Cell Cycle M-Phase Genes Are Highly Upregulated in Anaplastic Thyroid Carcinoma

Abstract

Background: Anaplastic thyroid carcinoma (ATC) accounts for only 3% of thyroid cancers, yet strikingly, it accounts for almost 40% of thyroid cancer deaths. Currently, no effective therapies exist. In an effort to identify ATC-specific therapeutic targets, we analyzed global gene expression data from multiple studies to identify ATC-specific dysregulated genes. Methods: The National Center for Biotechnology Information Gene Expression Omnibus database was searched for high-throughput gene expression microarray studies from human ATC tissue along with normal thyroid and/or papillary thyroid cancer (PTC) tissue. Gene expression levels in ATC were compared with normal thyroid or PTC using seven separate comparisons, and an ATC-specific gene set common in all seven comparisons was identified. We investigated these genes for their biological functions and pathways. Results: There were three studies meeting inclusion criteria, (including 32 ATC patients, 69 PTC, and 75 normal). There were 259 upregulated genes and 286 downregulated genes in ATC with at least two-fold change in all seven comparisons. Using a five-fold filter, 36 genes were upregulated in ATC, while 40 genes were downregulated. Of the 10 top globally upregulated genes in ATC, 4/10 (MMP1, ANLN, CEP55, and TFPI2) are known to play a role in ATC progression; however, 6/10 genes (TMEM158, CXCL5, E2F7, DLGAP5, MME, and ASPM) had not been specifically implicated in ATC. Similarly, 3/10 (SFTA3, LMO3, and C2orf40) of the most globally downregulated genes were novel in this context, while 7/10 genes (SLC26A7, TG, TSHR, DUOX2, CDH1, PDE8B, and FOXE1) have been previously identified in ATC. We experimentally validated a significant correlation for seven transcription factors (KLF16, SP3, ETV6, FOXC1, SP1, EGFR1, and MAFK) with the ATC-specific genes using microarray analysis of ATC cell lines. Ontology clustering of globally altered genes revealed that ''mitotic cell cycle'' is highly enriched in the globally upregulated gene set (44% of top upregulated genes, p-value <10 -30 ). Conclusions: By focusing on globally altered genes, we have identified a set of consistently altered biological processes and pathways in ATC. Our data are consistent with an important role for M-phase cell cycle genes in ATC, and may provide direction for future studies to identify novel therapeutic targets for this disease.

Global RNA Expression and DNA Methylation Patterns in Primary Anaplastic Thyroid Cancer

“…Furthermore, we found relatively low expression of TSHR and SLC26A7, encoding the thyroid-stimulating hormone receptor and an iodine receptor highly expressed in normal thyroid, respectively, as well as aberrant DNA methylation in their gene bodies (Table S12). Both of these genes have been previously reported to display low expression in ATC, and aberrant methylation has previously been reported for TSHR [5,18]. However, a link between expression and methylation has not been previously reported in primary ATC.…”

“…Gene expression analyses using microarrays have shown upregulation of genes involved in mitotic cell cycle, epithelial to mesenchymal transition, and TGF-beta signaling in ATC compared with papillary thyroid cancer (PTC) and/or normal thyroid tissue. In contrast, genes related to thyroid hormone synthesis and differentiation have been reported to be downregulated [4][5][6][7][8][9]. However, all expression studies published so far were conducted on small cohorts, including ≤20 cases.…”

ANLN-induced EZH2 upregulation promotes pancreatic cancer progression by mediating miR-218-5p/LASP1 signaling axis

“…Thus, ANLN may be a useful prognostic indicator and an important therapeutic target in the treatment of pancreatic cancer. Previous studies have shown that ANLN is upregulated in many cancers and may serve as a promising prognostic biomarker for cancer [13][14][15][16][17][18]. For example, ANLN was upregulated in bladder urothelial carcinoma, and elevated ANLN expression was correlated with poor progression-free and recurrence-free survival [16].…”

“…In normal tissues, ANLN expression is higher in the placenta, brain and testis, and lower in the lung, heart, liver and spleen [8]. Many recent studies suggests that ANLN is upregulated in numerous cancer types, including cervical cancer, prostate cancer, anaplastic thyroid carcinoma, breast cancer, lung carcinogenesis, bladder urothelial carcinoma, pancreatic cancer and nasopharyngeal carcinoma [9][10][11][12][13][14][15][16]. Functionally, increasing evidence has indicated that ANLN is critical for growth and metastasis of cancer cells.…”

A User Relinquishment-based Resource Assignment Scheme to Maximize the Net Profit of Cloud Service Providers

“…The biggest example is the recent deal between a very famous application company called Snapchat and Google to rent the entire application development infrastructure through the Google Cloud Platform (GCP) service [5] [6] [7]. Other than that, various reputable organizations and financial institutions are expected to be multi-billion markets for the cloud computing industry [8].…”