TGF-β-induced apoptosis of B-cell lymphoma Ramos cells through reduction of MS4A1/CD20

被引：32

作者：

Kawabata, K. C. ^{[1
]}

Ehata, S. ^{[1
]}

Komuro, A. ^{[1
]}

Takeuchi, K. ^{[2
]}

Miyazono, K. ^{[1
]}

机构：

[1] Univ Tokyo, Dept Mol Pathol, Grad Sch Med, Tokyo 1130033, Japan

[2] Japanese Fdn Canc Res, Inst Canc, Pathol Project Mol Targets, Tokyo 170, Japan

来源：

ONCOGENE | 2013年 / 32卷 / 16期

基金：

日本学术振兴会;

关键词：

B-cell lymphoma; apoptosis; TGF-beta; MS4A1/CD20; rituximab; BURKITT-LYMPHOMA; RITUXIMAB; INVOLVEMENT; RESISTANCE; EXPRESSION; ANTIBODIES; THERAPY; PROTEIN; LINES; NHL;

D O I：

10.1038/onc.2012.219

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Transforming growth factor-beta (TGF-beta) exhibits growth inhibitory effects on various types of tumor cells, including B-cell lymphoma cells. In the present study, the role of TGF-beta in the survival of Epstein-Barr virus-negative B-cell lymphoma Ramos cells was investigated. As TGF-beta-induced apoptosis of Ramos cells in vitro and in vivo, we attempted to identify novel target gene(s) responsible for their survival. Oligonucleotide microarray analysis and chromatin immunoprecipitation revealed that Smad proteins directly regulated the transcription of membrane-spanning 4-domains, subfamily A, member 1 (MS4A1), also known as CD20, in Ramos cells upon TGF-beta stimulation. In addition, immunohistochemical analysis using clinical samples from B-cell lymphoma patients showed an inverse correlation between the expression of MS4A1/CD20 and phosphorylation of Smad3. Although knockdown of MS4A1/CD20 in Ramos cells resulted in an increase of apoptotic cells, Ramos cells stably expressing MS4A1/CD20 were resistant to TGF-beta-induced apoptosis. This suggests that MS4A1/CD20 is responsible for TGF-beta-induced apoptosis of B-cell lymphoma cells. Moreover, downregulation of MS4A1/CD20 by TGF-beta attenuated the effects of the monoclonal anti-MS4A1/CD20 antibody, rituximab, on Ramos cells. Our findings suggest that the sensitivity of B-cell lymphoma cells to rituximab may be affected by TGF-beta signaling. Oncogene (2013) 32, 2096-2106; doi:10.1038/onc.2012.219; published online 4 June 2012

引用

页码：2096 / 2106

页数：11

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