Gene Summary

Gene:TOP2A; DNA topoisomerase II alpha
Aliases: TOP2, TP2A
Summary:This gene encodes a DNA topoisomerase, an enzyme that controls and alters the topologic states of DNA during transcription. This nuclear enzyme is involved in processes such as chromosome condensation, chromatid separation, and the relief of torsional stress that occurs during DNA transcription and replication. It catalyzes the transient breaking and rejoining of two strands of duplex DNA which allows the strands to pass through one another, thus altering the topology of DNA. Two forms of this enzyme exist as likely products of a gene duplication event. The gene encoding this form, alpha, is localized to chromosome 17 and the beta gene is localized to chromosome 3. The gene encoding this enzyme functions as the target for several anticancer agents and a variety of mutations in this gene have been associated with the development of drug resistance. Reduced activity of this enzyme may also play a role in ataxia-telangiectasia. [provided by RefSeq, Jul 2010]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:DNA topoisomerase 2-alpha
Source:NCBIAccessed: 30 August, 2019


What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 30 August 2019 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 30 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (6)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: TOP2A (cancer-related)

Zhong X, Huang G, Ma Q, et al.
Identification of crucial miRNAs and genes in esophageal squamous cell carcinoma by miRNA-mRNA integrated analysis.
Medicine (Baltimore). 2019; 98(27):e16269 [PubMed] Free Access to Full Article Related Publications
Esophageal squamous cell carcinoma (ESCC) is a malignancy that severely threatens human health and carries a high incidence rate and a low 5-year survival rate. MicroRNAs (miRNAs) are commonly accepted as a key regulatory function in human cancer, but the potential regulatory mechanisms of miRNA-mRNA related to ESCC remain poorly understood.The GSE55857, GSE43732, and GSE6188 miRNA microarray datasets and the gene expression microarray datasets GSE70409, GSE29001, and GSE20347 were downloaded from Gene Expression Omnibus databases. The differentially expressed miRNAs (DEMs) and differentially expressed genes (DEGs) were obtained using GEO2R. Gene ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis for DEGs were performed by Database for Annotation, Visualization and Integrated Discovery (DAVID). A protein-protein interaction (PPI) network and functional modules were established using the STRING database and were visualized by Cytoscape. Kaplan-Meier analysis was constructed based on The Cancer Genome Atlas (TCGA) database.In total, 26 DEMs and 280 DEGs that consisted of 96 upregulated and 184 downregulated genes were screened out. A functional enrichment analysis showed that the DEGs were mainly enriched in the ECM-receptor interaction and cytochrome P450 metabolic pathways. In addition, MMP9, PCNA, TOP2A, MMP1, AURKA, MCM2, IVL, CYP2E1, SPRR3, FOS, FLG, TGM1, and CYP2C9 were considered to be hub genes owing to high degrees in the PPI network. MiR-183-5p was with the highest connectivity target genes in hub genes. FOS was predicted to be a common target gene of the significant DEMs. Hsa-miR-9-3p, hsa-miR-34c-3p and FOS were related to patient prognosis and higher expression of the transcripts were associated with a poor OS in patients with ESCC.Our study revealed the miRNA-mediated hub genes regulatory network as a model for predicting the molecular mechanism of ESCC. This may provide novel insights for unraveling the pathogenesis of ESCC.

