p53 regulates epithelial-mesenchymal transition through microRNAs targeting ZEB1 and ZEB2

被引：505

作者：

Kim, Taewan ^{[1
,2
]}

Veronese, Angelo ^{[1
]}

Pichiorri, Flavia ^{[1
]}

Lee, Tae Jin ^{[1
]}

Jeon, Young-Jun ^{[1
,2
]}

Volinia, Stefano ^{[1
]}

Pineau, Pascal ^{[3
]}

Marchio, Agnes ^{[3
]}

Palatini, Jeff ^{[1
]}

Suh, Sung-Suk ^{[1
]}

Alder, Hansjuerg ^{[1
]}

Liu, Chang-Gong ^{[1
]}

Dejean, Anne ^{[3
]}

Croce, Carlo M. ^{[1
]}

机构：

[1] Ohio State Univ, Dept Mol Virol Immunol & Med Genet, Ctr Comprehens Canc, Columbus, OH 43210 USA

[2] Ohio State Univ, Mol Cellular & Dev Biol Program, Columbus, OH 43210 USA

[3] Inst Pasteur, INSERM, U579, Nucl Org & Oncogenesis Unit, F-75724 Paris 15, France

来源：

JOURNAL OF EXPERIMENTAL MEDICINE | 2011年 / 208卷 / 05期

关键词：

MIR-200; FAMILY; HEPATOCELLULAR-CARCINOMA; P53-INDUCIBLE MICRORNAS; CANCER-CELLS; IN-VIVO; METASTASIS; ACTIVATION; EXPRESSION; REPRESSORS; APOPTOSIS;

D O I：

10.1084/jem.20110235

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

071005 [微生物学]; 100108 [医学免疫学];

摘要：

p53 suppresses tumor progression and metastasis. Epithelial-mesenchymal transition (EMT) is a key process in tumor progression and metastasis. The transcription factors ZEB1 and ZEB2 promote EMT. Here, we show that p53 suppresses EMT by repressing expression of ZEB1 and ZEB2. By profiling 92 primary hepatocellular carcinomas (HCCs) and 9 HCC cell lines, we found that p53 up-regulates microRNAs (miRNAs), including miR-200 and miR-192 family members. The miR-200 family members transactivated by p53 then repress ZEB1/2 expression. p53-regulated miR-192 family members also repress ZEB2 expression. Inhibition or overexpression of the miRNAs affects p53-regulated EMT by altering ZEB1 and ZEB2 expression. Our findings indicate that p53 can regulate EMT, and that p53-regulated miRNAs are critical mediators of p53-regulated EMT.

引用

收藏

页码：875 / 883

页数：9

相关论文

共 29 条

[1]

MicroRNAs: Genomics, biogenesis, mechanism, and function (Reprinted from Cell, vol 116, pg 281-297, 2004) [J].

Bartel, David P. .

CELL, 2007, 131 (04) :11-29

[2]

A double-negative feedback loop between ZEB1-SIP1 and the microRNA-200 family regulates epithelial-mesenchymal transition [J].

Bracken, Cameron P. ;

Gregory, Philip A. ;

Kolesnikoff, Natasha ;

Bert, Andrew G. ;

Wang, Jun ;

Shannon, M. Frances ;

Goodall, Gregory J. .

CANCER RESEARCH, 2008, 68 (19) :7846-7854

[3]

p53-Responsive MicroRNAs 192 and 215 Are Capable of Inducing Cell Cycle Arrest [J].

Braun, Christian J. ;

Zhang, Xin ;

Savelyeva, Irina ;

Wolff, Sonja ;

Moll, Ute M. ;

Schepeler, Troels ;

Orntoft, Torben F. ;

Andersen, Claus L. ;

Dobbelstein, Matthias .

CANCER RESEARCH, 2008, 68 (24) :10094-10104

[4]

A reciprocal repression between ZEB1 and members of the miR-200 family promotes EMT and invasion in cancer cells [J].

Burk, Ulrike ;

Schubert, Joerg ;

Wellner, Ulrich ;

Schmalhofer, Otto ;

Vincan, Elizabeth ;

Spaderna, Simone ;

Brabletz, Thomas .

EMBO REPORTS, 2008, 9 (06) :582-589

[5]

MicroRNA signatures in human cancers [J].

Calin, George A. ;

Croce, Carlo M. .

NATURE REVIEWS CANCER, 2006, 6 (11) :857-866

[6]

Matlnspector and beyond: promoter analysis based on transcription factor binding sites [J].

Cartharius, K ;

Frech, K ;

Grote, K ;

Klocke, B ;

Haltmeier, M ;

Klingenhoff, A ;

Frisch, M ;

Bayerlein, M ;

Werner, T .

BIOINFORMATICS, 2005, 21 (13) :2933-2942

[7]

p53 regulates epithelial-mesenchymal transition and stem cell properties through modulating miRNAs [J].

Chang, Chun-Ju ;

Chao, Chi-Hong ;

Xia, Weiya ;

Yang, Jer-Yen ;

Xiong, Yan ;

Li, Chia-Wei ;

Yu, Wen-Hsuan ;

Rehman, Sumaiyah K. ;

Hsu, Jennifer L. ;

Lee, Heng-Huan ;

Liu, Mo ;

Chen, Chun-Te ;

Yu, Dihua ;

Hung, Mien-Chie .

NATURE CELL BIOLOGY, 2011, 13 (03) :317-U296

[8]

Transactivation of miR-34a by p53 broadly influences gene expression and promotes apoptosis [J].

Chang, Tsung-Cheng ;

Wentzel, Erik A. ;

Kent, Oliver A. ;

Ramachandran, Kalyani ;

Mullendore, Michael ;

Lee, Kwang Hyuck ;

Feldmann, Georg ;

Yamakuchi, Munekazu ;

Ferlito, Marcella ;

Lowenstein, Charles J. ;

Arking, Dan E. ;

Beer, Michael A. ;

Maitra, Anirban ;

Mendell, Joshua T. .

MOLECULAR CELL, 2007, 26 (05) :745-752

[9]

The p53 tumor suppressor network in cancer and the therapeutic modulation of cell death [J].

Chari, Nikhil S. ;

Pinaire, Nicole L. ;

Thorpe, Lynnelle ;

Medeiros, L. Jeffrey ;

Routbort, Mark J. ;

McDonnell, Timothy J. .

APOPTOSIS, 2009, 14 (04) :336-347

[10]

Loss of p53 and Ink4a/Arf cooperate in a cell autonomous fashion to induce metastasis of hepatocellular carcinoma cells [J].

Chen, Ya-Wen ;

Klimstra, David S. ;

Mongeau, Nfichelle E. ;

Tatem, Jessica L. ;

Boyartchuk, Victor ;

Lewis, Brian C. .

CANCER RESEARCH, 2007, 67 (16) :7589-7596