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

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• 作者：Florian  ; A. Karreth¹ ; Yvonne Tay¹ ; Daniele Perna³ ; Ugo Ala¹ ;   ; ⁴ ; Shen  ; Mynn Tan⁵ ; Alistair  ; G. Rust⁶ ; Gina DeNicola² ; Kaitlyn  ; A. Webster¹ ; Dror Weiss¹ ; Pedro  ; A. Perez-Mancera³ ; Michael Krauthammer⁷ ; Ruth Halaban⁸ ; Paolo Provero⁴ ; David  ; J. Adams⁶ ; David  ; A. Tuveson³ ; Pier  ; Paolo Pandolfi¹ ;   ; ^{ppandolf@bidmc.harvard.edu}
• 刊名：Cell
• 出版年：2011
• 出版时间：14 October 2011
• 年：2011
• 卷：147
• 期：2
• 页码：382-395
• 全文大小：1885 K

文摘

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Summary

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.