Fan X, Wang Y, Tang XQ
Extracting predictors for lung adenocarcinoma based on Granger causality test and stepwise character selection.
BMC Bioinformatics. 2019; 20(Suppl 7):197 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Lung adenocarcinoma is the most common type of lung cancer, with high mortality worldwide. Its occurrence and development were thoroughly studied by high-throughput expression microarray, which produced abundant data on gene expression, DNA methylation, and miRNA quantification. However, the hub genes, which can be served as bio-markers for discriminating cancer and healthy individuals, are not well screened.
RESULT: Here we present a new method for extracting gene predictors, aiming to obtain the least predictors without losing the efficiency. We firstly analyzed three different expression microarrays and constructed multi-interaction network, since the individual expression dataset is not enough for describing biological behaviors dynamically and systematically. Then, we transformed the undirected interaction network to directed network by employing Granger causality test, followed by the predictors screened with the use of the stepwise character selection algorithm. Six predictors, including TOP2A, GRK5, SIRT7, MCM7, EGFR, and COL1A2, were ultimately identified. All the predictors are the cancer-related, and the number is very small fascinating diagnosis. Finally, the validation of this approach was verified by robustness analyses applied to six independent datasets; the precision is up to 95.3% ∼ 100%.
CONCLUSION: Although there are complicated differences between cancer and normal cells in gene functions, cancer cells could be differentiated in case that a group of special genes expresses abnormally. Here we presented a new, robust, and effective method for extracting gene predictors. We identified as low as 6 genes which can be taken as predictors for diagnosing lung adenocarcinoma.

Kuwano M, Shibata T, Watari K, Ono M
Oncogenic Y-box binding protein-1 as an effective therapeutic target in drug-resistant cancer.
Cancer Sci. 2019; 110(5):1536-1543 [PubMed] Free Access to Full Article Related Publications
Y-box binding protein-1 (YBX1), a multifunctional oncoprotein containing an evolutionarily conserved cold shock domain, dysregulates a wide range of genes involved in cell proliferation and survival, drug resistance, and chromatin destabilization by cancer. Expression of a multidrug resistance-associated ATP binding cassette transporter gene, ABCB1, as well as growth factor receptor genes, EGFR and HER2/ErbB2, was initially discovered to be transcriptionally activated by YBX1 in cancer cells. Expression of other drug resistance-related genes, MVP/LRP, TOP2A, CD44, CD49f, BCL2, MYC, and androgen receptor (AR), is also transcriptionally activated by YBX1, consistently indicating that YBX1 is involved in tumor drug resistance. Furthermore, there is strong evidence to support that nuclear localization and/or overexpression of YBX1 can predict poor outcomes in patients with more than 20 different tumor types. YBX1 is phosphorylated by kinases, including AKT, p70S6K, and p90RSK, and translocated into the nucleus to promote the transcription of resistance- and malignancy-related genes. Phosphorylated YBX1, therefore, plays a crucial role as a potent transcription factor in cancer. Herein, a novel anticancer therapeutic strategy is presented by targeting activated YBX1 to overcome drug resistance and malignant progression.

Chen YJ, Guo YN, Shi K, et al.
Down-regulation of microRNA-144-3p and its clinical value in non-small cell lung cancer: a comprehensive analysis based on microarray, miRNA-sequencing, and quantitative real-time PCR data.
Respir Res. 2019; 20(1):48 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Previous studies have shown that miR-144-3p might be a potential biomarker in non-small cell lung cancer (NSCLC). Nevertheless, the comprehensive mechanism behind the effects of miR-144-3p on the origin, differentiation, and apoptosis of NSCLC, as well as the relationship between miR-144-3p and clinical parameters, has been rarely reported.
METHODS: We investigated the correlations between miR-144-3p expression and clinical characteristics through data collected from Gene Expression Omnibus (GEO) microarrays, the relevant literature, The Cancer Genome Atlas (TCGA), and real-time quantitative real-time PCR (RT-qPCR) analyses to determine the clinical role of miR-144-3p in NSCLC. Furthermore, we investigated the biological function of miR-144-3p by Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. Protein-protein interaction (PPI) network was created to identify the hub genes.
RESULTS: From the comprehensive meta-analysis, the combined SMD of miR-144-3p was - 0.95 with 95% CI of (- 1.37, - 0.52), indicating that less miR-144-3p was expressed in the NSCLC tissue than in the normal tissue. MiR-144-3p expression was significantly correlated with stage, lymph node metastasis and vascular invasion (all P <  0.05). As for the bioinformatics analyses, a total of 37 genes were chosen as the potential targets of miR-144-3p in NSCLC. These promising target genes were highly enriched in various key pathways such as the protein digestion and absorption and the thyroid hormone signaling pathways. Additionally, PPI revealed five genes-C12orf5, CEP55, E2F8, STIL, and TOP2A-as hub genes with the threshold value of 6.
CONCLUSIONS: The current study validated that miR-144-3p was lowly expressed in NSCLC. More importantly, miR-144-3p might function as a latent tumor biomarker in the prognosis prediction for NSCLC. The results of bioinformatics analyses may present a new method for investigating the pathogenesis of NSCLC.

