The BRAF Pseudogene Functions as a Competitive Endogenous RNA and Induces Lymphoma In Vivo

被引：287

作者：

Karreth, Florian A. ^{[1
]}

Reschke, Markus ^{[1
]}

Ruocco, Anna ^{[1
]}

Ng, Christopher ^{[1
]}

Chapuy, Bjoern ^{[2
]}

Leopold, Valentine ^{[1
]}

Sjoberg, Marcela ^{[3
]}

Keane, Thomas M. ^{[3
]}

Verma, Akanksha ^{[4
]}

Ala, Ugo ^{[1
]}

Tay, Yvonne ^{[1
]}

Wu, David ^{[5
]}

Seitzer, Nina ^{[1
]}

Velasco-Herrera, Martin Del Castillo ^{[3
]}

Bothmer, Anne ^{[1
]}

Fung, Jacqueline ^{[1
]}

Langellotto, Fernanda ^{[6
,7
]}

Rodig, Scott J. ^{[8
]}

Elemento, Olivier ^{[4
]}

Shipp, Margaret A. ^{[2
]}

Adams, David J. ^{[3
]}

Chiarle, Roberto ^{[6
,7
,9
]}

Pandolfi, Pier Paolo ^{[1
]}

机构：

[1] Harvard Univ, Beth Israel Deaconess Med Ctr, Beth Israel Deaconess Canc Ctr, Canc Res Inst,Dept Med & Pathol,Med Sch, Boston, MA 02215 USA

[2] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA

[3] Wellcome Trust Sanger Inst, Expt Canc Genet, Hinxton CB10 1HH, England

[4] Weill Cornell Med Coll, Inst Computat Biomed, Dept Physiol & Biophys, New York, NY 10021 USA

[5] Weill Cornell Med Coll, Meyer Canc Ctr, New York, NY 10021 USA

[6] Childrens Hosp, Dept Pathol, Boston, MA 02115 USA

[7] Harvard Univ, Sch Med, Boston, MA 02115 USA

[8] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA

[9] Univ Torino, Dept Mol Biotechnol & Hlth Sci, I-10124 Turin, Italy

来源：

CELL | 2015年 / 161卷 / 02期

基金：

英国惠康基金;

关键词：

B-CELL LYMPHOMA; X-CHROMOSOME; CERNA HYPOTHESIS; GENE-EXPRESSION; MICRORNA; PTEN; MALIGNANCIES; IDIC(X)(Q13); ACTIVATION; ABSENCE;

D O I：

10.1016/j.cell.2015.02.043

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：

Research over the past decade has suggested important roles for pseudogenes in physiology and disease. In vitro experiments demonstrated that pseudogenes contribute to cell transformation through several mechanisms. However, in vivo evidence for a causal role of pseudogenes in cancer development is lacking. Here, we report that mice engineered to overexpress either the full-length murine B-Raf pseudogene Braf-rs1 or its pseudo "CDS'' or "3' UTR'' develop an aggressive malignancy resembling human diffuse large B cell lymphoma. We show that Braf-rs1 and its human ortholog, BRAFP1, elicit their oncogenic activity, at least in part, as competitive endogenous RNAs (ceRNAs) that elevate BRAF expression and MAPK activation in vitro and in vivo. Notably, we find that transcriptional or genomic aberrations of BRAFP1 occur frequently in multiple human cancers, including B cell lymphomas. Our engineered mouse models demonstrate the oncogenic potential of pseudogenes and indicate that ceRNA-mediated microRNA sequestration may contribute to the development of cancer.

引用

页码：319 / 332

页数：14

共 45 条

[1] Integrated transcriptional and competitive endogenous RNA networks are cross-regulated in permissive molecular environments [J].