Comparative analysis of human and mouse expression data identifies distinct proto-oncogene PBF- and PTTG-associated genes in thyroid cancer

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Abstract

Introduction. Whilst the proto-oncogene PTTG and its binding partner PBF (PTTG1IP) have previously been shown to be up-regulated in differentiated thyroid cancer (DTC), there is a paucity of information regarding their co-expression and specific roles in tumour progression. PTTG and PBF have both been reported to modulate the tumour suppressor p53, whose activity is impaired in most human cancers. Hence, the role of PTTG and PBF in thyroid tumorigenesis may involve the disruption of p53 pathways that are central to DNA-damage repair (DDR), cell growth and apoptosis. In the present study we investigated whether PTTG and PBF expression are associated with p53-regulated genes in the TCGA thyroid cancer dataset, as well as in a bi-transgenic murine model overexpressing PTTG and PBF specifically in the thyroid gland. Material and Methods. A bi-transgenic model (Bi-Tg) of thyroid-specific PTTG and PBF overexpression was generated by crossing two FVB/N murine models of human PBF (PBF-Tg) and PTTG (PTTG-Tg) transgenes under the control of the bovine thyroglobulin promoter. Gene expression in primary murine thyrocytes was analysed using a DNA damage signalling pathway-focussed PCR array. Expression of PTTG, PBF and p53-regulated genes in human thyroid carcinomas was analysed in the TCGA publically available dataset. Results. Characterisation of primary murine Bi-Tg thyrocytes revealed that co-expression of PTTG and PBF caused extensive repression of DDR genes (39/82 genes; P<0.05). Of these, 31 genes were down-regulated >1.5-fold, including genes with key roles in maintaining genomic integrity such as Pms2 and Brca1. Irradiation exposure to increase intracellular p53 further showed that the most significant difference in overall DDR gene expression (n=82 genes) was between irradiated Bi-Tg and wild-type (WT) thyrocytes (P=2.4x10-4) compared with either PBF-Tg (P=1.5x10-3) or PTTG-Tg thyrocytes (P=NS). By comparison in the TCGA dataset, there were striking correlations observed with PTTG and PBF in well-characterised DDR and p53 gene panels (>60% of genes; P<0.05; 82-96 genes per panel; n=322 unmatched TCGA tumour samples). Importantly, nearly half of the significant DDR gene alterations in Bi-Tg thyrocytes (18/39 genes) were also present in TCGA (matched tumour/normal specimens) comparing samples with either low or high PTTG/PBF mRNA levels. Furthermore, the overall survival (P=0.0002) and disease-free survival (P=0.02) was poorer for TCGA patients with high tumoral PTTG/PBF expression (n=20) than for all other patients (n=255). Conclusion. We have identified a distinct panel of p53-regulated genes associated with PTTG and PBF co-expression in different thyroid cancer models. Together our findings provide important insights into the specific role of PTTG and PBF in thyroid tumorigenesis.

Details

Original languageEnglish
Article number202
Pages (from-to)S36
Number of pages1
JournalEuropean Journal of Cancer
Volume61
Issue numberSuppl 1
Publication statusPublished - 1 Jul 2016