Hepatitis B virus X protein specially regulates the sialyl lewis a synthesis among glycosylation events for metastasis.

Abstract

BACKGROUND:

The metastasis of hematogenous cancer cells is associated with abnormal glycosylation such as sialyl lewis antigens. Although the hepatitis B virus X protein (HBx) plays important role in liver disease, the precise function of HBx on aberrant glycosylation for metastasis remains unclear.

METHODS:

The human hepatocellular carcinoma tissues, HBx transgenic mice and HBx-transfected cells were used to check the correlation of expressions between HBx and Sialyl lewis antigen for cancer metastasis. To investigate whether expression levels of glycosyltransferases induced in HBx-transfected cells are specifically associated with sialyl lewis A (SLA) synthesis, which enhances metastasis by interaction of liver cancer cells with endothelial cells, ShRNA and siRNAs targeting specific glycosyltransferases were used.

RESULTS:

HBx expression in liver cancer region of HCC is associated with the specific synthesis of SLA. Furthermore, the SLA was specifically induced both in liver tissues from HBx-transgenic mice and in in vitro HBx-transfected cells. HBx increased transcription levels and activities of α2-3 sialyltransferases (ST3Gal III), α1-3/4 fucosyltransferases III and VII (FUT III and VII) genes, which were specific for SLA synthesis, allowing dramatic cell-cell adhesion for metastatic potential. Interestingly, HBx specifically induced expression of N-acetylglucosamine-β1-3 galactosyltransferase V (β1-3GalT 5) gene associated with the initial synthesis of sialyl lewis A, but not β1-4GalT I. The β1-3GalT 5 shRNA suppressed SLA expression by HBx, blocking the adhesion of HBx-transfected cells to the endothelial cells. Moreover, β1-3GalT 5 silencing suppressed lung metastasis of HBx-transfected cells in in vivo lung metastasis system.

CONCLUSION:

HBx targets the specific glycosyltransferases for the SLA synthesis and this process regulates hematogenous cancer cell adhesion to endothelial cells for cancer metastasis.

• Authors: Tae-Wook Chung, Seok-Jo Kim, Hee-Jung Choi, Kwon-Ho Song, Un-Ho Jin, Dae-Yeul Yu, Je-Kyung Seong, Jong-Guk Kim, Keuk-Jun Kim, Jeong-Heon Ko, Ki-Tae Ha, Young-Choon Lee, Cheorl-Ho Kim
• Journal: Molecular cancer (Mol Cancer) Vol. 13 Pg. 222 (Sep 25 2014) ISSN: 1476-4598 [Electronic] England
• PMID: 25255877 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CA-19-9 Antigen
• Lewis X Antigen
• Oligosaccharides
• Sialyl Lewis X Antigen
• Trans-Activators
• Viral Regulatory and Accessory Proteins
• hepatitis B virus X protein
• Glycosyltransferases

Topics

• Adult
• Animals
• CA-19-9 Antigen
• Carcinoma, Hepatocellular (metabolism, pathology, virology)
• Cell Line, Tumor
• Female
• Gene Expression Regulation, Neoplastic
• Glycosylation
• Glycosyltransferases (metabolism)
• Hepatitis B virus (physiology)
• Human Umbilical Vein Endothelial Cells
• Humans
• Lewis X Antigen (metabolism)
• Liver (metabolism, pathology, virology)
• Liver Neoplasms (metabolism, pathology, virology)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Middle Aged
• Neoplasm Metastasis (pathology)
• Oligosaccharides (metabolism)
• Sialyl Lewis X Antigen
• Trans-Activators (metabolism)
• Viral Regulatory and Accessory Proteins