The costimulatory molecule B7-H4 promote tumor progression and cell proliferation through translocating into nucleus.
The costimulatory molecule B7-H4 promote tumor progression and cell proliferation through translocating into nucleus.
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共刺激分子B7-H4通过转入细胞核促进肿瘤进展和细胞增殖
DOI：
10.1038/onc.2012.600
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发表时间：
2013-11-14
期刊：
影响因子：
8
通讯作者：
Zhang, X.
中科院分区：
文献类型：
--
作者：
Zhang, L.;Wu, H.;Lu, D.;Li, G.;Sun, C.;Song, H.;Li, J.;Zhai, T.;Huang, Lv;Hou, C.;Wang, W.;Zhou, B.;Chen, S.;Lu, B.;Zhang, X.
关键词：
B7-H4是B7家族的成员，是一种跨膜蛋白，抑制T细胞免疫。然而，在多种肿瘤细胞中，B7-H4主要在细胞内区室中检测到，其机制和功能未知。在这项研究中，我们分析了B7-H4的表达和亚细胞分布在肾细胞癌（RCC）组织的免疫组化。B7-H4蛋白在肿瘤细胞膜、胞浆和/或细胞核中均有表达。B7-H4在细胞膜和细胞核的表达与肾癌的分期密切相关。此外，B7-H4的膜定位与肿瘤浸润性淋巴细胞（TIL）的强度呈负相关，而B7-H4的核表达与TIL状态的密度之间没有观察到相关性。我们进一步鉴定了B7-H4是一个含有功能性核定位序列（NLS）基序的细胞质-核穿梭蛋白。B7-H4 NLS基序的点突变阻断了来普霉素B诱导的B7-H4核积聚。与野生型B7-H4转染细胞相比，稳定表达B7-H4 NLS突变体的HEK 293细胞由于其增加的表面表达而通过增加其表面表达而表现出对T细胞增殖和细胞因子产生的更有效抑制。最重要的是，野生型B7-H4在HEK 293细胞中的过表达增强了肿瘤细胞的体外增殖和体内致瘤性，促进了G1/S期转变。野生型B7-H4对细胞周期的调控部分是通过上调Cyclin D1和Cyclin E的表达。B7-H4 NLS基序的突变破坏了B7-H4介导的细胞增殖和细胞周期调控。此外，B7-H4野生型赋予RCC细胞系包括Caki-1和ACHN化学抗性活性。我们的研究提供了一个新的见解B7-H4在其亚细胞定位的功能意义。
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.
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DOI：
10.1111/igc.0b013e3181ad0fa2
发表时间：
2009-12-01
影响因子：
4.8
作者：
Cheng, Lei;Jiang, Jie;Kong, Beihua
通讯作者：
Kong, Beihua
影响因子：
--
作者：
Tan DS;Cook A;Chew SL
通讯作者：
Chew SL
影响因子：
2.6
作者：
Fei, Fei;Yu, Yingzhe;Schmitt, Michael
通讯作者：
Schmitt, Michael
影响因子：
15.8
作者：
Azuma T;Zhu G;Xu H;Rietz AC;Drake CG;Matteson EL;Chen L
通讯作者：
Chen L
DOI：
10.1093/jnci/85.3.200
发表时间：
1993-02-03
期刊：
JOURNAL OF THE NATIONAL CANCER INSTITUTE
影响因子：
--
作者：
ALLRED, DC;CLARK, GM;MCGUIRE, WL
通讯作者：
MCGUIRE, WL