Hepatitis B x antigen up-regulates vascular endothelial growth factor receptor 3 in hepatocarcinogenesis.
Hepatitis B x antigen (HBxAg) is a trans-activating protein that contributes to liver cancer, in part, by altering the expression of cellular genes. However, few natural effectors of HBxAg have been identified. Hence, HBxAg positive and negative HepG2 cells were prepared and analyzed by PCR select cDNA subtraction. The results identified elevated vascular endothelial growth factor receptor-3 short form splice variant (VEGFR-3(S)) expression in HBxAg positive compared to negative cells. Normally, VEGFR-3 activates Akt signaling in lymphatic endothelial cells, resulting in lymphangiogenesis. In contrast, the results here show that the expression of VEGFR-3(S) is up-regulated in >75% of HBxAg positive hepatocellular carcinoma (HCC) nodules. VEGFR-3(S) up-regulation correlates with the expression of HBxAg, is associated with decreased survival in tumor bearing patients, and when over-expressed in HepG2 cells, strongly stimulated cell growth in culture, in soft agar, and accelerated tumor formation in a ligand independent manner. VEGFR-3(S) siRNA partially blocked the ability of HBxAg to promote hepatocellular growth. In conclusion, HBxAg may short circuit VEGFR-3(S) signaling in liver cancer. Blocking VEGFR-3(S) signaling may be effective in preventing tumor development and/or prolonging survival in tumor bearing patients.
Lian
Zhaorui
Z
Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, 1020 Locust Street, Philadelphia, PA 19107, USA.
Liu
Jie
J
Wu
Mengchao
M
Wang
Hong-Yang
HY
Arbuthnot
Patrick
P
Kew
Michael
M
Feitelson
Mark A
MA
D000362:Agar; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000473:pathology / Q000503:physiopathology* / Q000821:virology; D002455:Cell Division / Q000502:physiology; D045744:Cell Line, Tumor; D003001:Cloning, Molecular; D015972:Gene Expression Regulation, Neoplastic; D015967:Gene Expression Regulation, Viral; D006509:Hepatitis B / Q000473:pathology / Q000503:physiopathology*; D006515:Hepatitis B virus / Q000235:genetics*; D006801:Humans; D008099:Liver / Q000473:pathology / Q000502:physiology; D008113:Liver Neoplasms / Q000473:pathology / Q000503:physiopathology* / Q000821:virology; D051379:Mice; D008819:Mice, Nude; D018809:Proliferating Cell Nuclear Antigen / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034741:RNA, Small Interfering; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000502:physiology; D042582:Vascular Endothelial Growth Factor C / Q000494:pharmacology; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000235:genetics* / Q000378:metabolism; D054334:Viral Regulatory and Accessory Proteins
D018809:Proliferating Cell Nuclear Antigen; D034741:RNA, Small Interfering; D015534:Trans-Activators; D042582:Vascular Endothelial Growth Factor C; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein; D000362:Agar; D040321:Vascular Endothelial Growth Factor Receptor-3; D051057:Proto-Oncogene Proteins c-akt