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B7-H4, a member of B7 family, is a transmembrane protein and inhibits T-cells immunity. However, in a variety of tumor cells, B7-H4 was detected predominantly in intracellular compartments with unknown mechanism and functions. In this study, we analyzed B7-H4 expression and subcellular distribution by immunohistochemistry in renal cell carcinoma (RCC) tissues. B7-H4 protein was detected on the membrane, in the cytosol and/or in the nucleus in tumor tissues. The membrane and nuclear expression of B7-H4 was significantly correlated with the tumor stages of RCC. Moreover, the membrane localization of B7-H4 was inversely correlated with the intensity of tumor infiltrates lymphocyte (TILs), whereas no association was observed between nuclear expression of B7-H4 and the density of TILs status. We further identified that B7-H4 is a cytoplasmic-nuclear shuttling protein containing a functional nuclear localization sequence (NLS) motif. A point mutation of B7-H4 NLS motif blocked the leptomycin B -induced nuclear accumulation of B7-H4. HEK293 cells stably expressing B7-H4 NLS mutant exhibited more potent inhibition in T-cell proliferation and cytokine production through increasing its surface expression compared with wild-type B7-H4 transfected cells owing to their increased surface expression. Most importantly, overexpression of wild-type B7-H4 in HEK293 cells enhanced tumor cell proliferation in vitro and tumorigenicity in vivo, promoted G1/S phase transition. The regulation of cell cycle by wild-type B7-H4 was partialy due to upregulation of Cyclin D 1 and Cyclin E. A mutation of B7-H4 NLS motif abolished the B7-H4-mediated cell proliferation and cell cycle regulation. Furthermore, B7-H4 wild-type confers chemoresistance activity to RCC cell lines including Caki-1 and ACHN. Our study provides a new insight into the functional implication of B7-H4 in its subcellular localization.

The costimulatory molecule B7-H4 promote tumor progression and cell proliferation through translocating into nucleus