Abstract
BackgroundGalectin-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.Methodology/Principal FindingsWe 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/SignificanceOur 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.
Highlights
The family of the Homeodomain Interacting Protein Kinase (HIPK) genes was discovered thirteen years ago
Conclusions/Significance: Our results indicate that HIPK2 expression and function are impaired in well-differentiated thyroid carcinomas (WDTCs), in particular in papillary thyroid carcinomas (PTCs), and that this event explains Gal-3 overexpression typically observed in these types of tumours
In the present study we show that: i) HIPK2 protein expression is lost in PTCs; ii) HIPK2 mRNA levels are up-regulated in follicular hyperplasia (FH) and reduced in PTC and in follicular variants of PTC (FVPTC); iii) loss of heterozygosity (LOH) affecting the HIPK2 gene locus can be detected in more than one third of PTCs; iv) RNA interference (RNAi) or overexpression of HIPK2 in PTCderived K1 cells causes upregulation or downregulation respectively of Gal-3 expression
Summary
The family of the Homeodomain Interacting Protein Kinase (HIPK) genes was discovered thirteen years ago. Their ability to interact and phosphorylate specific serine/threonine residues in many different targets and partners has been extensively studied By virtue of their protein/protein interaction, HIPKs are involved in the regulation of gene transcription and in cell response to DNA damage [1]. HIPK2, the most studied member of the family, acts as co-regulator of an increasing number of transcription factors and modulates many different basic cellular processes such as apoptosis, proliferation, DNA damage response, differentiation, and development. Most of these effects are mediated by phosphorylation and activation of the oncosuppressor protein p53 [2,3,4,5]. 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
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