Identification and validation of SSBP1 as a key regulator involved in the development of multiple myeloma via p38MAPK signaling pathway

Abstract Background Multiple myeloma (MM) remains an incurable hematology malignancy. Identification of meaningful co-expressed gene clusters or representative biomarkers of MM may help to identify new pathological mechanisms and promote the development of new therapies. Methods Based on the expression profile and relevant clinical information of GSE6477 from the Gene Expression Omnibus (GEO) database, we performed weighted gene co-expression network analysis (WGCNA) to identify new candidate genes associated with MM development and prognosis. A series of bioinformatics analysis were used to identify the most significant hub candidate gene. In vitro and in vivo experiments further validated the function of hub gene. Results We conducted WGCNA with the expression profiles of GSE6477 and identified 7 meaningful co-expression modules. In the turquoise module of interest, through a series of bioinformatics analysis, SSBP1 was identified as a key regulator of MM development and related to poor prognosis. In our cohort, we also verified that MM patients with high SSBP1 expression had shorter overall survival than those with low SSBP1 expression. Furthermore, the disruption of SSBP1 expression by lentivirus mediated CRISPR/cas9 can significantly inhibit the proliferation of MM cells through inducing apoptosis and cell cycle arrest in G0/G1 phase. We also found that SSBP1 disruption significantly increased mitochondrial reactive oxygen species (mtROS) generation and the level of phosphorylated p38MAPK. Both Mito-TEMPO and SB203580 reversed the effects of SSBP1 disruption on MM cell apoptosis, the expressions of the p-p38MAPK and the apoptosis-related proteins. Mito-TEMPO also inhibited the accumulation of mtROS in MM cells caused by SSBP1 disruption, but SB203580 had no effect on mtROS. Furthermore, it was further verified that disruption of SSBP1 expression could inhibit the tumor growth via p38MAPK pathway in a human myeloma xenograft model. Conclusion SSBP1 promotes MM development and affects MM prognosis by regulating the p38MAPK pathway. There is evidence that SSBP1 could serve as a targetable oncogene and therapeutic biomarker for MM.