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Differences in Gene Expression Profile of Primary Tumors in Metastatic and Non-Metastatic Papillary Thyroid Carcinoma-Do They Exist?

ABSTRACT: Molecular mechanisms of distant metastases (M1) in papillary thyroid cancer (PTC) are poorly understood. We attempted to analyze the gene expression profile in PTC primary tumors to seek the genes associated with M1 status and characterize their molecular function. One hundred and twenty-three patients, including 36 M1 cases, were subjected to transcriptome oligonucleotide microarray analyses: (set A-U133, set B-HG 1.0 ST) at transcript and gene group level (limma, gene set enrichment analysis (GSEA)). An additional independent set of 63 PTCs, including 9 M1 cases, was used to validate results by qPCR. The analysis on dataset A detected eleven transcripts showing significant differences in expression between metastatic and non-metastatic PTC. These genes were validated on microarray dataset B. The differential expression was positively confirmed for only two genes: IGFBP3, (most significant) and ECM1. However, when analyzed on an independent dataset by qPCR, the IGFBP3 gene showed no differences in expression. Gene group analysis showed differences mainly among immune-related transcripts, indicating the potential influence of tumor immune infiltration or signal within the primary tumor. The differences in gene expression profile between metastatic and non-metastatic PTC, if they exist, are subtle and potentially detectable only in large datasets.

SUBMITTER: Szpak-Ulczok S

PROVIDER: S-EPMC7369779 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Differences in Gene Expression Profile of Primary Tumors in Metastatic and Non-Metastatic Papillary Thyroid Carcinoma-Do They Exist?

Szpak-Ulczok Sylwia S Pfeifer Aleksandra A Rusinek Dagmara D Oczko-Wojciechowska Malgorzata M Kowalska Malgorzata M Tyszkiewicz Tomasz T Cieslicka Marta M Handkiewicz-Junak Daria D Fujarewicz Krzysztof K Lange Dariusz D Chmielik Ewa E Zembala-Nozynska Ewa E Student Sebastian S Kotecka-Blicharz Agnieszka A Kluczewska-Galka Aneta A Jarzab Barbara B Czarniecka Agnieszka A Jarzab Michal M Krajewska Jolanta J

International journal of molecular sciences 20200629 13

Molecular mechanisms of distant metastases (M1) in papillary thyroid cancer (PTC) are poorly understood. We attempted to analyze the gene expression profile in PTC primary tumors to seek the genes associated with M1 status and characterize their molecular function. One hundred and twenty-three patients, including 36 M1 cases, were subjected to transcriptome oligonucleotide microarray analyses: (set A-U133, set B-HG 1.0 ST) at transcript and gene group level (limma, gene set enrichment analysis ( ...[more]

PMID: 32610693

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Project description:Papillary thyroid carcinoma (PTC) is the most common endocrine cancer with a significantly increase of the incidence recently. Several cytokines, such as thyroid peroxidase (TPO), cluster of differentiation 56 (CD56), Galectin-3, mesothelial cell (MC), cytokeratin 19 (CK19) and BRAF (B-raf) were recommended to be tested by immunohistochemistry (IHC) for a definitive diagnosis, but were still limited in clinical use because of their relative lower sensitivity and specificity. MicroRNA (miRNA), as a new molecular biomarkers, however, has not been reported yet so far. To address this, hsa-miR-200a-5p, a miRNA, was selected and detected in PTC patients by in situ hybrization with benign thyroid tumor with papillary hyperplasia as a control, and the differential expression of hsa-miR-200a-5p between fresh PTC tissues and control was detected by qRT-PCR. Expressive levels of cytokines of TPO, CD56, Galectin-3, MC, CK19 and B-raf were also detected by immunohistochemistry. The correlation was analyzed by SPSS software using Spearman methods. As expected, the hsa-miR-200a-5p expressive level was significantly increased in PTC patients, compared to that of control, and was consistent with that of TPO, CD56, Galectin-3, MC, CK19 and B-raf. In addition, expression of hsa-miR-200a-5p showed negative correlation to that of TPO (rs = - 0.734; **: P < 0.01) and CD56 (rs = - 0.570; **: P < 0.01), but positive correlation to that of Galectin-3 (rs = 0.601; **: P < 0.01), MC (rs = 0.508; **: P < 0.01), CK19 (rs = 0.712; **: P < 0.01) and B-raf (rs = 0.378; **: P < 0.01). PTC and papillary benign thyroid papillary hyperplasia are difficult to distinguish in morphology, so requiring immunohistochemistry to further differentiate the diagnosis, however, for the existing clinical common diagnostic marker for immunohistochemistry, the sensitivity and accuracy are low, it is easy to miss diagnosis. Therefore, there is an urgent need for a rapid and sensitive molecular marker. So miR-200a-5p can be used to assist in the diagnosis of PTC at the molecular level, and as a biomarker, can be effectively used to distinguish between PTC and benign thyroid tumor with papillary hyperplasia.

