B7-H3 promotes multiple myeloma cell survival and proliferation by ROS-dependent activation of Src/STAT3 and c-Cbl-mediated degradation of SOCS3
B7-H3 promotes multiple myeloma cell survival and proliferation by ROS-dependent activation of Src/STAT3 and c-Cbl-mediated degradation of SOCS3
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B7-H3 通过 ROS 依赖性的 Src/STAT3 激活和 c-Cbl 介导的 SOCS3 降解促进多发性骨髓瘤细胞存活和增殖
DOI：
10.1038/s41375-018-0331-6
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发表时间：
2019-06-01
期刊：
影响因子：
11.4
通讯作者：
Ge, Qing
中科院分区：
文献类型：
--
作者：
Lin, Liang;Cao, Li;Ge, Qing
B7-H3（CD 276）在多种人类癌症中广泛过表达。它在肿瘤进展中起着至关重要的作用，并已被接受为抑制性B7家族检查点分子之一。为探讨B7-H3在多发性骨髓瘤中的作用及其机制，我们分析了B7-H3在骨髓瘤患者中的表达，并利用B7-H3的siRNA和过表达质粒研究了B7-H3在骨髓瘤细胞系中的作用及其下游信号分子。结果表明，骨髓瘤样品和细胞系中B7-H3的表面表达上调。B7-H3在骨髓瘤细胞中的低表达与更好的无进展生存期相关。B7-H3可促进骨髓瘤细胞存活、耐药性和肿瘤生长。B7-H3的这些功能作用的分子基础涉及通过氧化还原介导的氧化和Src的活化来活化JAK 2/STAT 3。我们进一步确定了STAT 3促进信号通路，通过该通路氧化剂介导的Src磷酸化导致E3泛素连接酶c-Cbl的二次激活。活化的c-Cbl随后引起SOCS 3的特异性蛋白酶体降解，SOCS 3是JAK 2/STAT 3的负调节因子。这些数据表明B7-H3在多发性骨髓瘤中的ROS/Src/c-Cbl通路的激活中的重要作用，该通路在STAT 3抑制剂的降解水平上整合了氧化还原调节和持续的STAT 3激活。
B7-H3 (CD276) is broadly overexpressed by multiple human cancers. It plays a vital role in tumor progression and has been accepted as one of the inhibitory B7 family checkpoint molecules. To identify the functions and underlying mechanisms of B7-H3 in multiple myeloma, we analyzed B7-H3 expression in myeloma patients and used siRNAs and overexpression plasmid of B7-H3 to investigate its roles and downstream signaling molecules in myeloma cell lines. The results showed that surface expression of B7-H3 was upregulated in myeloma samples and cell lines. Lower expression of B7-H3 in myeloma cells was associated with better progression-free survival. Myeloma cell survival, drug resistance, and tumor growth could be promoted by B7-H3. The molecular basis for these functional roles of B7-H3 involved the activation of JAK2/STAT3 via redox-mediated oxidation and activation of Src. We further identified a STAT3-promoting signaling pathway by which oxidant-mediated Src phosphorylation led to secondary activation of the E3 ubiquitin ligase c-Cbl. Activated c-Cbl subsequently caused specific proteasomal degradation of SOCS3, a negative regulator of JAK2/STAT3. These data indicate B7-H3’s important role in the activation of ROS/Src/c-Cbl pathway in multiple myeloma which integrates redox regulation and sustained STAT3 activation at the level of degradation of STAT3 suppressor.