Hepatitis B virus X antigen promotes transforming growth factor-beta1 (TGF-beta1) activity by up-regulation of TGF-beta1 and down-regulation of alpha2-macroglobulin.
Hepatitis B virus (HBV) X antigen (HBxAg) may contribute to the development of hepatocellular carcinoma (HCC) by activation of signalling pathways such as NF-kappaB. To identify NF-kappaB target genes differentially expressed in HBxAg-positive compared to -negative cells, HepG2 cells consistently expressing HBxAg (HepG2X cells) were stably transfected with pZeoSV2 or pZeoSV2-IkappaBalpha. mRNA from each culture was isolated and compared by PCR select cDNA subtraction. The results showed lower levels of alpha(2)-macroglobulin (alpha(2)-M) in HepG2X-pZeoSV2 compared to HepG2X-pZeoSV2-IkappaBalpha cells. This was confirmed by Northern and Western blotting, and by measurement of extracellular alpha(2)-M levels. Elevated transforming growth factor-beta1 (TGF-beta1) levels were also seen in HepG2X compared to control cells. Serum-free conditioned medium (SFCM) from HepG2X cells suppressed DNA synthesis in a TGF-beta-sensitive cell line, Mv1Lu. The latter was reversed when the SFCM was pretreated with exogenous, activated alpha(2)-M or with anti-TGF-beta. Since elevated TGF-beta1 promotes the development of many tumour types, these observations suggest that the HBxAg-mediated alteration in TGF-beta1 and alpha(2)-M production may contribute importantly to the pathogenesis of HCC.
Pan
Jingbo
J
Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Room 222 Alumni Hall, 1020 Locust Street, Philadelphia, PA 19107, USA.
Clayton
Marcy
M
Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Room 222 Alumni Hall, 1020 Locust Street, Philadelphia, PA 19107, USA.
Feitelson
Mark A
MA
Department of Microbiology and Immunology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.|Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Room 222 Alumni Hall, 1020 Locust Street, Philadelphia, PA 19107, USA.
D006528:Carcinoma, Hepatocellular; D002460:Cell Line; D005786:Gene Expression Regulation; D006801:Humans; D020672:I-kappa B Proteins / Q000235:genetics / Q000494:pharmacology; D008113:Liver Neoplasms; D000072000:NF-KappaB Inhibitor alpha; D012333:RNA, Messenger / Q000032:analysis; D015534:Trans-Activators / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D054334:Viral Regulatory and Accessory Proteins; D000511:alpha-Macroglobulins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*
D020672:I-kappa B Proteins; C000606204:NFKBIA protein, human; D012333:RNA, Messenger; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D054334:Viral Regulatory and Accessory Proteins; D000511:alpha-Macroglobulins; C057628:hepatitis B virus X protein; D000072000:NF-KappaB Inhibitor alpha