Involvement of PI3K in HCV-related lymphoproliferative disorders.
Hepatitis C virus (HCV) core protein has been shown to deregulate cell growth and programmed cell death in hepatoma cells, but only minimal informations are available about its possible role on B-lymphoproliferative disorders (LPDs). The aim of our work was to analyze the biological activity of HCV core protein on B-cell proliferation. We established Wil2-ns and Ramos B-cell lines that stably expressed the HCV core protein. Growth curve, thymidine incorporation analysis, as well as the expression of PCNA and activated-ERKs demonstrated that HCV core protein induced an increased growth in both cell lines. Interestingly, the HCV core protein expression determined, in our model, a downregulation of DNp73 and an upregulation of DNp63, which was essential for the maintenance of viral-dependent effects on cell growth. Finally, we have identified phosphoinositide 3-kinase (PI3K) as mediator of HCV core-dependent transcriptional increase of DNp63, which in turn correlated with the increasing of lymphocyte proliferation. In primary B-lymphocytes, derived from HCV-related low-grade non-Hodgkin's lymphoma patients, consistent results were obtained. These findings provide evidence for a possible pathogenetic role played by HCV core protein in HCV-related lymphomagenesis; it could occur through the deregulation of PI3K activity, consequent activation of Akt and overexpression of DNp63.
Alisi
Anna
A
Laboratory of Molecular Virology and Oncology, Fondazione A. Cesalpino, University of Rome La Sapienza, Rome, Italy.
Giannini
Carlo
C
Spaziani
Alessandra
A
Caini
Patrizio
P
Zignego
Anna L
AL
Balsano
Clara
C
D000911:Antibodies, Monoclonal / Q000378:metabolism; D001402:B-Lymphocytes / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D001483:Base Sequence; D016022:Case-Control Studies; D002452:Cell Count; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002999:Clone Cells; D016895:Culture Media, Serum-Free; D018274:Electroporation; D004789:Enzyme Activation; D016174:Hepacivirus / Q000235:genetics / Q000378:metabolism*; D019698:Hepatitis C, Chronic / Q000821:virology; D006801:Humans; D018189:Immunomagnetic Separation / Q000379:methods; D007700:Kinetics; D008232:Lymphoproliferative Disorders / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D008969:Molecular Sequence Data; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010957:Plasmids; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000032:analysis; D034741:RNA, Small Interfering / Q000737:chemistry / Q000494:pharmacology; D015398:Signal Transduction; D013936:Thymidine / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D014758:Viral Core Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics
D000911:Antibodies, Monoclonal; D016895:Culture Media, Serum-Free; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D014758:Viral Core Proteins; D019869:Phosphatidylinositol 3-Kinases; D013936:Thymidine