Gao Z, Man X, Li Z, et al.
Expression profiles analysis identifies the values of carcinogenesis and the prognostic prediction of three genes in adrenocortical carcinoma.
Oncol Rep. 2019; 41(4):2440-2452 [PubMed] Related Publications
Adrenocortical carcinoma (ACC) is a rare disease associated with a poor prognosis. Furthermore, the underlying molecular mechanism of carcinogenesis is poorly understood, and prognostic prediction of ACC has low accuracy. In the present study, a bioinformatics approach was used to investigate the molecular mechanisms and prognosis of ACC. Samples of adrenal tumors were collected from patients undergoing adrenalectomy at the Department of Urology, the First Hospital of China Medical University. The analyzed gene datasets were downloaded from the Gene Expression Omnibus and The Cancer Genome Atlas (TCGA) database. Following this, the differentially expressed genes (DEGs) were included in Gene Ontology enrichment, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, protein‑protein interaction network and survival analyses. MTT colorimetric assays, colony formation assays and 5‑ethynyl‑20‑deoxyuridine incorporation assays were also conducted to evaluate ACC cell proliferation. The identified DEGs included 20 downregulated genes and 51 upregulated genes, which were highly associated with the cell cycle, organelle fission, chromosome segregation, cell division and spindle stability. The top 14 hub genes were subsequently confirmed by reverse transcription‑quantitative polymerase chain reaction in ACC and adrenocortical adenoma samples. It was identified that the nuclear division cycle 80, cyclin B2 and topoisomerase 2‑α may serve important roles in adrenocortical tumor development. Furthermore, these three genes predicted overall survival and recurrence‑free survival in patients with ACC from the TCGA cohort. The findings identified three novel genes that have important roles in carcinogenesis and in the prognostic prediction of ACC.

Niotis A, Tsiambas E, Fotiades PP, et al.
ki-67 and Topoisomerase IIa proliferation markers in colon adenocarcinoma.
J BUON. 2018; 23(7):24-27 [PubMed] Related Publications
Aberrant cell proliferation is a major cause in the development and progression of carcinogenic process. Epithelia characterized by increased mitotic rates accumulate easily gross numerical and structural chromosomes (polysomy/aneuploidy) and specific gene (deletions, amplifications, point mutations, translocations) deregulations that lead to their progressive neoplastic and finally malignant transformation. Molecules that are critical for evaluating the proliferation status of the corresponding tissues include mainly ki-67 (cytogenetic band: 10q26.2), and also Topoisomerase IIa/Topo IIa (cytogenetic band: 17q21.2). Both of them demonstrate different expression patterns in every cell cycle phase and their estimated expression as Nuclear Labeling Index (NLI) is a very useful tool for assessing the aggressiveness of the examined pre- and malignant tissues. In fact, ki-67 expression increases as a cell progresses through the cell cycle, with highest expression being seen in G2/M phase cell, whereas Topo IIa is expressed in proliferating cells in the late S phase with a peak in G2-M phases. Concerning colon adenocarcinoma, high expression levels of them seem to correlate with advanced disease and also with modified response rates to specific chemotherapeutic agents, such as doxorubicin, an inhibitor of Topo IIa. In the current molecular review we explored the role of these proliferative markers in colon adenocarcinoma and their influence in the tumor biological behavior.

