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Purpose The study aims to uncover molecular mechanisms of PTC (papillary thyroid carcinoma) progression and provide therapeutic biomarkers. Methods The paired tumor and control tissues were obtained from 5 PTC patients. RNA was extracted and cDNA libraries were constructed. RNA-sequencing (RNA-seq) was performed on the Illumina HiSeq2000 platform using paired-end method. After preprocessing of the RNA-seq data, gene expression value was calculated by RPKM. Then the differentially expressed genes (DEGs) were identified with edgeR. Functional enrichment and protein-protein interaction (PPI) network analyses were conducted for the DEGs. Module analysis of the PPI network was also performed. Transcription factors (TFs) of DEGs were predicted. Results A cohort of 496 up-regulated DEGs mainly correlating with the ECM degradation pathways, and 440 down-regulated DEGs predominantly enriching in transmembrane transport process were identified. Hub nodes in the PPI network were RRM2 and a set of collagens (COL1A1, COL3A1 and COL5A1), which were also remarkable in module 3 and module 5, respectively. Genes in module 3 were associated with cell cycle pathways, while in module 5 were related to ECM degradation pathways. PLAU, PSG1 and EGR2 were the crucial TFs with higher transcriptional activity in PTC than in control. Conclusion Several genes including COL1A1 , COL3A1 , RRM2 , PLAU , and EGR2 might be used as biomarkers of PTC therapy. Among them, COL1A1 and COL3A1 might exert their functions via involving in ECM degradation pathway, while RRM2 through cell cycle pathway. PLAU might be an active TF, whereas EGR2 might be a tumor suppressor. [ABSTRACT FROM AUTHOR]