title: Dual specificity phosphatase 6 as a predictor of invasiveness in papillary thyroid cancer.
abstract: OBJECTIVE
  The genetic mutations causing the constitutive activation of MEK/ERK have been regarded as an initiating factor in papillary thyroid carcinoma (PTC). The ERK-specific dual specificity phosphatase 6 (DUSP6) is part of the ERK-dependent transcriptional output. Therefore, the coordinated regulation of the activities of ERK kinases and DUSP6 may need to be reestablished to make new balances in PTC.
  
  
  METHODS
  To investigate the role of DUSP6 in the regulation of ERK1/2 (MAPK3/1)-dependent transcription, 42 benign neoplasms and 167 PTCs were retrospectively analyzed by immunohistochemistry with dideoxy sequencing to detect BRAF(V600E) mutation.
  
  
  RESULTS
  The expressions of total ERK1/2, DUSP6, c-Fos (FOS), c-Myc (MYC), cyclin D1, and PCNA were markedly increased in PTC compared with those in benign neoplasms. However, phospho-ERK1/2 was detected in only eight (4.8%) cases out of 167 PTC samples. Unexpectedly, the staining intensity and nuclear localization of ERK1/2 were not affected by the presence or absence of the BRAF(V600E) mutation. However, the expressions of c-Fos and PCNA were elevated in BRAF(V600E)-positive PTC compared with those in BRAF(V600E)-negative PTC. Interestingly, the higher staining intensities of DUSP6 were associated with the level of total ERK1/2 expression (P=0.04) and with high-risk biological features such as age (P=0.05), tumor size (P=0.01), and extrathyroidal extension (linear by linear association, P=0.02). In addition, DUSP6 silencing significantly decreased the cell viability and migration rate of FRO cells.
  
  
  CONCLUSIONS
  The coordinated upregulation of total ERK1/2 and its phosphatase, DUSP6, is related to bare detection of phospho-ERK1/2 in PTC regardless of BRAF(V)(600E) mutation status. A link between DUSP6 expression and high-risk features of PTC suggested that DUSP6 is an important independent factor affecting the signaling pathways in established PTC.
authors.affiliation: Department of Pathology, St Mary's Hospital, Catholic University of Korea, 64 Daeheung-ro, Chungku Daejeon 301-723, Korea.
authors.forename: Jung Uee
authors.initials: JU
authors.lastname: Lee
authors.forename: Songmei
authors.initials: S
authors.lastname: Huang
authors.forename: Min Hee
authors.initials: MH
authors.lastname: Lee
authors.forename: Seong Eun
authors.initials: SE
authors.lastname: Lee
authors.forename: Min Jeong
authors.initials: MJ
authors.lastname: Ryu
authors.forename: Soung Jung
authors.initials: SJ
authors.lastname: Kim
authors.forename: Yong Kyung
authors.initials: YK
authors.lastname: Kim
authors.forename: Seul Young
authors.initials: SY
authors.lastname: Kim
authors.forename: Kyong Hye
authors.initials: KH
authors.lastname: Joung
authors.forename: Jin Man
authors.initials: JM
authors.lastname: Kim
authors.forename: Minho
authors.initials: M
authors.lastname: Shong
authors.forename: Young Suk
authors.initials: YS
authors.lastname: Jo
mesh_terms: D000328:Adult; D002291:Carcinoma, Papillary / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D054642:Dual Specificity Phosphatase 6 / Q000378:metabolism*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009361:Neoplasm Invasiveness / Q000473:pathology*; D010766:Phosphorylation; D011237:Predictive Value of Tests; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D012189:Retrospective Studies; D015398:Signal Transduction; D013964:Thyroid Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
chemical_list: D018809:Proliferating Cell Nuclear Antigen; D016760:Proto-Oncogene Proteins c-fos; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D054642:Dual Specificity Phosphatase 6