Wu M, Liu Z, Zhang A, Li N
Identification of key genes and pathways in hepatocellular carcinoma: A preliminary bioinformatics analysis.
Medicine (Baltimore). 2019; 98(5):e14287 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most prevalent cancers worldwide. However, the precise mechanisms of the development and progression of HCC remain unclear. The present study attempted to identify and functionally analyze the differentially expressed genes between HCC and cirrhotic tissues by using comprehensive bioinformatics analyses.
METHODS: The GSE63898 gene expression profile was downloaded from the Gene Expression Omnibus (GEO) and analyzed using the online tool GEO2R to identify differentially expressed genes (DEGs). Gene ontology (GO) functional analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of the DEGs were performed in DAVID. The STRING database was used to evaluate the interactions of DEGs and to construct a protein-protein interaction (PPI) network using Cytoscape software. Hub genes were selected using the cytoHubba plugin and were validated with the cBioPortal database.
RESULTS: A total of 301 DEGs were identified between HCC and cirrhotic tissues. The GO analysis results showed that these DEGs were significantly enriched in certain biological processes including negative regulation of growth and cell chemotaxis. Several significant pathways, including the p53 signaling pathway, were identified as being closely associated with these DEGs. The top 12 hub genes were screened and included TTK, NCAPG, TOP2A, CCNB1, CDK1, PRC1, RRM2, UBE2C, ZWINT, CDKN3, AURKA, and RACGAP1. The cBioPortal analysis found that alterations in hub genes could result in significantly reduced disease-free survival in HCC.
CONCLUSION: The present study identified a series of key genes and pathways that may be involved in the tumorigenicity and progression of HCC, providing a new understanding of the underlying molecular mechanisms of carcinogenesis in HCC.

Eltohamy MI, Badawy OM, El kinaai N, et al.
Topoisomerase II α Gene alteration in Triple Negative Breast Cancer and Its Predictive Role for Anthracycline-Based Chemotherapy (Egyptian NCI Patients)
Asian Pac J Cancer Prev. 2018; 19(12):3581-3589 [PubMed] Free Access to Full Article Related Publications
Objective: Triple negative breast cancer is an aggressive variant of breast cancer; it forms about 15% of breast cancer cases. It lacks the responsiveness to hormonal and targeted therapies. Anthracyclines remain the treatment option for these patients. Anthracyclines are cardiotoxic, so predicting sensitivity of response by biological predictors may have a role in selecting suitable candidates for these drugs. Material and methods: This study included 50 TNBC cases, from National Cancer Institute, Cairo University(NCI-CU), Egypt, who underwent surgery and received adjuvant chemotherapy. Archived blocks were obtained and immunostaining for Ki-67 LI and Fluorescent In situ Hybridization (FISH) technique to assess TOP2A gene copy number and chromosome 17CEP status were done. Analysis of association between TOP2A alterations and CEP17 polysomy as well as Ki-67 LI with other clinicopathological parameters was done. Associations between the biological markers and event free survival (EFS) and overall survival (OS), were also performed. Results: TOP2A alteration was seen in 9/50 cases (5 amplified and 4 deleted). CEP17 Polysomy was detected in 14% of cases. Most of patients (80%) showed Ki-67 LI ≥20%. There was a significant association between TOP2A gene and CEP17 status. Outcome was better with abnormal TOP2A gene status and CEP17 polysomy, radiotherapy and combined anthracyclines and taxanes in the adjuvant setting, however P-values were not significant. Conclusion: TOP2A gene alterations and CEP17 polysomy may have prognostic and predictive role in TNBC treated with adjuvant Anthracyclines.

Song J, Ma Q, Hu M, et al.
The Inhibition of miR-144-3p on Cell Proliferation and Metastasis by Targeting TOP2A in HCMV-Positive Glioblastoma Cells.
Molecules. 2018; 23(12) [PubMed] Free Access to Full Article Related Publications
Glioblastoma (GBM), the most common type of primary tumor in the central nervous system, is a very aggressive brain tumor with poor prognosis and a high recurrence rate. Increasing evidence suggests that human cytomegalovirus (HCMV) infection is related to GBM and leads to GBM cell growth and metastasis. MicroRNAs are important regulators in the growth and metastasis of glioblastoma. This study aimed to demonstrate the role of miR-144-3p in HCMV-positive glioblastoma. We found that, after HCMV infection, the expression of miR-144-3p decreased, whereas the expression of TOP2A increased. Bioinformatics analyses indicated that miR-144-3p directly targets the TOP2A 3'-UTR (Untranslated Region). We discovered that the overexpression of miR-144-3p downregulated the overexpression of TOP2A and inhibited the proliferation, clone formation, and invasion of HCMV-positive glioma in vitro. Taken together, these results show that miR-144-3p inhibited growth and promoted apoptosis in glioma cells by targeting TOP2A.

