5 k4 {; V' M6 o/ E4 bAn Extensive MicroRNA-Mediated Network of RNA-RNA Interactions Regulates Established Oncogenic Pathways in Glioblastoma1 c; s p2 b, z; p* u2 V % w% e/ {- r o Z' N1 h: a3 rCell, Volume 147, Issue 2, 370-381, 14 October 2011 . C3 o o. `0 h& qCopyright 2011 Elsevier Inc. All rights reserved.1 U9 a9 z4 X9 {! C$ o9 \
10.1016/j.cell.2011.09.041 ; u0 Y$ M+ |- H# @& x7 x+ R& p. Y' ^7 {- ?0 H
Authors6 [! i( O, y3 x* P: |( ^. e
Pavel Sumazin, Xuerui Yang, Hua-Sheng Chiu, Wei-Jen Chung, Archana Iyer, David Llobet-Navas, Presha Rajbhandari, Mukesh Bansal, Paolo Guarnieri, Jose Silva, Andrea CalifanoSee AffiliationsHint: Rollover Authors and Affiliations Columbia Initiative in Systems Biology, Columbia University, New York, NY 10032, USA0 S J' _/ u; O/ t) Y" w
Center for Computational Biology and Bioinformatics, Columbia University, New York, NY 10032, USA 5 z) F1 e; A( U Department of Biomedical Informatics, Columbia University, New York, NY 10032, USA# n% J4 e# H" g1 `8 @1 o
Department of Pathology and Cell Biology, Columbia University, New York, NY 10032, USA + w& g0 J7 H6 S9 X Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA. }2 V. j8 g+ @- N6 u8 `
Institute for Cancer Genetics, Columbia University, New York, NY 10032, USA( y& ]* n+ [ N# [ `2 P
Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, USA 0 o2 k9 u, ?" J) }! [+ m Corresponding author 1 u8 y& q2 C9 f4 k8 }) }- N These authors contributed equally to this workHighlights1 j# g+ l' Y3 r7 Z& Z
Computational inference reveals a network of miR-mediated interactions in glioblastoma 3 c ?: f2 l) b
These interactions regulate thousands of genes, including oncogenes and tumor suppressors v+ J/ X3 }- QThese interactions regulate miR targets without affecting miR expression 7 q/ h m, i4 LThese interactions enable crosstalk between established oncogenic pathways3 I/ Y6 w9 E" s
3 c1 \# F2 t OSummary ! e+ W% j1 N p; H: SBy analyzing gene expression data in glioblastoma in combination with matched microRNA profiles, we have uncovered a posttranscriptional regulation layer of surprising magnitude, comprising more than 248,000 microRNA (miR)-mediated interactions. These include 7,000 genes whose transcripts act as miR sponges and 148 genes that act through alternative, nonsponge interactions. Biochemical analyses in cell lines confirmed that this network regulates established drivers of tumor initiation and subtype implementation, including PTEN, PDGFRA, RB1, VEGFA, STAT3, and RUNX1, suggesting that these interactions mediate crosstalk between canonical oncogenic pathways. siRNA silencing of 13 miR-mediated PTEN regulators, whose locus deletions are predictive of PTEN expression variability, was sufficient to downregulate PTEN in a 3UTR-dependent manner and to increase tumor cell growth rates. Thus, miR-mediated interactions provide a mechanistic, experimentally validated rationale for the loss of PTEN expression in a large number of glioma samples with an intact PTEN locus. 6 Z/ ~1 ^! I# j4 T9 ` . @; s9 G t2 V, T- [http://www.cell.com/abstract/S0092-8674(11)01152-4 + G" |$ U! J: O) Y. V
( }; P/ U) X2 r w# tIn Vivo Identification of Tumor- Suppressive PTEN ceRNAs in an Oncogenic BRAF-Induced Mouse Model of Melanoma0 h7 v! b m5 [$ x, C% G
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Cell, Volume 147, Issue 2, 382-395, 14 October 2011+ B% \3 U4 {5 c+ j" Z% b# B, B% r) b
Copyright 2011 Elsevier Inc. All rights reserved. 7 }$ S$ j) ?" D ?9 l% Y10.1016/j.cell.2011.09.032/ y# N) a2 z, y1 o7 y) M
' F7 p, `* Q7 n+ y# nAuthors ' N+ C8 U' Z: V% o4 M* AFlorian A. Karreth, Yvonne Tay, Daniele Perna, Ugo Ala, Shen Mynn Tan, Alistair G. Rust, Gina DeNicola, Kaitlyn A. Webster, Dror Weiss, Pedro A. Perez-Mancera, Michael Krauthammer, Ruth Halaban, Paolo Provero, David J. Adams, David A. Tuveson, Pier Paolo PandolfiSee AffiliationsHint: Rollover Authors and Affiliations Cancer Genetics Program, Division of Genetics, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA' V$ b2 `5 ?8 M* l5 @6 b1 E
Division of Signal Transduction, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA! y" T2 }' b% k
Li-Ka Shing Centre, Cambridge Research Institute, CRUK, Robinson Way, Cambridge CB2 0RE, UK 9 \0 t1 ^" Q6 d3 S, V/ f3 P Molecular Biotechnology Center and Department of Genetics, Biology and Biochemistry, University of Turin, Turin, Italy 3 T& S" G5 u/ y2 s. ?& H" p: I Immune Disease Institute and Program in Cellular and Molecular Medicine, Children's Hospital Boston, and Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA # u6 Q7 k4 F9 l+ @5 N Experimental Cancer Genetics, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, CB10 1HH, UK k+ @+ b2 E! q* G
Department of Pathology, Yale University, New Haven, CT 06520, USA% o9 q- R% I9 p. A0 T! s
Department of Dermatology, Yale University, New Haven, CT 06520, USA( u! ^: K& N7 n0 h. _
Corresponding authorHighlights * d5 C L. T: N. fA Sleeping Beauty screen followed by MuTaME analysis discovered putative PTEN ceRNAs , A: f) H8 h3 i3 oThe PTEN ceRNA ZEB2 regulates PTEN in a miRNA-independent manner ; S, g7 W: h. V9 c
ZEB2 loss activates PI3K/AKT signaling and promotes cell transformation ! g, ]6 [# S+ ~
Attenuated ZEB2 expression is found in melanoma and other human cancers, x- a3 N h! D
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Summary7 ?5 g3 [$ z# l# g
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 BRAFV600E to promote melanomagenesis.* ?8 b2 o& b1 Z u# ]/ T
9 W5 b8 T/ d! K4 K' l2 {/ I: b http://www.cell.com/abstract/S0092-8674(11)01143-3 - z9 S1 i& n9 Z$ W& J% T6 o5 y; \" `9 k
% }" m) z+ ^9 r. x6 a% d * R7 e/ j9 R8 T% v7 @7 ]作者: daviddow 时间: 2011-10-20 00:27
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