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Blood Cancer J. 2018 Feb 13;8(2):20. doi: 10.1038/s41408-018-0053-z.

The small GTPase RhoU lays downstream of JAK/STAT signaling and mediates cell migration in multiple myeloma.

Author information

1
Department of Medicine, Division of Hematology, University of Padova, Padova, Italy.
2
Laboratory of Normal and Malignant Hematopoiesis, Venetian Institute of Molecular Medicine, Padova, Italy.
3
Hematology Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy.
4
Department of Oncology and Hemato-Oncology, University of Milano, Milano, Italy.
5
Surgical Pathology and Cytopathology Unit, Department of Medicine - DIMED, University of Padova, Padova, Italy.
6
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
7
Department of Medicine, Division of Hematology, University of Padova, Padova, Italy. francesco.piazza@unipd.it.
8
Laboratory of Normal and Malignant Hematopoiesis, Venetian Institute of Molecular Medicine, Padova, Italy. francesco.piazza@unipd.it.

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.

PMID:
29440639
PMCID:
PMC5811530
DOI:
10.1038/s41408-018-0053-z
[Indexed for MEDLINE]
Free PMC Article

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