title: FBX8 is a metastasis suppressor downstream of miR-223 and targeting mTOR for degradation in colorectal carcinoma.
abstract: 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.
authors.affiliation: Department of Pathology, Southern Medical University, Guangzhou 510515, Guangdong Province, People's Republic of China; Guangdong Province Key Laboratory of Molecular Tumor Pathology, Guangzhou 510515, Guangdong Province, People's Republic of China.
authors.forename: F F
authors.initials: FF
authors.lastname: Wang
authors.affiliation: Department of Pathology, Southern Medical University, Guangzhou 510515, Guangdong Province, People's Republic of China; Department of Pathology, Shenzhen University, Shenzhen 518060, People's Republic of China.
authors.forename: X J
authors.initials: XJ
authors.lastname: Zhang
authors.affiliation: Department of Pathology, Southern Medical University, Guangzhou 510515, Guangdong Province, People's Republic of China; Guangdong Province Key Laboratory of Molecular Tumor Pathology, Guangzhou 510515, Guangdong Province, People's Republic of China.
authors.forename: Y R
authors.initials: YR
authors.lastname: Yan
authors.affiliation: Department of Pathology, Southern Medical University, Guangzhou 510515, Guangdong Province, People's Republic of China; Guangdong Province Key Laboratory of Molecular Tumor Pathology, Guangzhou 510515, Guangdong Province, People's Republic of China.
authors.forename: X H
authors.initials: XH
authors.lastname: Zhu
authors.affiliation: Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong Province, People's Republic of China.
authors.forename: J
authors.initials: J
authors.lastname: Yu
authors.affiliation: Department of Radiotherapy, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong Province, People's Republic of China.
authors.forename: Y
authors.initials: Y
authors.lastname: Ding
authors.affiliation: Department of Pathology, Southern Medical University, Guangzhou 510515, Guangdong Province, People's Republic of China; Guangdong Province Key Laboratory of Molecular Tumor Pathology, Guangzhou 510515, Guangdong Province, People's Republic of China.
authors.forename: J L
authors.initials: JL
authors.lastname: Hu
authors.affiliation: Department of Pathology, Southern Medical University, Guangzhou 510515, Guangdong Province, People's Republic of China; Guangdong Province Key Laboratory of Molecular Tumor Pathology, Guangzhou 510515, Guangdong Province, People's Republic of China.
authors.forename: W J
authors.initials: WJ
authors.lastname: Zhou
authors.affiliation: Department of Pathology, Southern Medical University, Guangzhou 510515, Guangdong Province, People's Republic of China; Guangdong Province Key Laboratory of Molecular Tumor Pathology, Guangzhou 510515, Guangdong Province, People's Republic of China.
authors.forename: Z C
authors.initials: ZC
authors.lastname: Zeng
authors.affiliation: Department of Pathology, Southern Medical University, Guangzhou 510515, Guangdong Province, People's Republic of China; Guangdong Province Key Laboratory of Molecular Tumor Pathology, Guangzhou 510515, Guangdong Province, People's Republic of China.
authors.forename: W T
authors.initials: WT
authors.lastname: Liao
authors.affiliation: Department of Pathology, Southern Medical University, Guangzhou 510515, Guangdong Province, People's Republic of China; Guangdong Province Key Laboratory of Molecular Tumor Pathology, Guangzhou 510515, Guangdong Province, People's Republic of China.
authors.forename: Y Q
authors.initials: YQ
authors.lastname: Ding
authors.affiliation: Department of Pathology, Southern Medical University, Guangzhou 510515, Guangdong Province, People's Republic of China; Guangdong Province Key Laboratory of Molecular Tumor Pathology, Guangzhou 510515, Guangdong Province, People's Republic of China. Electronic address: redsnow007@hotmail.com.
authors.forename: L
authors.initials: L
authors.lastname: Liang
mesh_terms: D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D015536:Down-Regulation; D044783:F-Box Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D035683:MicroRNAs / Q000378:metabolism*; D009362:Neoplasm Metastasis; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D044783:F-Box Proteins; C555947:FBXO8 protein, human; C000608124:MIRN233 microRNA, human; D035683:MicroRNAs; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases
keywords: Colorectal carcinoma; FBX8; Ubiquitin degradation; mTOR; miR-223