Analysis of PLAGL1 Expression in Thyroid Carcinomas

Abstract

The PLAGL1 gene encodes for a zinc finger transcription factor proposed to act as a tumor suppressor involved in cell cycle arrest and apoptosis. However, PLAGL1 is overexpressed in some neoplasms suggesting an oncogenic function. Our aim was to study PLAGL1 expression in Thyroid Carcinomas (TC) and the association between high PLAGL1 levels and poor prognosis. PLAGL1 expression was evaluated by IHC in human thyroid tissue samples and by RT-PCR and Western blot on a large panel of human thyroid cell lines. For transcriptomic analysis we downloaded datasets from Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) data from papillary thyroid carcinomas (PTC). DNA methylation analysis and clinical characteristics were obtained from the PTC-TCGA dataset. We detected the expression of the large and short isoforms of PLAGL1 in different TC cell lines. Furthermore, in TC samples, we identified cytoplasmic and nuclear expression of PLAGL1. Transcriptomic analysis indicated a significant (P<0.0001) downregulation of PLAGL1 in differentiated and poorly differentiated carcinomas compared with nonneoplastic thyroid tissue, while PLAGL1 overexpression (P=0.003) was observed in anaplastic carcinomas. We have found no association between PLAGL1 expression levels and the methylation status on their promoter (P=0.09). In PTC-TCGA database, we found two subtypes of tumors that displayed distinct PLAGL1 levels (P<0.0001). PTC with high PLAGL1 expression tend to have a higher degree of malignancy regarding shorter disease-free survival (P=0.016), association with BRAF mutations (P<0.0001), increased dedifferentiation (P=0.046), advanced T stage (P=0.03), a greater number of lymph node metastases (P=0.03), and a strong correlation with the number of M2 macrophages (P<0.0001).Here we describe an association between high PLAGL1 expression and an aggressive phenotype of thyroid tumors suggesting that this transcription factor might serve as a cancer risk predictor.