Project description:BackgroundDifferently expressed circular RNAs (circRNAs) have been reported to play a considerable role in tumor behavior; however, the expression profile and biological function of circRNAs in papillary thyroid carcinoma (PTC) remains unknown. Thus, the study was aimed to characterize the circRNA expression profile to comprehensively understand the biological behavior of PTC.MethodsWe investigated the expression profile of circRNAs using circRNA microarray in three pairs of PTC and adjacent normal tissues. Quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) was used to validate eight candidate circRNAs in 40 paired PTC tumors and adjacent normal samples. Next, we employed a bioinformatics tool to identify putative miRNA and circRNA-associated downstream genes, followed by constructing a network map of circRNA-miRNA-mRNA interactions and exploring the potential role of the candidate circRNAs.ResultsIn total, 206 up- and 177 downregulated circRNAs were identified in PTC tissues (fold change >1.5; P < 0.05). The expression levels of eight candidate circRNAs confirmed by qRT-PCR were significantly different between the PTC and normal samples. The downstream genes of candidate circRNAs participated in various biological processes and signaling pathways. The most up and downregulated circRNAs were hsa_circRNA_007148 and hsa_circRNA_047771. The lower expression level of hsa_circRNA_047771 was associated BRAFV600 mutation, lymph node metastasis (LNM), as well as with advanced TNM stage (all P < 0.05). The higher expression level of hsa_circRNA_007148 was significantly correlated with LNM (P < 0.05). The areas under receiver operating curve were 0.876 (95% CI [0.78-0.94]) for hsa_circRNA_047771 and 0.846 (95% CI [0.75-0.96]) for hsa_circRNA_007148.DiscussionThe study suggests that dysregulated circRNAs play a critical role in PTC pathogenesis. PTC-related hsa_circRNA_047771 and hsa_circRNA_007148 may serve as potential diagnostic biomarkers and prognostic predictors for PTC patients.

Project description:In order to better understand basic mechanisms of tumor development and identify potential new biomarkers, we have performed difference gel electrophoresis (DIGE) and peptide mass fingerprinting on pooled protein extracts from patients with papillary thyroid carcinoma (PTC) compared with matched normal thyroid tissue. Image analysis of DIGE gels comparing PTC and matched normal thyroid tissue protein indicated that 25% of the protein spots were differentially expressed at a 2.5-fold cutoff and 35% at two-fold. Comparison between two different pools of protein from normal thyroid tissues revealed differential protein expression of only 4% at 2.5-fold and 6% at two-fold cutoff. One hundred ninety-two protein spots were identified by MALDI-TOFMS, representing 90 distinct proteins. Excluding albumin, globins and thyroglobulin, imaging software determined 31 proteins to be differentially expressed at the two-fold (or greater) level. Individual gel comparisons (PTC vs. matched normal) from five patients established that 15/31 (48%) of these proteins exhibited statistically significant differential expression. Previously identified molecular markers in this group of proteins include cathepsin B, cytokeratin 19, and galectin-3. Novel differentially expressed proteins include S100A6, moesin, HSP70 (BiP), peroxiredoxin 2, protein phosphatase 2, selenium binding protein 1, vitamin D binding protein, and proteins involved in mitochondrial function. The use of two-dimensional gel electrophoresis (2DGE) revealed a significantly altered protein mass and/or pI in 10%-15% of proteins, suggesting alternatively spliced forms and other posttranslational modification of proteins revealed by this approach. We confirmed S100A6 as a potentially useful biomarker using immunohistochemical analysis (85% sensitivity and 69% specificity for distinguishing benign from malignant thyroid neoplasms). In summary, proteomic analysis of PTC using DIGE and mass spectrometry has confirmed several known biomarkers, uncovered novel potential biomarkers, and provided insights into global pathophysiologic changes in PTC. Many of the differences observed would not have been detected by genomic or other proteomic approaches.

Dataset Information

Differences in Gene Expression Profile of Primary Tumors in Metastatic and Non-Metastatic Papillary Thyroid Carcinoma-Do They Exist?

Publications

Differences in Gene Expression Profile of Primary Tumors in Metastatic and Non-Metastatic Papillary Thyroid Carcinoma-Do They Exist?

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