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Knockdown of Mgat5 Inhibits Breast Cancer Cell Growth with Activation of CD4⁺ T Cells and Macrophages¹

Dongqing Li^*, Yanmei Li, Xianglei Wu^*, Qiao Li, Jing Yu^*, Jie Gen^* and Xiao-Lian Zhang^2,*

^* State Key Laboratory of Virology, Department of Immunology, Hubei Province Key Laboratory of Allergy and Immunology, Wuhan University School of Medicine, Wuhan, China; Department of Chemistry, Tsinghua University, Beijing, China; and University of Michigan Medical Center, Ann Arbor, MI 48109

N-acetylglucosaminyltransferase V (Mgat5 or GnT-V) is an enzyme that catalyzes β1–6 branching of N-acetylglucosamine on asparagine (N)-linked oligosaccharides (N-glycan) of cell proteins. The levels of Mgat5 glycan products commonly are increased in malignancies. Although Mgat5 is known to be important in tumor metastases, the effects of Mgat5 on host immune responses are not fully defined. In this study, a Mgat5 specific-short hairpin RNA (shRNA) vector was transfected into murine mammary adenocarcinoma MA782 cells to assess the effects of Mgat5 on tumor cell growth, T cells, and macrophages following inoculation of mice with shRNA-transfected cancer cells. The results showed that blocking expression of Mgat5-modified glycans in MA782 cells significantly suppressed tumor progression both in vivo and in vitro, strongly stimulated Th1 cytokine production, and enhanced opsonophagocytic capability of macrophages in vivo. Importantly, reduction of complex N-glycans on MA782 tumor cells by Mgat5-shRNA resulted in significantly increased proliferation and CD45 surface expression of CD4⁺ T cells. Our data suggest Mgat5-shRNA could serve as a useful tool to treat breast cancer as well as a powerful tool for the functional investigation of N-glycans and glycoprotein synthesis. Our data suggest that knockdown of Mgat5 inhibits breast cancer cells’ growth with activation of CD4⁺ T cells and macrophages.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants to X.-L.Z. from the National Natural Science Foundation of China (30370310, 20532020, and 30670098), 973 Program 2006CB504300, the Ministry of Education Scientific Research Foundation for Outstanding New Century Scholars and Outstanding Young Teachers (NCET-04- 0685), Hubei Province Science Technology Department (2006ABD007 and 2005AA304B04), Hubei Ministry of Public Health (JX1B074), and the Open Research Fund Program of the State Key Laboratory of Virology of China (III-2005007).

² Address correspondence and reprint requests to Dr. Xiao-Lian Zhang, Department of Immunology, Wuhan University School of Medicine, Donghu Road 165, Wuhan 430071, China. E-mail address: ZhangXL65{at}whu.edu.cn

³ Abbreviations used in this paper: GlcNAc, N-acetylglucosamine; shRNA, short hairpin RNA; Mgat5 or GnT-V, N-acetylglucosaminyltransferase V; L-PHA, leukoagglutinin; RFP, red fluorescent protein; IP, index of phagocytosis; MFI, mean fluorescence intensity.