title: The costimulatory molecule B7-H4 promote tumor progression and cell proliferation through translocating into nucleus.
abstract: 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.
authors: 1] Jiangsu Stem Cell Key Laboratory, Institute of Medical Biotechnology, Medical College of Soochow University, Suzhou, China [2] Department of Pharmacy, College of Pharmaceutical Science, Soochow University, Suzhou, China.
authors: L
authors: L
authors: Zhang
authors: H
authors: H
authors: Wu
authors: D
authors: D
authors: Lu
authors: G
authors: G
authors: Li
authors: C
authors: C
authors: Sun
authors: H
authors: H
authors: Song
authors: J
authors: J
authors: Li
authors: T
authors: T
authors: Zhai
authors: Lv
authors: L
authors: Huang
authors: C
authors: C
authors: Hou
authors: W
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authors: Wang
authors: B
authors: B
authors: Zhou
authors: S
authors: S
authors: Chen
authors: B
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authors: Lu
authors: X
authors: X
authors: Zhang
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002292:Carcinoma, Renal Cell / Q000378:metabolism* / Q000473:pathology; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism*; D049109:Cell Proliferation; D018450:Disease Progression; D005260:Female; D006801:Humans; D007680:Kidney Neoplasms / Q000378:metabolism* / Q000473:pathology; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008875:Middle Aged; D008969:Molecular Sequence Data; D019913:Nuclear Localization Signals; D017354:Point Mutation; D021381:Protein Transport; D017386:Sequence Homology, Amino Acid; D013601:T-Lymphocytes / Q000276:immunology; D060907:V-Set Domain-Containing T-Cell Activation Inhibitor 1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D019913:Nuclear Localization Signals; D060907:V-Set Domain-Containing T-Cell Activation Inhibitor 1; C475826:VTCN1 protein, human