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ß₂-Microglobulin Promotes the Growth of Human Renal Cell Carcinoma through the Activation of the Protein Kinase A, Cyclic AMP–Responsive Element-Binding Protein, and Vascular Endothelial Growth Factor Axis

Authors' Affiliations: ¹ Molecular Urology and Therapeutics Program, Department of Urology and Winship Cancer Institute; Departments of ² Pathology and Laboratory Medicine and ³ Urology; and ⁴ Division of Endocrinology and Metabolism and Lipids, Emory University School of Medicine, Atlanta, Georgia; ⁵ Department of Oncological Science (Urology), Oita University Faculty of Medicine, Oita, Japan; and ⁶ Department of Pathology, The University of Alabama at Birmingham, Birmingham, Alabama

Requests for reprints: Leland W.K. Chung, Molecular Urology and Therapeutics Program, Department of Urology and Winship Cancer Institute, Emory University School of Medicine, Room B5101, 1365-B Clifton Road, Atlanta, GA 30322. Phone: 404-778-3672; Fax: 404-778-3675; E-mail: lwchung{at}emory.edu.

Purpose: ß₂-Microglobulin (ß2M), a soluble protein secreted by cancer and host inflammatory cells, has various biological functions, including antigen presentation. Because aberrant expression of ß2M has been reported in human renal cell carcinoma, we investigated the effects of ß2M overexpression on cancer cell growth and analyzed its molecular signaling pathway.

Experimental Design: We established clonal cell lines that overexpressed ß2M in human renal cell carcinoma (SN12C) cells and then examined cell growth in vitro and in vivo and studied the ß2M-mediated downstream cell signaling pathway.

Results: Our results showed that ß2M expression positively correlates with (a) in vitro growth on plastic dishes and as Matrigel colonies, (b) cell invasion and migration in Boyden chambers, and (c) vascular endothelial growth factor (VEGF) expression and secretion by cells. We found, in addition, that ß2M mediates its action through increased phosphorylation of cyclic AMP–responsive element-binding protein (CREB) via the protein kinase A-CREB axis, resulting in increased VEGF expression and secretion. In convergence with this signal axis, ß2M overexpression also activated both phosphatidylinositol 3-kinase/Akt and mitogen-activated protein kinase pathways. ß2M overexpression induced accelerated growth of SN12C in mouse subcutis and bone. Interrupting the ß2M signaling pathway using small interfering RNA led to apoptosis with increased activation of caspase-3 and caspase-9 and cleaved poly(ADP-ribose) polymerase.

Conclusions: Our results showed for the first time that the ß2M-protein kinase A-CREB-VEGF signaling axis plays a crucial role in support of renal cell carcinoma growth and progression and reveals a novel therapeutic target.

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