Gan BL, Zhang LJ, Gao L, et al.
Downregulation of miR‑224‑5p in prostate cancer and its relevant molecular mechanism via TCGA, GEO database and in silico analyses.
Oncol Rep. 2018; 40(6):3171-3188 [PubMed] Free Access to Full Article Related Publications
The function of the expression of microRNA (miR)‑224‑5p in prostate adenocarcinoma (PCa) remains to be elucidated, therefore, the present study aimed to investigate the clinical significance and potential molecular mechanism of miR‑224‑5p in PCa. Data on the expression of miR‑224‑5p in PCa were extracted from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), ArrayExpress and previous literature, and meta‑analyses with standardized mean difference (SMD) and summary receiver operating characteristic (sROC) methods were performed for statistical analyses. The prospective target genes of miR‑224‑5p were collected by overlapping the differentially expressed mRNAs in TCGA and GEO, and target genes predicted by miRWalk2.0. Subsequently, in silico analysis was performed to examine the associated pathways of miR‑224‑5p in PCa. The expression of miR‑224‑5p was markedly lower in PCa; the overall SMD was ‑0.562, and overall sROC area under the curve was 0.80. In addition, Kyoto Encyclopedia of Genes and Genomes analysis revealed that the prospective target genes of miR‑224‑5p were largely enriched in the amino sugar and nucleotide sugar metabolism signaling pathway, and three genes [UDP‑N‑acetylglucosamine pyrophosphorylase 1 (UAP1), hexokinase 2 (HK2) and chitinase 1 (CHIT1)] enriched in this pathway showed higher expression (P<0.05). In addition, key genes in the protein‑protein interaction network analysis [DNA topoisomerase 2‑α (TOP2A), ATP citrate lyase (ACLY) and ribonucleotide reductase regulatory subunit M2 (RRM2)] exhibited significantly increased expression (P<0.05). The results suggested that the downregulated expression of miR‑224‑5p may be associated with the clinical progression and prognosis of PCa. Furthermore, miR‑224‑5p likely exerts its effects by targeting genes, including UAP1, HK2, CHIT1, TOP2A, ACLY and RRM2. However, in vivo and in vitro experiments are required to confirm these findings.

Sasanuma H, Tsuda M, Morimoto S, et al.
BRCA1 ensures genome integrity by eliminating estrogen-induced pathological topoisomerase II-DNA complexes.
Proc Natl Acad Sci U S A. 2018; 115(45):E10642-E10651 [PubMed] Free Access to Full Article Related Publications
Women having BRCA1 germ-line mutations develop cancer in breast and ovary, estrogen-regulated tissues, with high penetrance. Binding of estrogens to the estrogen receptor (ER) transiently induces DNA double-strand breaks (DSBs) by topoisomerase II (TOP2) and controls gene transcription. TOP2 resolves catenated DNA by transiently generating DSBs, TOP2-cleavage complexes (TOP2ccs), where TOP2 covalently binds to 5' ends of DSBs. TOP2 frequently fails to complete its catalysis, leading to formation of pathological TOP2ccs. We have previously shown that the endonucleolytic activity of MRE11 plays a key role in removing 5' TOP2 adducts in G

