title: Down-regulation of TRPS1 stimulates epithelial-mesenchymal transition and metastasis through repression of FOXA1.
abstract: The tricho-rhino-phalangeal syndrome 1 gene (TRPS1), which was initially found to be associated with tricho-rhino-phalangeal syndrome, is critical for the development and differentiation of bone, hair follicles and kidney. However, its role in cancer progression is largely unknown. In this study, we demonstrated that down-regulation of TRPS1 correlated with distant metastasis, tumour recurrence and poor survival rate in cancer patients. TRPS1 was frequently down-regulated in high-metastatic cancer cell lines from the breast, colon and nasopharynx. Silencing of TRPS1 stimulated epithelial-mesenchymal transition (EMT), migration and invasion in vitro and metastasis in vivo, while TRPS1 over-expression exhibited the opposite effects. Using quantitative proteomics, FOXA1, a negative regulator of epithelial-mesenchymal transition (EMT), was shown to be down-regulated by TRPS1 knockdown. Ectopic expression of FOXA1 blocked the enhancement of EMT, migration and invasion induced by TRPS1 silencing. Mechanistically, TRPS1, acting as a transcription activator, directly induced FOXA1 transcription by binding to the FOXA1 promoter. We further showed that down-regulation of TRPS1 was induced by miR-373 binding to the 3' UTR of TRPS1. Over-expression of TRPS1, but not TRPS1 3' UTR, blocked the enhancement of migration and invasion induced by miR-373. Taken together, we consider that down-regulation of TRPS1 by miR-373, acting as a transcriptional activator, promotes EMT and metastasis by repressing FOXA1 transcription, expanding upon its previously reported role as a transcription repressor. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
authors.affiliation: Institutes of Life and Health Engineering, Jinan University; and Biomedicine Research Centre, Third Affiliated Hospital of Guangzhou Medical University, People's Republic of China.
authors.forename: Jin-Zhou
authors.initials: JZ
authors.lastname: Huang
authors.affiliation: Institutes of Life and Health Engineering, Jinan University; and Biomedicine Research Centre, Third Affiliated Hospital of Guangzhou Medical University, People's Republic of China.
authors.forename: Min
authors.initials: M
authors.lastname: Chen
authors.affiliation: Institutes of Life and Health Engineering, Jinan University; and Biomedicine Research Centre, Third Affiliated Hospital of Guangzhou Medical University, People's Republic of China.
authors.forename: Ming
authors.initials: M
authors.lastname: Zeng
authors.affiliation: Institutes of Life and Health Engineering, Jinan University; and Biomedicine Research Centre, Third Affiliated Hospital of Guangzhou Medical University, People's Republic of China.
authors.forename: Song-Hui
authors.initials: SH
authors.lastname: Xu
authors.affiliation: Institutes of Life and Health Engineering, Jinan University; and Biomedicine Research Centre, Third Affiliated Hospital of Guangzhou Medical University, People's Republic of China.
authors.forename: Fei-Yan
authors.initials: FY
authors.lastname: Zou
authors.affiliation: Biomedicine Research Centre and Department of Surgery, Third Affiliated Hospital of Guangzhou Medical University, People's Republic of China.|Key Laboratory for Major Obstetric Diseases of Guangdong Province, Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, Guangzhou, People's Republic of China.
authors.forename: De
authors.initials: D
authors.lastname: Chen
authors.affiliation: Institutes of Life and Health Engineering, Jinan University; and Biomedicine Research Centre, Third Affiliated Hospital of Guangzhou Medical University, People's Republic of China.|Biomedicine Research Centre and Department of Surgery, Third Affiliated Hospital of Guangzhou Medical University, People's Republic of China.|Key Laboratory for Major Obstetric Diseases of Guangdong Province, Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, Guangzhou, People's Republic of China.
authors.forename: Guang-Rong
authors.initials: GR
authors.lastname: Yan
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D051541:Hepatocyte Nuclear Factor 3-alpha / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D035683:MicroRNAs / Q000235:genetics*; D009303:Nasopharyngeal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D012097:Repressor Proteins; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D020413:3' Untranslated Regions; D004268:DNA-Binding Proteins; C496499:FOXA1 protein, human; D051541:Hepatocyte Nuclear Factor 3-alpha; C527114:MIRN373 microRNA, human; D035683:MicroRNAs; D012097:Repressor Proteins; C108387:TRPS1 protein, human; D014157:Transcription Factors
keywords: EMT; FOXA1; TRPS1; metastasis; miR-373