期刊
CANCER LETTERS
卷 388, 期 -, 页码 85-95出版社
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2016.11.031
关键词
FBX8; miR-223; mTOR; Ubiquitin degradation; Colorectal carcinoma
类别
资金
- National Basic Research Program of China (973 Program) [2015CB554002]
- Key project of National Natural Science Fund (Guangdong Province NSFC- joint fund) [U1201226]
- National Natural Science Foundation of China [81272759, 81172382, 81472313, 81401927]
- Natural Science Foundation of Guangdong Province [S2013010014544]
F-box proteins are critical components of the SKP1-CUL1-F-box (SCF) E3 ubiquitin ligases and involved in the ubiquitin-dependent proteolytic pathway. Dysregulation of F-box protein-mediated, proteolysis often leads to,human malignancies. F-box only protein 8 (FBX8), a novel component of F-box proteins, is down regulated in several tumors and closely correlates with tumor progression. However, little is known about its function, regulatory mechanisms and substrates in the progression of colorectal carcinoma (CRC). Combining microRNA (miRNA) assay, functional characterization, mechanistic studies with clinical validation, we identify FBX8 as a CRC metastasis suppressor downstream of miR-223, a metastasis promoting miRNA that is transcriptionally regulated by Myocyte enhancer factor (MEF2A). mTOR is a substrate of FBX8 for ubiquitin-mediated degradation and is required for FBX8 induced cell proliferation and invasion in CRC cells. FBX8 is down-regulated in human CRC tissues and correlates with MEF2A, miR-223 and mTOR expression levels. Notably, low FBX8 expression status in CRC tissues was a significant prognostic factor for poor overall survival of patients. These findings illustrate FBX8 as a metastasis suppressor that functions through mTOR signaling pathway and has significant prognostic power. (C) 2016 Elsevier Ireland Ltd. All rights reserved.
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