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学科主题: 临床医学
题名:
TGF-beta Regulates DNA Methyltransferase Expression in Prostate Cancer, Correlates with Aggressive Capabilities, and Predicts Disease Recurrence
作者: Zhang, Qiang1,2; Chen, Lin1; Helfand, Brian T.1; Jang, Thomas L.3; Sharma, Vidit1; Kozlowski, James1,2; Kuzel, Timothy Michael4; Zhu, Lihua J.5; Yang, Ximing J.2,6; Javonovic, Borko2,7; Guo, Yinglu8; Lonning, Scott9; Harper, Jay9; Teicher, Beverly A.9; Brendler, Charles10; Yu, Nengwang1; Catalona, William J.1,2; Lee, Chung1,2
刊名: PLOS ONE
发表日期: 2011-09-30
DOI: 10.1371/journal.pone.0025168
卷: 6, 期:9
收录类别: SCI
文章类型: Article
WOS标题词: Science & Technology
类目[WOS]: Multidisciplinary Sciences
研究领域[WOS]: Science & Technology - Other Topics
关键词[WOS]: CD8(+) T-CELLS ; GROWTH-FACTOR ; PROTEIN EXPRESSION ; METHYLATION ; TUMOR ; INHIBITION ; PATHWAY ; PROLIFERATION ; MECHANISM ; ERK
英文摘要:

Background: DNA methyltransferase (DNMT) is one of the major factors mediating the methylation of cancer related genes such as TGF-beta receptors (T beta Rs). This in turn may result in a loss of sensitivity to physiologic levels of TGF-beta in aggressive prostate cancer (CaP). The specific mechanisms of DNMT′s role in CaP remain undetermined. In this study, we describe the mechanism of TGF-beta-mediated DNMT in CaP and its association with clinical outcomes following radical prostatectomy.

Methodology/Principal Findings: We used human CaP cell lines with varying degrees of invasive capability to describe how TGF-beta mediates the expression of DNMT in CaP, and its effects on methylation status of TGF-beta receptors and the invasive capability of CaP in vitro and in vivo. Furthermore, we determined the association between DNMT expression and clinical outcome after radical prostatectomy. We found that more aggressive CaP cells had significantly higher TGF-b levels, increased expression of DNMT, but reduced T beta Rs when compared to benign prostate cells and less aggressive prostate cancer cells. Blockade of TGF-beta signaling or ERK activation (p-ERK) was associated with a dramatic decrease in the expression of DNMT, which results in a coincident increase in the expression of T beta Rs. Blockade of either TGF-beta signaling or DNMT dramatically decreased the invasive capabilities of CaP. Inhibition of TGF-beta in an TRAMP-C2 CaP model in C57BL/6 mice using 1D11 was associated with downregulation of DNMTs and p-ERK and impairment in tumor growth. Finally, independent of Gleason grade, increased DNMT1 expression was associated with biochemical recurrence following surgical treatment for prostate cancer.

Conclusions and Significance: Our findings demonstrate that CaP derived TGF-beta may induce the expression of DNMTs in CaP which is associated with methylation of its receptors and the aggressive potential of CaP. In addition, DNMTs is an independent predictor for disease recurrence after prostatectomy, and may have clinical implications for CaP prognostication and therapy.

语种: 英语
所属项目编号: 2 P50CA090386-06A2 ; U01 CA152738 ; 08-22 ; W81XWH-09-1-0311 ; ACS-IRG 93-037-12
项目资助者: National Cancer Institute, NIH ; National Cancer Institute ; American Cancer Society, Illinois ; Department of Defense ; Portes Center/Institute of Medicine of Chicago ; American Cancer Society ; Genzyme Corporation ; Northshore University Healthsystem
WOS记录号: WOS:000295941300021
Citation statistics:
内容类型: 期刊论文
URI标识: http://ir.bjmu.edu.cn/handle/400002259/56419
Appears in Collections:北京大学第一临床医学院_泌尿外科_期刊论文

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作者单位: 1.Genzyme Corp, Framingham, MA 01701 USA
2.Northshore Univ Heathsyst, Dept Surg, Evanston, IL USA
3.Northwestern Univ, Feinberg Sch Med, Dept Urol, Chicago, IL 60611 USA
4.Northwestern Univ, Robert H Lurie Comprehens Canc Ctr, Chicago, IL 60611 USA
5.Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Canc Inst New Jersey, New Brunswick, NJ USA
6.Northwestern Univ, Feinberg Sch Med, Dept Med, Chicago, IL 60611 USA
7.Univ Massachusetts, Sch Med, Program Gene Funct & Express, Boston, MA 02125 USA
8.Northwestern Univ, Feinberg Sch Med, Dept Pathol, Chicago, IL 60611 USA
9.Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, Chicago, IL 60611 USA
10.Peking Univ, Inst Urol, Dept Urol, Hosp 1, Beijing 100871, Peoples R China

Recommended Citation:
Zhang, Qiang,Chen, Lin,Helfand, Brian T.,et al. TGF-beta Regulates DNA Methyltransferase Expression in Prostate Cancer, Correlates with Aggressive Capabilities, and Predicts Disease Recurrence[J]. PLOS ONE,2011,6(9).
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