MicroRNA-Antagonism Regulates Breast Cancer Stemness and Metastasis via TET-Family-Dependent Chromatin Remodeling

被引：407

作者：

Song, Su Jung ^{[1
]}

Poliseno, Laura ^{[1
]}

Song, Min Sup ^{[1
]}

Ala, Ugo ^{[1
]}

Webster, Kaitlyn ^{[1
]}

Ng, Christopher ^{[1
,2
]}

Beringer, Gary ^{[4
]}

Brikbak, Nicolai J. ^{[5
]}

Yuan, Xin ^{[3
]}

Cantley, Lewis C. ^{[2
,4
]}

Richardson, Andrea L. ^{[5
]}

Pandolfi, Pier Paolo ^{[1
]}

机构：

[1] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Canc Genet Program,Div Genet,Dept Med & Pathol, Boston, MA 02115 USA

[2] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Div Signal Transduct,Dept Med, Boston, MA 02115 USA

[3] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Hematol Oncol Div,Dept Med, Boston, MA 02115 USA

[4] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA 02115 USA

[5] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA

来源：

CELL | 2013年 / 154卷 / 02期

关键词：

ESTROGEN-RECEPTOR-ALPHA; MESENCHYMAL TRANSITION; 5-HYDROXYMETHYLCYTOSINE CONTENT; EPITHELIAL PHENOTYPE; DOWN-REGULATION; MIR-200; FAMILY; MESSENGER-RNA; HUMAN GENES; TGF-BETA; CELLS;

D O I：

10.1016/j.cell.2013.06.026

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：

Tumor cells metastasize to distant organs through genetic and epigenetic alterations, including changes in microRNA (miR) expression. Here we find miR-22 triggers epithelial-mesenchymal transition (EMT), enhances invasiveness and promotes metastasis in mouse xenografts. In a conditional mammary gland-specific transgenic (TG) mouse model, we show that miR-22 enhances mammary gland side-branching, expands the stem cell compartment, and promotes tumor development. Critically, miR-22 promotes aggressive metastatic disease in MMTV-miR-22 TG mice, as well as compound MMTV-neu or -PyVT-miR-22 TG mice. We demonstrate that miR-22 exerts its metastatic potential by silencing antimetastatic miR-200 through direct targeting of the TET (Ten eleven translocation) family of methylcytosine dioxygenases, thereby inhibiting demethylation of the mir-200 promoter. Finally, we show that miR-22 overexpression correlates with poor clinical outcomes and silencing of the TET-miR-200 axis in patients. Taken together, our findings implicate miR-22 as a crucial epigenetic modifier and promoter of EMT and breast cancer stemness toward metastasis.

引用

页码：311 / 324

页数：14

共 60 条

[1] miR-200 Expression Regulates Epithelial-to-Mesenchymal Transition in Bladder Cancer Cells and Reverses Resistance to Epidermal Growth Factor Receptor Therapy [J].