progression in rat hepatocytes by extracellular matrix.
M. Nagaki (2000)
10.1016/S0092-8674(00)80459-6
Putting It All Together: Building a Prereplicative Complex
C. Newlon (1997)
Liver regeneration, liver cancers and cyclins.
T. Kitamura (1998)
10.1016/S0378-1119(00)00020-2
Initiation of genome replication: assembly and disassembly of replication-competent chromatin.
M. Ritzi (2000)
DNA replication licensing and human cell proliferation.
K. Stoeber (2001)
10.1126/SCIENCE.287.5456.1253
Inhibition of experimental liver cirrhosis in mice by telomerase gene delivery.
K. Rudolph (2000)
Minichromosome maintenance proteins as biological markers of dysplasia and malignancy.
A. Freeman (1999)
10.1002/HEP.510290622
Role of transforming growth factor β type II receptor in hepatic fibrosis: Studies of human chronic hepatitis C and experimental fibrosis in rats
D. Roulot (1999)
10.1002/HEP.510230625
Hepatocyte proliferative activity in chronic liver damage as assessed by the monoclonal antibody MIB1 Ki67 in archival material: The role of etiology, disease activity, iron, and lipid peroxidation
F. Farinati (1996)
10.1073/PNAS.93.19.10189
XMCM7, a novel member of the Xenopus MCM family, interacts with XMCM3 and colocalizes with it throughout replication.
P. Romanowski (1996)
10.1016/S0140-6736(94)92179-2
Proliferating cell nuclear antigen as a marker of hepatocyte proliferation
R. Harrison (1994)
10.1056/NEJM199306243282508
The Cellular Basis of Hepatic Fibrosis -- Mechanisms and Treatment Strategies
S. Friedman (1993)
10.1016/S0140-6736(94)92025-7
Hepatocyte proliferation as an indicator of outcome in acute alcoholic hepatitis
J. W. Fang (1994)
Hepatitis virus-related carcinogenesis
O Hino (1994)
10.1111/J.1600-0676.1985.TB00252.X
[The streaming liver].
N. Arber (1991)
10.1096/fasebj.9.14.7589981
The extracellular matrix in hepatic regeneration
Antonio Martinez‐Hern Andez (1995)
10.1172/JCI116449
Detection of genomic and intermediate replicative strands of hepatitis C virus in liver tissue by in situ hybridization.
K. N. Nouri Aria (1993)
10.1016/S0168-8278(00)80017-3
Hepatocellular proliferation in patients with chronic hepatitis C and persistently normal or abnormal aminotransferase levels.
B. Kronenberger (2000)
Hepatocytes from non-hepatic adult stem cells
MR Alison (2000)
10.1111/jgh.1998.13.s1.96
Liver regeneration, liver cancers and cyclins
T. Kitamura (1998)
10.1002/HEP.510230510
Relationship between hepatocyte proliferative activity and liver functional reserve in human cirrhosis
M. Delhaye (1996)
10.1016/0955-0674(92)90024-7
Cell proliferation and control
J. Pines (1992)
10.1056/NEJM193206162062401
Cirrhosis of the Liver
F. B. Mallory (1932)
10.1006/BBRC.1995.1774
Telomere shortening in chronic liver diseases.
T. Kitada (1995)
10.1073/PNAS.94.1.142
A human protein related to yeast Cdc6p.
R. S. Williams (1997)
10.1073/PNAS.95.25.14932
Improved cervical smear assessment using antibodies against proteins that regulate DNA replication.
G. Williams (1998)
10.1074/JBC.M008329200
Modulation of Cell Growth by the Hepatitis C Virus Nonstructural Protein NS5A*
N. Arima (2001)
Seminars in medicine of the Beth Israel Hospital, Boston. The cellular basis of hepatic fibrosis. Mechanisms and treatment strategies.
S. Friedman (1993)
10.1128/JVI.75.10.4475-4481.2001
Herpesvirus Lytic Replication and the Cell Cycle: Arresting New Developments
E. Flemington (2001)
10.1159/000150368
Hepatitis virus-related hepatocarcinogenesis.
O. Hino (1994)
Cirrhosis of the liver. A regenerative process.
F. Callea (1991)
10.1002/HEP.510260307
Ki‐67 expression during rat liver regeneration after partial hepatectomy
C. Gerlach (1997)
10.1111/J.1600-0676.1988.TB00972.X
The streaming liver. II. Hepatocyte life history.
N. Arber (1988)
10.1136/jcp.49.6.465
Fibrosis and other histological features in chronic hepatitis C virus infection: a statistical model.
V. Wong (1996)



This paper is referenced by
10.7727/wimj.2015.052
Study on the Clinicopathological Features and Prognostic Factors of Extranodal NK/T Cell Lymphoma, Nasal Type (with 18 cases).
