Study of Rho GTPases in multiple myeloma: involvement of RhoU in disease initiation and progression
Year: 2017
Type: dissertation
Abstract: Multiple myeloma (MM) is a cancer of post-germinal center B cells characterized by a clonal proliferation of long-lived plasma cells inside the bone marrow. MM cells typically exhibit numerous structural and numerical chromosomal aberrations besides the presence of mutations in oncogenes and tumor-suppressor genes. Recently, a lot of attention has been drawn towards the tumor microenvironment. The interaction between malignant plasma cells and other cells inside the bone marrow is thought to be essential for the survival and expansion of MM. Indeed, stromal cells are able to produce growth factors that are important in sustaining the proliferation of MM cells, for example, interleukin-6 (IL-6). IL-6 triggers the signal downstream of its receptor IL-6R, leading to the activation of the JAK/STAT pathway. An important target of this pathway is STAT3 transcription factor. STAT3 binds to the promotor region of a set of genes that regulate cell growth, proliferation, survival, mitosis, adhesion/migration, and are extremely important in controlling the inflammatory response. RhoU is an atypical member of the Rho GTPase family that lies downstream of STAT3 activation. This GTPase is constitutively active whenever expressed and could mediate the effects of STAT3 in regulating the cytoskeleton dynamics. In MM nothing is known about this G protein. Here we demonstrate for the first time a role for RhoU in regulating the F-actin cytoskeleton of MM cells. RhoU was found heterogeneously expressed in MM patients’ cells, significantly modulated with disease progression, and expressed at higher levels in patients with bad prognosis mutations including t(4;14), del(13) and 1q gain. Different levels of RhoU mRNA correlate with a diverse gene expression profile in 557 genes. We have also found that it significantly clusters with cell cycle and DNA damage genes. Importantly, its expression positively correlates with cyclin D2 expression, and negatively correlates with the expression of cell cycle control and DNA damage response genes. In MM cell lines, RhoU is over-expressed in IL-6 dependent cell lines, while its expression is down-modulated in those that can proliferate independently of IL-6 stimulus. MM cell lines were able to up-regulate RhoU mRNA expression in response to IL-6 stimulus through the activation of STAT3. RhoU silencing led to an accumulation of actin stress fibers, an increase in adhesion and a blockade in migration. Lastly, immunomodulatory drugs (IMIDs) were recently found to control the activation of classical GTPases like Cdc42 and RhoA. In accordance with this, Lenalidomide positively regulated STAT3 activation leading to an increase in RhoU expression that resulted in a higher migration capability of MM cell lines, indicating that IMIDs can also alter the expression of atypical GTPases.
Author: Canovas Nunes, Sara Jose'
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W6987413292