Astrocyte elevated gene-1 is a proliferation promoter in breast cancer via suppressing transcriptional factor FOXO1

被引:115
作者
Li, J. [2 ,3 ]
Yang, L. [1 ,3 ]
Song, L. [4 ]
Xiong, H. [1 ,3 ]
Wang, L. [1 ,3 ]
Yan, X. [2 ,3 ]
Yuan, J. [2 ,3 ]
Wu, J. [1 ,3 ]
Li, M. [1 ,3 ]
机构
[1] Sun Yat Sen Univ, Zhongshan Sch Med, Dept Microbiol, Guangzhou 510080, Guangdong, Peoples R China
[2] Sun Yat Sen Univ, Zhongshan Sch Med, Dept Biochem, Guangzhou 510080, Guangdong, Peoples R China
[3] Sun Yat Sen Univ, Key Lab Trop Dis Control, Minist Educ, Guangzhou 510080, Guangdong, Peoples R China
[4] Sun Yat Sen Univ, Ctr Canc, State Key Lab Oncol So China, Guangzhou 510080, Guangdong, Peoples R China
关键词
AEG-1; FOXO1; p27(Kip1); p21(Cip1); Akt; breast cancer; TUMOR PROGRESSION; PROSTATE-CANCER; CELL-SURVIVAL; BCCIP-ALPHA; PROTEIN; METASTASIS; DEGRADATION; INTEGRATION; ACTIVATION; EXPRESSION;
D O I
10.1038/onc.2009.171
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
We have previously reported that astrocyte elevated gene-1 (AEG-1) was upregulated in human breast cancer. However, the biological function of AEG-1 in the development and progression of breast cancer remains to be clarified. In this study, we examined the effect of AEG-1 on cell proliferation and found that AEG-1 upregulation was significantly linked to increased Ki67 (P < 0.001). Ectopic expression of AEG-1 in MCF-7 and MDA-MB-435 breast cancer cells dramatically enhanced cell proliferation and their ability of anchorage-independent growth, whereas silencing endogenous AEG-1 with shRNAs inhibited cell proliferation and colony-forming ability of the cells on soft agar. Furthermore, these proliferative effects were significantly associated with decreases of p27(Kip1) and p21(Cip1) two key cell-cycle inhibitors. Moreover, we further demonstrated that AEG-1 could downregulate the transcriptional activity of FOXO1 by inducing its phosphorylation through the PI3K/Akt signaling pathway. These observations were further confirmed in clinical human primary breast cancer specimens, in which high-level expression of AEG-1 was inversely correlated with the expression of FOXO1. Taken together, our results provide the first demonstration of a novel mechanism by which AEG-1 induces proliferation of breast cancer cell, and our findings suggest that AEG-1 might play an important role in tumorigenesis of breast cancer. Oncogene (2009) 28, 3188-3196; doi: 10.1038/onc.2009.171; published online 27 July 2009
引用
收藏
页码:3188 / 3196
页数:9
相关论文
共 29 条
[21]   BCCIP Functions through p53 to regulate the expression of p21Waf1/Cip1 [J].
Meng, XB ;
Lu, HM ;
Shen, ZY .
CELL CYCLE, 2004, 3 (11) :1457-1462
[22]   Forkhead transcription factors are critical effectors of cell death and cell cycle arrest downstream of PTEN [J].
Nakamura, N ;
Ramaswamy, S ;
Vazquez, F ;
Signoretti, S ;
Loda, M ;
Sellers, WR .
MOLECULAR AND CELLULAR BIOLOGY, 2000, 20 (23) :8969-8982
[23]   Phosphorylation of the transcription factor forkhead family member FKHR by protein kinase B [J].
Rena, G ;
Guo, SD ;
Cichy, SC ;
Unterman, TG ;
Cohen, P .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1999, 274 (24) :17179-17183
[24]   PAX3-FOXO1 controls expression of the p57Kip2 cell-cycle regulator through degradation of EGR1 [J].
Roeb, Wendy ;
Boyer, Antonia ;
Cavenee, Webster K. ;
Arden, Karen C. .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2007, 104 (46) :18085-18090
[25]   Molecular basis of nuclear Factor-κB activation by astrocyte elevated gene-1 [J].
Sarkar, Devanand ;
Park, Eun Sook ;
Emdad, Luni ;
Lee, Seok-Geun ;
Su, Zao-zhong ;
Fisher, Paul B. .
CANCER RESEARCH, 2008, 68 (05) :1478-1484
[26]   Integration of Smad and Forkhead pathways in the control of neuroepithelial and glioblastoma cell proliferation [J].
Seoane, J ;
Le, HV ;
Shen, LJ ;
Anderson, SA ;
Massagué, J .
CELL, 2004, 117 (02) :211-223
[27]   Negative regulation of the forkhead transcription factor FKHR by Akt [J].
Tang, ED ;
Nuñez, G ;
Barr, FG ;
Guan, KL .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1999, 274 (24) :16741-16746
[28]  
TRENT RJ, 2006, MOL MED, P93
[29]   The regulation and function of the forkhead transcription factor, forkhead box O1, is dependent on the progesterone receptor in endometrial carcinoma [J].
Ward, Erin C. ;
Hoekstra, Anna V. ;
Blok, Leen J. ;
Hanifi-Moghaddam, P. ;
Lurain, John R. ;
Singh, Diljeet K. ;
Buttin, Barbara M. ;
Schink, Julian C. ;
Kim, J. Julie .
ENDOCRINOLOGY, 2008, 149 (04) :1942-1950