title: The loss of the p53 activator HIPK2 is responsible for galectin-3 overexpression in well differentiated thyroid carcinomas.
abstract: BACKGROUND
  Galectin-3 (Gal-3) is an anti-apoptotic molecule involved in thyroid cells transformation. It is specifically overexpressed in thyroid tumour cells and is currently used as a preoperative diagnostic marker of thyroid malignancy. Gal-3 expression is downregulated by wt-p53 at the transcriptional level. In well-differentiated thyroid carcinomas (WDTCs) there is an unexplained paradoxical concomitant expression of Gal-3 and wt-p53. HIPK2 is a co-regulator of different transcription factors, and modulates basic cellular processes mainly through the activation of wt-p53. Since we demonstrated that HIPK2 is involved in p53-mediated Gal-3 downregulation, we asked whether HIPK2 deficiency might be responsible for such paradoxical Gal-3 overexpression in WDTC.
  
  
  RESULTS
  We analyzed HIPK2 protein and mRNA levels, as well as loss of heterozygosity (LOH) at the HIPK2 locus (7q32-34), in thyroid tissue samples. HIPK2 protein levels were high in all follicular hyperplasias (FHs) analyzed. Conversely, HIPK2 was undetectable in 91.7% of papillary thyroid carcinomas (PTCs) and in 60.0% of follicular thyroid carcinomas (FTCs). HIPK2 mRNA levels were upregulated in FH compared to normal thyroid tissue (NTT), while PTC showed mean HIPK2 mRNA levels lower than FH and, in 61.5% of cases, also lower than NTT. We found LOH at HIPK-2 gene locus in 37.5% of PTCs, 14.3% of FTCs and 18.2% of follicular adenomas. To causally link these data with Gal-3 upregulation, we performed in vitro experiments, using the PTC-derived K1 cells, in which HIPK2 expression was manipulated by RNA interference (RNAi) or plasmid-mediated overexpression. HIPK2 RNAi was associated with Gal-3 upregulation, while HIPK2 overexpression with Gal-3 downregulation.
  
  
  CONCLUSIONS
  Our results indicate that HIPK2 expression and function are impaired in WDTCs, in particular in PTCs, and that this event explains Gal-3 overexpression typically observed in these types of tumours. Therefore, HIPK2 can be considered as a new tumour suppressor gene for thyroid cancers.
authors.affiliation: Research Center, St. Pietro Fatebenefratelli Hospital, Rome, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Lavra
authors.forename: Cinzia
authors.initials: C
authors.lastname: Rinaldo
authors.forename: Alessandra
authors.initials: A
authors.lastname: Ulivieri
authors.forename: Emidio
authors.initials: E
authors.lastname: Luciani
authors.forename: Paolo
authors.initials: P
authors.lastname: Fidanza
authors.forename: Laura
authors.initials: L
authors.lastname: Giacomelli
authors.forename: Carlo
authors.initials: C
authors.lastname: Bellotti
authors.forename: Alberto
authors.initials: A
authors.lastname: Ricci
authors.forename: Maria
authors.initials: M
authors.lastname: Trovato
authors.forename: Silvia
authors.initials: S
authors.lastname: Soddu
authors.forename: Armando
authors.initials: A
authors.lastname: Bartolazzi
authors.forename: Salvatore
authors.initials: S
authors.lastname: Sciacchitano
mesh_terms: D000328:Adult; D000368:Aged; D015153:Blotting, Western; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002897:Chromosomes, Human, Pair 7; D005260:Female; D037502:Galectin 3 / Q000235:genetics*; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D019656:Loss of Heterozygosity; D008297:Male; D008875:Middle Aged; D009857:Oncogenes; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000473:pathology
chemical_list: D002352:Carrier Proteins; D037502:Galectin 3; D012333:RNA, Messenger; C115114:HIPK2 protein, human; D017346:Protein Serine-Threonine Kinases