title: MiR-29c mediates epithelial-to-mesenchymal transition in human colorectal carcinoma metastasis via PTP4A and GNA13 regulation of β-catenin signaling.
abstract: BACKGROUND
  Distant metastasis is the major cause of cancer-related death, and epithelial-to-mesenchymal transition (EMT) has a critical role in this process. Accumulating evidence indicates that EMT can be regulated by microRNAs (miRNAs). miR-29c has been implicated as a tumor suppressor in several human cancers. However, the role of miR-29c in the progression of colorectal cancer (CRC) metastasis remains largely unknown.
  
  
  METHODS
  The expression of miR-29c was examined by qRT-PCR in a cohort of primary CRC (PC) and distant liver metastasis (LM) tissues. A series of in vivo and in vitro assays were carried out in order to elucidate the functions of miR-29c and the molecular mechanisms underlying the pathogenesis of metastatic CRC.
  
  
  RESULTS
  miR-29c was markedly downregulated in PCs with distant metastasis and determined to be an independent predictor of shortened patient survival. But LM tissues showed higher levels of miR-29c than that in PC tissues. In CRC cells, miR-29c dramatically suppressed cell migration and invasion abilities in vitro and cancer metastasis in vivo. In addition, miR-29c inhibited EMT and negatively regulated Wnt/β-catenin signaling pathway. Guanine nucleotide binding protein alpha13 (GNA13) and protein tyrosine phosphatase type IVA (PTP4A) were identified as direct targets of miR-29c, which acted through ERK/GSK3β/β-catenin and AKT/GSK3β/β-catenin pathways, respectively, to regulate EMT. Furthermore, significant associations between miR-29c, its target genes (GNA13 and PTP4A) and EMT markers were validated in both PC and LM tissues.
  
  
  CONCLUSIONS
  Our findings highlight the important role of miR-29c in regulating CRC EMT via GSK-3β/β-catenin signaling by targeting GNA13 and PTP4A and provide new insights into the metastatic basis of CRC.
authors.affiliation: The State Key Laboratory of Oncology in South China; Department of Pathology, Sun Yat-Sen University Cancer Center, Guangzhou.
authors.forename: J X
authors.initials: JX
authors.lastname: Zhang
authors.affiliation: The State Key Laboratory of Oncology in South China.
authors.forename: S J
authors.initials: SJ
authors.lastname: Mai
authors.affiliation: The State Key Laboratory of Oncology in South China.
authors.forename: X X
authors.initials: XX
authors.lastname: Huang
authors.affiliation: The State Key Laboratory of Oncology in South China.
authors.forename: F W
authors.initials: FW
authors.lastname: Wang
authors.affiliation: The State Key Laboratory of Oncology in South China.
authors.forename: Y J
authors.initials: YJ
authors.lastname: Liao
authors.affiliation: The State Key Laboratory of Oncology in South China, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: M C
authors.initials: MC
authors.lastname: Lin
authors.affiliation: The State Key Laboratory of Oncology in South China; The State Key Laboratory of Oncology in South China, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: H F
authors.initials: HF
authors.lastname: Kung
authors.affiliation: The State Key Laboratory of Oncology in South China.
authors.forename: Y X
authors.initials: YX
authors.lastname: Zeng
authors.affiliation: The State Key Laboratory of Oncology in South China; Department of Pathology, Sun Yat-Sen University Cancer Center, Guangzhou. Electronic address: xiedan@sysucc.org.cn.
authors.forename: D
authors.initials: D
authors.lastname: Xie
mesh_terms: D018797:Cell Cycle Proteins / Q000096:biosynthesis* / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics; D035683:MicroRNAs / Q000235:genetics*; D009362:Neoplasm Metastasis; D017027:Protein Tyrosine Phosphatases / Q000096:biosynthesis* / Q000235:genetics; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000235:genetics*
chemical_list: D018797:Cell Cycle Proteins; C532045:MIRN29a microRNA, human; D008565:Membrane Proteins; D035683:MicroRNAs; D051176:beta Catenin; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; C490198:PTP4A1 protein, human; D017027:Protein Tyrosine Phosphatases
keywords: GNA13; PTP4A; colorectal carcinoma; epithelial-to-mesenchymal transition; metastasis; miR-29c