Hepatitis C virus core protein enhances B lymphocyte proliferation.
HCV chronic infection leads to liver diseases and also to a wide range of extrahepatic disorders including benign, but pre-lymphomatous forms (mixed cryoglobulinemia) to frank hematological neoplasia (non-Hodgkin's lymphoma). Recent data showed the involvement of p53 superfamily members in the pathogenesis of different lymphatic malignancies. In fact, tymomas and a subset of non-Hodgkin's lymphomas (NHLs) express high levels of p63. Thus, we analyzed whether alterations in p53 superfamily gene expression are observable in B lymphocytes isolated from HCV-infected patients with and without lymphoproliferative disorders. We showed, by real-time PCR, a significant induction of DNp63 mRNAs in B lymphocytes obtained from HCV-positive low grade non-Hodgkin's lymphoma patients. Since our current understanding of HCV proteins emphasizes the ability of the HCV core protein to deregulate the expression and activity of p53-related proteins, we established different B lymphocyte cell lines (Wil2-ns, Daudi and Ramos) stably expressing HCV core protein, in order to investigate the possible involvement of the viral protein in the upregulation of DNp63 in B lymphocytes. The analysis of p63 family transcripts showed no transcriptional changes for the p63 TA isoforms, whereas an increase (>5 times) of DNp63 mRNA occurred. In all cell lines, this abnormal expression was associated with a significant increase of cell proliferation that was specifically inhibited by silencing DNp63 mRNA. These findings suggest a pathogenetic role of the HCV core in HCV-related lymphomagenesis, through the induction of DNp63's pro-proliferative effects.
Alisi
A
A
Laboratory of Molecular Virology and Oncology, Fondazione A. Cesalpino, University of Rome La Sapienza, Rome, Italy.
Giannini
C
C
Spaziani
A
A
Anticoli
S
S
Caini
P
P
Zignego
A L
AL
Balsano
C
C
D017209:Apoptosis / Q000502:physiology; D001402:B-Lymphocytes / Q000502:physiology*; D002455:Cell Division / Q000502:physiology; D002478:Cells, Cultured; D016174:Hepacivirus / Q000502:physiology*; D006801:Humans; D008565:Membrane Proteins / Q000502:physiology*; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation; D014758:Viral Core Proteins / Q000502:physiology*
C081876:CKAP4 protein, human; D008565:Membrane Proteins; D012333:RNA, Messenger; D014758:Viral Core Proteins