In Vivo Identification of Tumor-Suppressive PTEN ceRNAs in an Oncogenic BRAF-Induced Mouse Model of Melanoma

被引：584

作者：

Karreth, Florian A. ^{[1
]}

Tay, Yvonne ^{[1
]}

Perna, Daniele ^{[3
]}

Ala, Ugo ^{[1
,4
,5
]}

Tan, Shen Mynn ^{[6
,7
,8
]}

Rust, Alistair G. ^{[9
]}

DeNicola, Gina ^{[2
]}

Webster, Kaitlyn A. ^{[1
]}

Weiss, Dror ^{[1
]}

Perez-Mancera, Pedro A. ^{[3
]}

Krauthammer, Michael ^{[10
]}

Halaban, Ruth ^{[11
]}

Provero, Paolo ^{[4
,5
]}

Adams, David J. ^{[9
]}

Tuveson, David A. ^{[3
]}

Pandolfi, Pier Paolo ^{[1
]}

机构：

[1] Harvard Univ, Beth Israel Deaconess Canc Ctr, Beth Israel Deaconess Med Ctr, Canc Genet Program,Div Genet,Dept Med & Pathol,Me, Boston, MA 02215 USA

[2] Harvard Univ, Beth Israel Deaconess Canc Ctr, Beth Israel Deaconess Med Ctr, Div Signal Transduct,Dept Med & Pathol,Med Sch, Boston, MA 02215 USA

[3] CRUK, Li Ka Shing Ctr, Cambridge Res Inst, Cambridge CB2 0RE, England

[4] Univ Turin, Mol Biotechnol Ctr, Turin, Italy

[5] Univ Turin, Dept Genet Biol & Biochem, Turin, Italy

[6] Harvard Univ, Sch Med, Immune Dis Inst, Boston, MA 02215 USA

[7] Harvard Univ, Sch Med, Program Cellular & Mol Med, Childrens Hosp Boston, Boston, MA 02215 USA

[8] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02215 USA

[9] Wellcome Trust Sanger Inst, Hinxton CB10 1HH, England

[10] Yale Univ, Dept Pathol, New Haven, CT 06520 USA

[11] Yale Univ, Dept Dermatol, New Haven, CT 06520 USA

来源：

CELL | 2011年 / 147卷 / 02期

基金：

英国惠康基金;

关键词：

EPITHELIAL-MESENCHYMAL TRANSITION; MIR-200; FAMILY; REPRESSORS ZEB1; TARGETING ZEB1; MESSENGER-RNAS; MICRORNAS; CANCER; GENE; MUTATIONS;

D O I：

10.1016/j.cell.2011.09.032

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 recently proposed that competitive endogenous RNAs (ceRNAs) sequester microRNAs to regulate mRNA transcripts containing common microRNA recognition elements (MREs). However, the functional role of ceRNAs in cancer remains unknown. Loss of PTEN, a tumor suppressor regulated by ceRNA activity, frequently occurs in melanoma. Here, we report the discovery of significant enrichment of putative PTEN ceRNAs among genes whose loss accelerates tumorigenesis following Sleeping Beauty insertional mutagenesis in a mouse model of melanoma. We validated several putative PTEN ceRNAs and further characterized one, the ZEB2 transcript. We show that ZEB2 modulates PTEN protein levels in a microRNA-dependent, protein coding-independent manner. Attenuation of ZEB2 expression activates the PI3K/AKT pathway, enhances cell transformation, and commonly occurs in human melanomas and other cancers expressing low PTEN levels. Our study genetically identifies multiple putative microRNA decoys for PTEN, validates ZEB2 mRNA as a bona fide PTEN ceRNA, and demonstrates that abrogated ZEB2 expression cooperates with BRAF(V600E) to promote melanomagenesis.

引用

页码：382 / 395

页数：14

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