期刊
CELL
卷 147, 期 2, 页码 382-395出版社
CELL PRESS
DOI: 10.1016/j.cell.2011.09.032
关键词
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资金
- Harvard Catalyst
- The Harvard Clinical and Translational Science Center (NIH) [UL1 RR 025758]
- Harvard University and its affiliated academic health care centers
- University of Cambridge,
- Cancer Research UK
- The Li Ka Shing Foundation
- Hutchison Whampoa Limited
- NIHR Cambridge Biomedical Research Centre
- The Wellcome Trust
- The Leukemia & Lymphoma Society
- Italian Association for Cancer Research (AIRC)
- Fundacion Ibercaja
- Fondazione per la Ricerca Biomedica ONLUS of Torino
- Department of Defense
- AIRC [IG-9408]
- Yale SPORE in Skin Cancer
- National Cancer Institute [1 P50 CA121974]
- NIH [R01 CA-82328-09]
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.
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