Abstract
Multiple myeloma (MM) is an incurable cancer characterized by clonal expansion of malignant plasma cells in the bone marrow and their egress into peripheral blood. The mechanisms of myeloma cells migration/invasion have remained unclear. Herein, we found SH3GL3 was highly expressed in the CD138-negative (CD138−) myeloma cells. The migration/invasion capability of CD138− cells was significantly higher than that in the CD138-positive (CD138+) cells. Silencing SH3GL3 using shRNA reduced myeloma cells migration/invasion. Conversely, overexpression of SH3GL3 increased myeloma cells migration/invasion. Moreover, SH3GL3 is also associated with the stemness and chemo-resistance of CD138− myeloma cells. Elevated expression of stem cell and multi-drug resistant markers were seen in the myeloma cells with overexpressed SH3GL3; while knocking-down SH3GL3 reduced the expression of these markers. A marked increase in p-PI3K and p-FAK was observed in the cells with overexpressed SH3GL3. To test if FAK/PI3K signaling pathway was involved in the SH3GL3-mediated myeloma cells migration, the cells transfected w/wo SH3GL3 cDNA were treated with FAK inhibitor 14 and PI3K inhibitor LY294002. Inhibition of FAK and PI3K attenuated SH3GL3-mediated migration /invasion. Our findings indicate that SH3GL3 plays an important role in myeloma cell migration/invasion, stemness and chemo-resistance. The SH3GL3-mediated myeloma cell migration/invasion is mediated by FAK/PI3K signaling pathway.
Highlights
Multiple myeloma (MM) is the second most prevalent hematologic malignancy
Our findings indicate that SH3-domain GRB2-like 3 (SH3GL3) plays an important role in myeloma cell migration/invasion, stemness and chemo-resistance
Inhibition of focal adhesion kinase p125 (FAK) or Phosphatidylinositol-3 kinases (PI3Ks) attenuated SH3GL3-enhanced cell migration. These findings reveal, at the first time, that the SH3GL3-induced cell migration/ invasion is mediated by FAK/PI3K signaling pathway
Summary
Multiple myeloma (MM) is the second most prevalent hematologic malignancy It is characterized by the clonal expansion of malignant plasma cells [1] and remains largely incurable in spite of the advent of several therapeutic strategies [2]. A number of studies have suggested that a small fraction of cells responsible for disease relapse is capable of clonogenic growth and resistant to the therapeutic drugs [4, 5]. This subpopulation is termed as multiple myeloma stem cells [4, 5]. Matsui et al [4] found that CD138− CD19+ CD27+ cells isolated from the peripheral blood of MM patients were able to engraft in the NOD/ SCID mice and generate mature CD138+ myeloma cells
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