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PMID: 22000016 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

In vivo identification of tumor- suppressive PTEN ceRNAs in an oncogenic BRAF-induced mouse model of melanoma.

Cell ·Vol. 147 ·No. 2 ·2011-10-14 ·Pages 382-95

Karreth FA, Tay Y, Perna D, Ala U, Tan SM, Rust AG, DeNicola G, Webster KA, Weiss D, Perez-Mancera PA, Krauthammer M, Halaban R, Provero P, Adams DJ, Tuveson DA, Pandolfi PP

Abstract

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.

MeSH Terms
3' Untranslated Regions Animals Disease Models, Animal Homeodomain Proteins/genetics,metabolism Humans Melanoma/genetics Mice MicroRNAs/metabolism Mutagenesis, Insertional PTEN Phosphohydrolase/genetics,metabolism Proto-Oncogene Proteins B-raf/genetics RNA, Messenger/metabolism Repressor Proteins/genetics,metabolism Zinc Finger E-box Binding Homeobox 2
Chemicals
3' Untranslated Regions Homeodomain Proteins MicroRNAs RNA, Messenger Repressor Proteins ZEB2 protein, mouse Zinc Finger E-box Binding Homeobox 2 Braf protein, mouse Proto-Oncogene Proteins B-raf PTEN Phosphohydrolase PTEN protein, human Pten protein, mouse
Authors & Affiliations
16 authors, click to expand affiliations / ORCID
Karreth Florian A
Cancer Genetics Program, Division of Genetics, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Harvard Medical School, Boston, MA 02215, USA.
Tay Yvonne
Perna Daniele
Ala Ugo
Tan Shen Mynn
Rust Alistair G
DeNicola Gina
Webster Kaitlyn A
Weiss Dror
Perez-Mancera Pedro A
Krauthammer Michael
Halaban Ruth
Provero Paolo
Adams David J
Tuveson David A
Pandolfi Pier Paolo
References (33)
33 references, click to expand
  1. Genetic interaction between NRAS and BRAF mutations and PTEN/MMAC1 inactivation in melanoma.
    J Invest Dermatol. 2004 Feb;122(2):337-41 PMID: 15009714
  2. MicroRNA-200 family members differentially regulate morphological plasticity and mode of melanoma cell invasion.
    PLoS One. 2010 Oct 04;5(10): PMID: 20957176
  3. Identification of the miR-106b~25 microRNA cluster as a proto-oncogenic PTEN-targeting intron that cooperates with its host gene MCM7 in transformation.
    Sci Signal. 2010 Apr 13;3(117):ra29 PMID: 20388916
  4. Characterization of melanocyte-specific inducible Cre recombinase transgenic mice.
    Genesis. 2006 May;44(5):262-7 PMID: 16676322
  5. Mutations of the BRAF gene in human cancer.
    Nature. 2002 Jun 27;417(6892):949-54 PMID: 12068308
  6. The miR-200 family determines the epithelial phenotype of cancer cells by targeting the E-cadherin repressors ZEB1 and ZEB2.
    Genes Dev. 2008 Apr 1;22(7):894-907 PMID: 18381893
  7. Cancer gene discovery in solid tumours using transposon-based somatic mutagenesis in the mouse.
    Nature. 2005 Jul 14;436(7048):272-6 PMID: 16015333
  8. MicroRNAs: target recognition and regulatory functions.
    Cell. 2009 Jan 23;136(2):215-33 PMID: 19167326
  9. Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets.
    Cell. 2005 Jan 14;120(1):15-20 PMID: 15652477
  10. Integrative analysis of epigenetic modulation in melanoma cell response to decitabine: clinical implications.
    PLoS One. 2009;4(2):e4563 PMID: 19234609
  11. Desperately seeking microRNA targets.
    Nat Struct Mol Biol. 2010 Oct;17(10):1169-74 PMID: 20924405
  12. An atlas of tissue-specific conserved coexpression for functional annotation and disease gene prediction.
    Eur J Hum Genet. 2011 Nov;19(11):1173-80 PMID: 21654723
  13. Braf(V600E) cooperates with Pten loss to induce metastatic melanoma.
    Nat Genet. 2009 May;41(5):544-52 PMID: 19282848
  14. microRNA-141 is involved in a nasopharyngeal carcinoma-related genes network.