S. Yang (2015)
10.1186/1471-2407-14-65
Peritumoral ductular reaction: a poor postoperative prognostic factor for hepatocellular carcinoma
M. Xu (2013)
10.1186/s12885-019-5436-4
Correction to: Minichromosome Maintenance (MCM) family as potential diagnostic and prognostic tumor markers for human gliomas
Cong Hua (2019)
10.3390/proteomes4040030
Global Proteome Changes in Liver Tissue 6 Weeks after FOLFOX Treatment of Colorectal Cancer Liver Metastases
J. Urdzik (2016)
10.1385/SCR:1:3:253
Liver stem cells
M. Alison (2007)
10.1038/ncb3335
HSF1 critically attunes proteotoxic-stress sensing by mTORC1 to combat stress and promote growth
Kuo-Hui Su (2016)
10.2147/JHC.S221187
Hepatocellular Carcinoma Mechanisms Associated with Chronic HCV Infection and the Impact of Direct-Acting Antiviral Treatment
S. Dash (2020)
10.1186/1471-2334-9-125
Modulations of cell cycle checkpoints during HCV associated disease
Saira Sarfraz (2009)
10.1053/J.GASTRO.2004.09.076
Relation between hepatocyte G1 arrest, impaired hepatic regeneration, and fibrosis in chronic hepatitis C virus infection.
A. Marshall (2005)
10.1186/1471-2407-14-526
Minichromosome Maintenance (MCM) Family as potential diagnostic and prognostic tumor markers for human gliomas
C. Hua (2014)
10.1002/hep4.1106
Activin A is a prominent autocrine regulator of hepatocyte growth arrest
Srividyameena Haridoss (2017)
10.1111/j.1468-1293.2006.00384.x
Risk factors for fibrosis progression in HIV/HCV coinfected patients from a retrospective analysis of liver biopsies in 1985–2002
M. Schiavini (2006)
10.12816/0021409
The Fundamental Role Played by Cell Cycle Proteins in Controlling Cell Proliferation in Chronic Hepatitis C Virus Infection.
Saadia Farid (2016)
10.1007/s10620-009-0861-x
Stem Cell Origins and Animal Models of Hepatocellular Carcinoma
R. Aravalli (2009)
10.14670/HH-25.351
MCM proteins as diagnostic and prognostic tumor markers in the clinical setting.
C. Giaginis (2010)
10.1186/1471-2180-8-133
Altered expression of cell cycle and apoptotic proteins in chronic hepatitis C virus infection
Saira Sarfraz (2008)
10.1002/hep.21018
The sources of parenchymal regeneration after chronic hepatocellular liver injury in mice
P. Vig (2006)
Large Liver Cell Dysplasia in Hepatitis B Virus-Related Chronic Liver Disease
H. Kim (2008)
10.1111/j.1365-2184.2005.00354.x
Liver cancer: the role of stem cells
M. Alison (2005)
10.1016/J.TRSL.2006.03.002
Chronic iron overload stimulates hepatocyte proliferation and cyclin D1 expression in rodent liver.
K. Brown (2006)
Colorectal Cancer Liver Metastases : Effects of Chemotherapy on Liver Parenchyma and Resections
Jozef Urdzik (2014)
10.1111/j.1478-3231.2009.02040.x
Liver cancer stem cells: implications for a new therapeutic target
T. Lee (2009)
10.1371/journal.pcbi.1003934
Inferring Viral Dynamics in Chronically HCV Infected Patients from the Spatial Distribution of Infected Hepatocytes
Frederik Graw (2014)
10.1016/j.puhe.2016.08.002
Tackling the burden of the hepatitis C virus in the UK: characterizing and assessing the clinical and economic consequences.
T. Ward (2016)
10.1099/VIR.0.80204-0
Hepatitis C virus NS5A: tales of a promiscuous protein.
A. Macdonald (2004)
10.1371/journal.pone.0035351
Novel Small-Molecule Inhibitors of Hepatitis C Virus Entry Block Viral Spread and Promote Viral Clearance in Cell Culture
G. A. Coburn (2012)
10.2147/SCCAA.S6886
Progress in stem cell-derived technologies for hepatocellular carcinoma
R. Aravalli (2010)
10.1002/hep.22484
Histological changes in HCV antibody–positive, HCV RNA–negative subjects suggest persistent virus infection
M. Hoare (2008)
10.1155/2016/5702873
A Transcriptomic Signature of Mouse Liver Progenitor Cells
A. Passman (2016)
10.1128/JVI.01047-12
Rapid Intracellular Competition between Hepatitis C Viral Genomes as a Result of Mitosis
Brian L. Webster (2012)
10.1016/j.febslet.2009.10.009
The interaction between EAP30 and ELL is modulated by MCM2
A. Mathews (2009)
10.1002/lt.20347
Hepatocyte expression of minichromosome maintenance protein‐2 predicts fibrosis progression after transplantation for chronic hepatitis C virus: A pilot study
A. Marshall (2005)
See more
Semantic Scholar Logo Some data provided by SemanticScholar