The type III transforming growth factor-? receptor inhibits proliferation, migration, and adhesion in human myeloma cells.

ABSTRACT: Transforming growth factor-? (TGF-?) plays an important role in regulating hematopoiesis, inhibiting proliferation while stimulating differentiation when appropriate. We previously demonstrated that the type III TGF-? receptor (T?RIII, or betaglycan) serves as a novel suppressor of cancer progression in epithelial tumors; however, its role in hematologic malignancies is unknown. Here we demonstrate that T?RIII protein expression is decreased or lost in the majority of human multiple myeloma specimens. Functionally, restoring T?RIII expression in myeloma cells significantly inhibited cell growth, proliferation, and motility, largely independent of its ligand presentation role. In a reciprocal fashion, shRNA-mediated silencing of endogenous T?RIII expression enhanced cell growth, proliferation, and motility. Although apoptosis was not affected, T?RIII inhibited proliferation through induction of the cyclin-dependent kinase inhibitors p21 and p27. T?RIII further regulated myeloma cell adhesion, increasing homotypic myeloma cell adhesion while decreasing myeloma heterotropic adhesion to bone marrow stromal cells. Mechanistically, live cell imaging of myeloma and stroma cell cocultures revealed that T?RIII-mediated inhibition of heterotropic adhesion was associated with decreased duration of myeloma/bone marrow stromal cell interaction. These results suggest that loss of T?RIII expression during multiple myeloma progression contributes to disease progression through its functional effects on increased cell growth, proliferation, motility, and adhesion.

SUBMITTER: Lambert KE 

PROVIDER: S-EPMC3084669 | biostudies-literature | 2011 May

REPOSITORIES: biostudies-literature