间质细胞
破骨细胞
兰克尔
XBP1型
细胞生物学
癌症研究
骨髓
细胞生长
生物
化学
免疫学
激活剂(遗传学)
受体
生物化学
核糖核酸
RNA剪接
基因
作者
Guoshuang Xu,Kai Liu,Judy M. Anderson,Kenneth D. Patrene,Suzanne Lentzsch,G. David Roodman,Hongjiao Ouyang
出处
期刊:Blood
[American Society of Hematology]
日期:2012-05-03
卷期号:119 (18): 4205-4214
被引量:61
标识
DOI:10.1182/blood-2011-05-353300
摘要
BM stromal cells (BMSCs) are key players in the microenvironmental support of multiple myeloma (MM) cell growth and bone destruction. A spliced form of the X-box-binding protein-1 (XBP1s), a major proximal effector of unfolded protein response signaling, is highly expressed in MM cells and plays an indispensable role in MM pathogenesis. In the present study, we found that XBP1s is induced in the BMSCs of the MM microenvironment. XBP1s overexpression in healthy human BMSCs enhanced gene and/or protein expression of VCAM-1, IL-6, and receptor activator of NF-κB ligand (RANKL), enhancing BMSC support of MM cell growth and osteoclast formation in vitro and in vivo. Conversely, deficiency of XBP1 in healthy donor BMSCs displayed a range of effects on BMSCs that were opposite to those cells with overexpression of XBP1s. Knock-down of XBP1 in MM patient BMSCs greatly compromised their increased VCAM-1 protein expression and IL-6 and RANKL secretion in response to TNFα and reversed their enhanced support of MM-cell growth and osteoclast formation. Our results demonstrate that XBP1s is a pathogenic factor underlying BMSC support of MM cell growth and osteoclast formation and therefore represents a therapeutic target for MM bone disease.
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