The type III transforming growth factor-β receptor inhibits proliferation, migration, and adhesion in human myeloma cells.
The type III transforming growth factor-β receptor inhibits proliferation, migration, and adhesion in human myeloma cells.
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DOI：
10.1091/mbc.e10-11-0877
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发表时间：
2011-05
影响因子：
3.3
通讯作者：
Blobe GC
中科院分区：
文献类型：
--
作者：
Lambert KE;Huang H;Mythreye K;Blobe GC
在这里，我们证明了转化生长因子-β (TGF-β)超家族共受体，III型TGF-β受体，通过抑制多发性骨髓瘤细胞增殖，异源性细胞-细胞粘附和迁移，以一种很大程度上独立于其配体呈递作用的方式，抑制多发性骨髓瘤疾病的进展。转化生长因子-β (TGF-β)在调节造血、抑制增殖、适当刺激分化中发挥重要作用。我们之前已经证明III型TGF-β受体（t -β riii，或β多糖）在上皮性肿瘤中作为一种新的癌症进展抑制因子；然而，它在血液恶性肿瘤中的作用尚不清楚。在这里，我们证明TβRIII蛋白表达在大多数人类多发性骨髓瘤标本中减少或丢失。功能上，恢复TβRIII在骨髓瘤细胞中的表达可显著抑制细胞生长、增殖和运动，这在很大程度上独立于其配体呈递作用。shrna介导的内源性TβRIII表达的沉默以相互作用的方式增强了细胞的生长、增殖和运动性。虽然细胞凋亡不受影响，但TβRIII通过诱导细胞周期蛋白依赖性激酶抑制剂p21和p27抑制细胞增殖。TβRIII进一步调节骨髓瘤细胞粘附，增加同型骨髓瘤细胞粘附，降低骨髓瘤对骨髓基质细胞的异向粘附。从机制上讲，骨髓瘤和基质细胞共培养的活细胞成像显示，t β riii介导的异异性粘附抑制与骨髓瘤/骨髓基质细胞相互作用持续时间的缩短有关。这些结果表明，在多发性骨髓瘤进展过程中，TβRIII表达的缺失通过其对细胞生长、增殖、运动性和粘附性增加的功能影响，促进了疾病的进展。
Here we demonstrate that the transforming growth factor-β (TGF-β) superfamily coreceptor, the type III TGF-β receptor, functions to suppress multiple myeloma disease progression through inhibition of multiple myeloma cell proliferation, heterotropic cell–cell adhesion, and migration, in a manner largely independent of its ligand presentation role. Transforming growth factor-β (TGF-β) plays an important role in regulating hematopoiesis, inhibiting proliferation while stimulating differentiation when appropriate. We previously demonstrated that the type III TGF-β receptor (TβRIII, 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 TβRIII protein expression is decreased or lost in the majority of human multiple myeloma specimens. Functionally, restoring TβRIII 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 TβRIII expression enhanced cell growth, proliferation, and motility. Although apoptosis was not affected, TβRIII inhibited proliferation through induction of the cyclin-dependent kinase inhibitors p21 and p27. TβRIII 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 TβRIII-mediated inhibition of heterotropic adhesion was associated with decreased duration of myeloma/bone marrow stromal cell interaction. These results suggest that loss of TβRIII expression during multiple myeloma progression contributes to disease progression through its functional effects on increased cell growth, proliferation, motility, and adhesion.