    Carcinogenesis. 2010 Apr;31(4):559-66 PMID: 20053927
  15. A translation-independent role of oskar RNA in early Drosophila oogenesis.
    Development. 2006 Aug;133(15):2827-33 PMID: 16835436
  16. Most mammalian mRNAs are conserved targets of microRNAs.
    Genome Res. 2009 Jan;19(1):92-105 PMID: 18955434
  17. SIP1/ZEB2 induces EMT by repressing genes of different epithelial cell-cell junctions.
    Nucleic Acids Res. 2005 Nov 24;33(20):6566-78 PMID: 16314317
  18. MicroRNAs and prostate cancer.
    Acta Biochim Biophys Sin (Shanghai). 2010 Jun 15;42(6):363-9 PMID: 20539944
  19. Metrics for comparing regulatory sequences on the basis of pattern counts.
    Bioinformatics. 2004 Feb 12;20(3):399-406 PMID: 14764560
  20. MicroRNA targeting specificity in mammals: determinants beyond seed pairing.
    Mol Cell. 2007 Jul 6;27(1):91-105 PMID: 17612493
  21. A coding-independent function of gene and pseudogene mRNAs regulates tumour biology.
    Nature. 2010 Jun 24;465(7301):1033-8 PMID: 20577206
  22. MicroRNAs and their target gene networks in breast cancer.
    Breast Cancer Res. 2010;12(2):201 PMID: 20346098
  23. High frequency of BRAF mutations in nevi.
    Nat Genet. 2003 Jan;33(1):19-20 PMID: 12447372
  24. p53 regulates epithelial-mesenchymal transition through microRNAs targeting ZEB1 and ZEB2.
    J Exp Med. 2011 May 9;208(5):875-83 PMID: 21518799
  25. P53 mRNA controls p53 activity by managing Mdm2 functions.
    Nat Cell Biol. 2008 Sep;10(9):1098-105 PMID: 19160491
  26. A ceRNA hypothesis: the Rosetta Stone of a hidden RNA language?
    Cell. 2011 Aug 5;146(3):353-8 PMID: 21802130
  27. Oncogenic Braf induces melanocyte senescence and melanoma in mice.
    Cancer Cell. 2009 Apr 7;15(4):294-303 PMID: 19345328
  28. Pseudogenes in metazoa: origin and features.
    Brief Funct Genomic Proteomic. 2004 Aug;3(2):157-67 PMID: 15355597
  29. The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1.
    Nat Cell Biol. 2008 May;10(5):593-601 PMID: 18376396
  30. The miR-200 family inhibits epithelial-mesenchymal transition and cancer cell migration by direct targeting of E-cadherin transcriptional repressors ZEB1 and ZEB2.
    J Biol Chem. 2008 May 30;283(22):14910-4 PMID: 18411277
  31. Role of microRNAs in ovarian cancer pathogenesis and potential clinical implications.
    Int J Biochem Cell Biol. 2010 Aug;42(8):1262-72 PMID: 20035894
  32. Expression of versican 3'-untranslated region modulates endogenous microRNA functions.
    PLoS One. 2010 Oct 25;5(10):e13599 PMID: 21049042
  33. BRAF and RAS mutations in human lung cancer and melanoma.
    Cancer Res. 2002 Dec 1;62(23):6997-7000 PMID: 12460918
Article Info
Journal
Cell
Abbr.
Cell
ISSN
1097-4172
DOI
10.1016/j.cell.2011.09.032
Published
2011-10-14
Pages
382-95
Language
English
Region
United States
NLM ID
0413066
PMCID
PMC3236086
Subset
IM
Grants
NCRR NIH HHS · UL1 RR025758-04 · United States
NCI NIH HHS · R01 CA082328 · United States
Wellcome Trust · United Kingdom
NCI NIH HHS · R01 CA-82328-09 · United States
NCI NIH HHS · R01 CA082328-09 · United States
NCI NIH HHS · P50 CA121974 · United States
NCRR NIH HHS · UL1 RR025758 · United States
NCI NIH HHS · P50 CA121974-01 · United States
Cancer Research UK · United Kingdom
NCI NIH HHS · 1P50 CA121974 · United States
Corrections
ErratumIn
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CommentIn
PMID: 22048565
CommentIn
PMID: 22048663
CommentIn
PMID: 22048709
CommentIn
PMID: 22196719
External Links
PubMed source DOI: 10.1016/j.cell.2011.09.032 PMC Full Text View journal details
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