title: Mitogen-inducible gene-6 is a multifunctional adaptor protein with tumor suppressor-like activity in papillary thyroid cancer.
abstract: BACKGROUND
  Low tumoral expression of mitogen-inducible gene-6 (Mig-6) is associated with papillary thyroid cancer (PTC) recurrence after thyroidectomy.
  
  
  OBJECTIVE
  We hypothesize that Mig-6 behaves as a tumor suppressor in PTC.
  
  
  METHODS
  Mig-6 expression and promoter methylation status were compared in 31 PTC specimens with matched normal thyroid tissue from the same patient. The impact of Mig-6 loss and gain of function on nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) activation, global tyrosine kinase phosphorylation, and cellular invasion was determined in vitro.
  
  
  RESULTS
  Mig-6 protein was abundant in all normal thyroid specimens, whereas 77% of PTC had low Mig-6 expression. Mig-6 promoter methylation was found in 79% of PTC with low Mig-6 expression. Low Mig-6 expression in PTC specimens was associated with low NF-κB activity but high levels of epidermal growth factor receptor (EGFR) and ERK phosphorylation. Mig-6 expression inversely correlated with PTC size but had no association with other clinicopathological variables including age, extrathyroidal extension, lymphovascular invasion, or histological subtype. Mig-6 knockdown in thyroid cancer cell lines resulted in EGFR phosphorylation and diminished NF-κB activity, whereas Mig-6 overexpression had the opposite effects. Mig-6 knockdown activated ErbB2, Met, and Src phosphorylation. Furthermore, Mig-6 regulated ERK phosphorylation independent from its effects on EGFR. Mig-6 knockdown promoted cellular proliferation, as determined by clonogenic survival. Lastly, Mig-6 knockdown increased matrix metalloproteinase-2 and -9 activities and increased cellular invasion.
  
  
  CONCLUSIONS
  Mig-6 has tumor suppressor-like activity in PTC. In vivo studies are required to confirm that Mig-6 is a putative tumor suppressor in PTC, and future studies should investigate the utility of Mig-6 as a diagnostic marker.
authors.affiliation: Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Chi-Iou
authors.initials: CI
authors.lastname: Lin
authors.forename: Jinyan
authors.initials: J
authors.lastname: Du
authors.forename: Wen T
authors.initials: WT
authors.lastname: Shen
authors.forename: Edward E
authors.initials: EE
authors.lastname: Whang
authors.forename: David B
authors.initials: DB
authors.lastname: Donner
authors.forename: Nick
authors.initials: N
authors.lastname: Griff
authors.forename: Frank
authors.initials: F
authors.lastname: He
authors.forename: Francis D
authors.initials: FD
authors.lastname: Moore
authors.forename: Orlo H
authors.initials: OH
authors.lastname: Clark
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Ruan
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D015153:Blotting, Western; D002277:Carcinoma; D002291:Carcinoma, Papillary / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000737:chemistry; D002478:Cells, Cultured; D003600:Cytosol / Q000737:chemistry; D004273:DNA, Neoplasm / Q000235:genetics / Q000302:isolation & purification; D015194:Diffusion Chambers, Culture; D015536:Down-Regulation; D066246:ErbB Receptors / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D016147:Genes, Tumor Suppressor / Q000502:physiology*; D006801:Humans; D016328:NF-kappa B / Q000235:genetics; D009361:Neoplasm Invasiveness / Q000235:genetics; D010766:Phosphorylation; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077273:Thyroid Cancer, Papillary; D013964:Thyroid Neoplasms / Q000235:genetics / Q000473:pathology; D014410:Tumor Stem Cell Assay; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004273:DNA, Neoplasm; C484017:ERRFI1 protein, human; D016328:NF-kappa B; D025521:Tumor Suppressor Proteins; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases