• Dysregulation of TPO in a ceRNA network promotes anaplastic thyroid cancer: integrated gene expression profiling and systems biology analyses
  • Yeganeh sadat Mousavian,1 Mohammad Rezaei,2 Mansoureh Azadeh,3,*
    1. Zist Fanavari Novin Biotechnology Institute, Isfahan, Iran
    2. Department of Biology and Biotechnology, University of Pavia, Pavian, Italy
    3. Zist Fanavari Novin Biotechnology Institute, Isfahan, Iran


  • Introduction: Anaplastic thyroid cancer (ATC) is an uncommon and the most aggressive malignancy of the thyroid gland with a high mortality rate. This type of cancer is most common in elderly people over the age of 60 years. Although this fatal abnormality makes up less than 2% of all thyroid cancer cases, the median survival of patients with ATC is about 5 months and less than 20% 1-year survival. Due to the immediate spreadability of the disease, an opportune diagnosis is critical. Therefore, determining reliable genetic biomarkers would improve the prognosis and treatment of ATC. The Competing Endogenous RNA (ceRNA) network hypothesis proposes that lncRNAs and mRNAs competitively bind to limited miRNAs through miRNA response element (MRE) to regulate the suppression or induction of gene expression. Thus this network could be used to construct a potential model for the diagnosis and treatment of ATC. The present study aimed to identify potential biomarkers and biological networks of gene interaction, including mRNAs, lncRNAs, and miRNAs, that have a remarkable impact on ATC progression.
  • Methods: In the first place, the Anaplastic thyroid cancer Microarray dataset (GSE33630) was extracted from NCBI Gene Expression Omnibus(GEO) to identify differentially expressed genes (DEGs) in ATC compared to normal thyroid samples. Subsequently, genes with significant decreases in expression regulation were analyzed by GEO2R. Further, expression analysis of elected gene was validated by GEPIA2 and ENCORI databases. According to the microarray data comparison between ATC and Normal tissue, the most significant gene with observable expression change was selected (|logFC| > 2 and adjusted p-value< 0.05). Furthermore, biological pathways were processed through KEGG and Reactome databases.Moreover, STRING database was utilized to find significant protein-protein interactions among our selected gene and related genes. In addition, miRWalk database was used to detect miRNA-mRNA interactions and find a significant miRNA. Finally, LncBase v.3 was employed to find an appropriate lncRNA that could complete the network. Furthermore, LncRRIsearch was utilized to ensure that the chosen lncRNA is highly significant in Anaplastic thyroid cancer.
  • Results: The GEO data analysis of GSE33630 revealed that among all the 352 genes that showed downregulation, TPO was identified to be the most significant down-regulated gene in ATC samples compared to controls with adj.P.Val = 2.17E-27 and logFC = -7.3149612. The TPO gene provides instructions for biosynthesizing thyroid hormone and also it is known to be associated with thyroid gland diseases. According to the STRING database analysis, TG, IYD, FOXE1, and DUOX2, had the most significant protein-protein interactions with TPO. Moreover, Analysis of possible mRNA-miRNA interactions by miRWalk, demonstrated a significant connection between TPO and hsa-miR-769-3p that was confirmed by ENCORI co-expression analysis(p-value = 9.26e-03). Finally, H19 was identified as a considerable lncRNA using the LncBase v.3 database, which has a strong interaction with our selected miRNA.
  • Conclusion: Based on the results of this investigation, TPO plays an important role in thyroid hormone synthesis. Also, the down-expression of TPO in Anaplastic thyroid cancer could establish a novel ceRNA regulatory network among hsa-miR-769-3p, TPO, and H19 that could be suggested as potential diagnostic and prognostic biomarkers associated with Anaplastic thyroid cancer.
  • Keywords: Anaplastic thyroid cancer TPO ceRNA network Microarray analysis