title: ZIC1 is a putative tumor suppressor in thyroid cancer by modulating major signaling pathways and transcription factor FOXO3a.
abstract: BACKGROUND
  ZIC1 has been reported to be overexpressed and plays an oncogenic role in some brain tumors, whereas it is inactivated by promoter hypermethylation and acts as a tumor suppressor in gastric and colorectal cancers. However, until now, its biological role in thyroid cancer remains totally unknown.
  
  
  OBJECTIVE
  The aim of this study is to explore the biological functions and related molecular mechanism of ZIC1 in thyroid carcinogenesis.
  
  
  METHODS
  Quantitative RT-PCR (qRT-PCR) was performed to evaluate mRNA expression of investigated genes. Methylation-specific PCR was used to analyze promoter methylation of the ZIC1 gene. The functions of ectopic ZIC1 expression in thyroid cancer cells were determined by cell proliferation and colony formation, cell cycle and apoptosis, as well as cell migration and invasion assays.
  
  
  RESULTS
  ZIC1 was frequently down-regulated by promoter hypermethylation in both primary thyroid cancer tissues and thyroid cancer cell lines. Moreover, our data showed that ZIC1 hypermethylation was significantly associated with lymph node metastasis in patients with papillary thyroid cancer. Notably, restoration of ZIC1 expression in thyroid cancer cells dramatically inhibited cell proliferation, colony formation, migration and invasion, and induced cell cycle arrest and apoptosis by blocking the activities of the phosphatidylinositol-3-kinase (PI3K)/Akt and RAS/RAF/MEK/ERK (MAPK) pathways, and enhancing FOXO3a transcriptional activity.
  
  
  CONCLUSIONS
  Our data demonstrate that ZIC1 is frequently inactivated by promoter hypermethyaltion and functions as a tumor suppressor in thyroid cancer through modulating PI3K/Akt and MAPK signaling pathways and transcription factor FOXO3a.
authors.affiliation: Department of Endocrinology (W.Q., Q.Y., W.L., S.L., B.S., P.H.), The First Affiliated Hospital of Xi'an Jiaotong University School of Medicine, Xi'an 710061, China; Department of Gerontology (Y.Z.), Shaanxi Provincial People's Hospital, Xi'an 710068, China; Department of Endocrinology and Metabolism (H.G.), The First Affiliated Hospital of China Medical University, Shenyang 110001, China; and Center for Translational Medicine (M.J.), The First Affiliated Hospital of Xi'an Jiaotong University School of Medicine, Xi'an 710061, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Qiang
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhao
authors.forename: Qi
authors.initials: Q
authors.lastname: Yang
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.forename: Haixia
authors.initials: H
authors.lastname: Guan
authors.forename: Siqing
authors.initials: S
authors.lastname: Lv
authors.forename: Meiju
authors.initials: M
authors.lastname: Ji
authors.forename: Bingyin
authors.initials: B
authors.lastname: Shi
authors.forename: Peng
authors.initials: P
authors.lastname: Hou
mesh_terms: D017209:Apoptosis / Q000235:genetics; D002277:Carcinoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002291:Carcinoma, Papillary; D049109:Cell Proliferation; D019175:DNA Methylation; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D016147:Genes, Tumor Suppressor; D006801:Humans; D009361:Neoplasm Invasiveness; D011401:Promoter Regions, Genetic; D015398:Signal Transduction / Q000235:genetics; D000077273:Thyroid Cancer, Papillary; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D014157:Transcription Factors / Q000502:physiology*; D014407:Tumor Cells, Cultured
chemical_list: C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D014157:Transcription Factors; C492123:ZIC1 protein, human