Abstract
Multiple myeloma is a post-germinal center B-cell neoplasm, characterized by the proliferation of malignant bone marrow plasma cells, whose survival and proliferation is sustained by growth factors and cytokines present in the bone marrow microenvironment. Among them, IL-6 triggers the signal downstream of its receptor, leading to the activation of the JAK/STAT pathway. The atypical GTPase RhoU lays downstream of STAT3 transcription factor and could be responsible for mediating its effects on cytoskeleton dynamics. Here we demonstrate that RHOU is heterogeneously expressed in primary multiple myeloma cells and significantly modulated with disease progression. At the mRNA level, RHOU expression in myeloma patients correlated with the expression of STAT3 and its targets MIR21 and SOCS3. Also, IL-6 stimulation of human myeloma cell lines up-regulated RHOU through STAT3 activation. On the other hand, RhoU silencing led to a decrease in cell migration with the accumulation of actin stress fibers, together with a decrease in cyclin D2 expression and in cell cycle progression. Furthermore, we found that even though lenalidomide positively regulated RhoU expression leading to higher cell migration rates, it actually led to cell cycle arrest probably through a p21 dependent mechanism. Lenalidomide treatment in combination with RhoU silencing determined a loss of cytoskeletal organization inhibiting cell migration, and a further increase in the percentage of cells in a resting phase. These results unravel a role for RhoU not only in regulating the migratory features of malignant plasma cells, but also in controlling cell cycle progression.
Highlights
Multiple myeloma (MM) is a post-Germinal Center cancer characterized by a multifocal proliferation of clonal, long-lived plasma cells (PCs) within the bone marrow (BM)[1]
Rho guanosine triphosphatases (GTPases) display altered expression in MM PCs We have assessed the expression of the Rho GTPase family members in PCs from BM biopsies of MM patients and in normal BM PCs from healthy donors, using the gene expression profiling (GEP) of 129 MM patient samples at diagnosis and four healthy controls included in the proprietary GEO data set GSE66293
Opposite to what was seen in other tumors where there is an over-expression of some of the members of this family[7], we have found that more than 50% of Rho GTPases are down-modulated in MM PCs when compared to healthy PCs
Summary
Multiple myeloma (MM) is a post-Germinal Center cancer characterized by a multifocal proliferation of clonal, long-lived plasma cells (PCs) within the bone marrow (BM)[1]. This multistep malignancy is preceded by an ageprogressive premalignant condition called monoclonal gammopathy of undetermined significance (MGUS)[1,2,3]. Rho GTPases are potent regulators of cytoskeleton dynamics and of the actin filament system, thereby affecting the morphologic and migratory properties of cells[8]. Due to their important roles in controlling these cellular processes, deregulated Rho GTPases could be at the basis of many tumorigenic events
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