Downregulation of microRNA-15b by hepatitis B virus X enhances hepatocellular carcinoma proliferation via fucosyltransferase 2-induced Globo H expression

Abstract

Globo H, a cancer-associated carbohydrate antigen, is highly expressed in various types of cancers. However, the role of Globo H in hepatocellular carcinoma (HCC) remains elusive. In our study, we performed glycan microarray analysis of 134 human serum samples to explore anti-Globo H antibody changes and found that Globo H is upregulated in hepatitis B virus (HBV)-positive HCC. Similarly, immunohistochemistry showed that Globo H expression was higher in tumors compared to normal tissues. In addition, fucosyltransferase 2 (FUT2), the main synthetic enzyme of Globo H, was also increased in HCC cells overexpressing HBV X protein (HBX). HBX plays an important role in promoting cell proliferation and may be related to increased levels of FUT2 and Globo H. Furthermore, using microRNA profiling, we observed that microRNA-15b (miR-15b) was downregulated in patients with HCC and confirmed association of FUT2 expression with expression of its product, Globo H. Therefore, our results suggest that HBX suppressed the expression of miR-15b, which directly targeted FUT2 and then increased levels of Globo H to enhance HCC cell proliferation. Additionally, proliferation of HBX-overexpressing HCC cells was significantly inhibited by treatment with Globo H antibody in vitro. In xenograft animal experiments, we found that overexpression of miR-15b effectively suppressed tumor growth. The newly identified HBX/miR-15b/FUT2/Globo H axis suggests one possible molecular mechanism of HCC cell proliferation and represents a new potential therapeutic target for HCC treatment. What's new? Elevated tumor expression of the cancer-associated carbohydrate antigen Globo H has raised questions about its role and underlying mechanisms in tumorigenesis. In this study, Globo H and one of its synthetic enzymes, fucosyltransferase 2 (FUT2), were found to be upregulated in hepatitis B virus (HBV)-positive hepatocellular carcinoma (HCC). Increased FUT2 and Globo H were further associated with overexpression of HBV X protein (HBX), which may suppress microRNA-15b and thereby promote FUT2 and Globo H expression. The HBX/miR-15b/FUT2/Globo H axis may be an important molecular mechanism guiding cell proliferation in HCC and a potential target for novel HCC therapies. © 2013 UICC.