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 (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.