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The effect of marrow stromal cells on TRAF6 expression levels in myeloma cells.

ABSTRACT: Tumor necrosis factor receptor-associated factor 6 (TRAF6) is an important E3 ubiquitin ligase, which is key to immunity. TRAF6 has been implicated in the invasive growth and metastasis of various types of cancer, including squamous cell carcinoma, gastric cancer, myelodysplastic syndromes and acute myeloid leukemia. In the present study, associations between multiple myeloma (MM) and TRAF6, its downstream component nuclear factor-κB (NF-κB) and bone marrow stromal cells (MSC) were investigated. The TRAF6 protein expression levels of 18 patients were positively correlated with the protein levels of β-2 microglobulin (r2=0.3472; P=0.01) and negatively correlated with albumin protein levels (r2=0.5494; P=0.0004). In vitro expression of the TRAF6 protein, phosphorylated transcription factor p65 and phosphorylated p100 in myeloma cell lines was induced by MSCs from patients with MM. In addition, the in vitro expression of TRAF6 was associated with an enhanced proliferation rate of myeloma cells, which was blocked by silencing TRAF6 using small interfering RNA. Due to the association between the TRAF6-NF-κB signaling pathway in myeloma cells and MSCs, this signaling pathway may be a useful prognostic and therapeutic target in myeloma.

SUBMITTER: Huang H

PROVIDER: S-EPMC5529903 | biostudies-other | 2017 Aug

REPOSITORIES: biostudies-other

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Project description:INTRODUCTION: Recent studies indicate that bone marrow stromal cells (BMSCs) derived from patients with multiple myeloma (MM) differ from those of healthy donors in their expression of extracellular matrix compounds and in cytokine production. It is not known whether these abnormalities are primary or are acquired by BMSCs on contact with MM cells. MATERIALS AND METHODS: Interleukin (IL)-6, IL-11, IL-10, and tumor necrosis factor (TNF)-alpha production by CD166+ mesenchymal BMSCs and the CD38+/CD138+ RPMI8226 myeloma cell line cultivated in vitro in monocultures or co-cultivated under cell-to-cell contact or non-contact conditions in the presence of a tissue culture insert were measured. Intracellular cytokines were measured by flow cytometry analysis as the percentage of cytokine-producing cells or by mean fluorescence intensity as the level of cytokine expression in cells. Additionally, ELISA was used to measure IL-6, soluble IL-6 receptor (sIL-6R), IL-11, IL-10, TNF-alpha, B-cell-activating factor of the TNF family (BAFF), hepatocyte growth factor (HGF), and osteopontin (OPN) production in the supernatants of the cultures and co-cultures. RESULTS: A higher ability of the BMSCs of MM patients than in controls was detected to produce IL-6, IL-10, TNF-alpha, OPN, and especially HGF and BAFF in response to the RPMI8226 cells. Moreover, the BMSCs of the MM patients significantly enhanced the production of sIL-6R by the RPMI8226 cells. DISCUSSION: Cytokines over-expressed by BMSCs of MM patients can function as growth factors for myeloma cells (IL-6, IL-10, HGF), migration stimulatory factors for tumor plasma cells (TNF-alpha, HGF), adhesion stimulatory factors (HGF, BAFF and OPN), stimulators of osteoclastogenesis (IL-6, TNF-alpha), and angiogenic factors (TNF-alpha). The results of this experiment strongly suggest that the BMSCs from MM patients differed in spontaneous and myeloma cell-induced production of cytokines, especially of HGF and BAFF, and these abnormalities were both primary and acquired by the BMSCs on contact with the MM cells. This in turn suggests the presence of an undefined, autocrine stimulation pathway resulting in a prolonged production of cytokines even in long-term cultures in vitro and in vivo. These abnormalities might provide optimal conditions for the proliferation and differentiation of residual tumor cells or their precursors in the affected bone marrow.

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The effect of marrow stromal cells on TRAF6 expression levels in myeloma cells.

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