RBMS1 enhances PDPK1 mRNA stability to promote multiple myeloma malignancy and M2 macrophage polarization.

Abstract

Multiple myeloma (MM) is an incurable malignancy of bone marrow plasma cells. Tumor-associated macrophages (TAMs) are the predominant immune cells in the bone marrow microenvironment of MM and play important roles in MM. The effect of RBMS1 on MM has not yet been reported. This study aimed to investigate the function of RBMS1 in MM. Through the analysis of GSE datasets, we identified RBMS1 as a potential pathogenic factor in MM. We further investigated the effects of RBMS1 on the proliferation of MM cells (RPMI8226, MM1S, and KMS11) and its regulation of TAM polarization. An animal model was established by intravenous injection of MM cells into 6-week-old male NOG mice. Bioinformatics analyses, including RRA, WGCNA, and GO enrichment, screened for potential pathogenic genes in MM. Kaplan - Meier survival identified RBMS1 as a prognostic marker associated with poor outcomes in MM. Functionally, RBMS1 enhanced MM cell proliferation, colony formation, and cell cycle. Moreover, RBMS1 promoted M2 polarization of macrophages, as evidenced by elevated levels of M2 macrophage markers, as well as increased CCL2 secretion. Consistently, in a male NOD/Shi-scid IL-2 Rγ^null mouse xenograft model, RBMS1 accelerated tumor growth and enhanced M2 macrophage polarization. Mechanistically, RBMS1 bound to the 3'UTR of PDPK1 mRNA, enhancing its stability and activating the pro-tumorigenic β-catenin signaling pathway, thereby promoting tumor growth. Collectively, this study is the first to report the functional role of RBMS1 in MM and highlights the importance of the RBMS1/PDPK1/β-catenin signaling axis in MM, providing new insights for basic research on MM.