Gao X, Wang X, Zhang S
Bioinformatics identification of crucial genes and pathways associated with hepatocellular carcinoma.
Biosci Rep. 2018; 38(6) [PubMed] Free Access to Full Article Related Publications
Hepatocellular carcinoma (HCC) is a major cause of cancer-related death worldwide. Up to date, HCC pathogenesis has not been fully understood. The aim of the present study was to identify crucial genes and pathways associated with HCC by bioinformatics methods. The differentially expressed genes (DEGs) between 14 HCC tissues and corresponding non-cancerous tissues were identified using limma package. Gene Ontology (GO) and KEGG pathway enrichment analysis of DEGs were performed by clusterProfiler package. The protein-protein interaction (PPI) network of DEGs was constructed and visualized by STRING database and Cytoscape software, respectively. The crucial genes in PPI network were identified using a Cytoscape plugin, CytoNCA. Furthermore, the effect of the expression level of the crucial genes on HCC patient survival was analyzed by an interactive web-portal, UALCAN. A total of 870 DEGs including 237 up-regulated and 633 down-regulated genes were identified in HCC tissues. KEGG pathway analysis revealed that DEGs were mainly enriched in complement and coagulation cascades pathway, chemical carcinogenesis pathway, retinol metabolism pathway, fatty acid degradation pathway, and valine, leucine and isoleucine degradation pathway. PPI network analysis showed that

Gerashchenko TS, Denisov EV, Novikov NM, et al.
Different morphological structures of breast tumors demonstrate individual drug resistance gene expression profiles.
Exp Oncol. 2018; 40(3):228-234 [PubMed] Related Publications
AIM: To identify gene expression profiles involved in drug resistance of different morphological structures (tubular, alveolar, solid, trabecular, and discrete) presented in breast cancer.
MATERIAL AND METHODS: Ten patients with luminal breast cancer have been included. A laser microdissection-assisted microarrays and qRT-PCR were used to perform whole-transcriptome profiling of different morphological structures, to select differentially expressed drug response genes, and to validate their expression.
RESULTS: We found 27 differentially expressed genes (p < 0.05) encoding drug uptake (SLC1A3, SLC23A2, etc.) and efflux (ABCC1, ABCG1, etc.) transporters, drug targets (TOP2A, TYMS, and Tubb3), and proteins that are involved in drug detoxification (NAT1 and ALDH1B1), cell cycle progression (CCND1, AKT1, etc.), apoptosis (CASP3, TXN2, etc.), and DNA repair (BRCA1 and USP11). Each type of structures showed an individual gene expression profile related to resistance and sensitivity to anticancer drugs. However, most of the genes (19/27; p < 0.05) were expressed in alveolar structures. Functional enrichment analysis showed that drug resistance is significantly associated with alveolar structures. Other structures demonstrated the similar number (10-13 out of 27) of expressed genes; however, the spectrum of resistance and sensitivity to different anticancer drugs varied.
CONCLUSION: Different morphological structures of breast cancer show individual expression of drug resistance genes.

Hu S, Liao Y, Chen L
Identification of Key Pathways and Genes in Anaplastic Thyroid Carcinoma via Integrated Bioinformatics Analysis.
Med Sci Monit. 2018; 24:6438-6448 [PubMed] Free Access to Full Article Related Publications
BACKGROUND To provide a better understanding of anaplastic thyroid carcinoma (ATC) at the molecular level, this study aimed to identify the genes and key pathways associated with ATC by using integrated bioinformatics analysis. MATERIAL AND METHODS Based on the microarray data GSE9115, GSE65144, and GSE53072 derived from the Gene Expression Omnibus, the differentially expressed genes (DEGs) between ATC samples and normal controls were identified. With DEGs, we performed a series of functional enrichment analyses. Then, a protein-protein interaction (PPI) network was constructed and visualized, with which the hub gene nodes were screened out. Finally, modules analysis for the PPI network was performed to further investigate the potential relationships between DEGs and ATC. RESULTS A total of 537 common DEGs were screened out from all 3 datasets, among which 247 genes were upregulated and 275 genes were downregulated. GO analysis indicated that upregulated DEGs were mainly involved in cell division and mitotic nuclear division and the downregulated DEGs were significantly enriched in ventricular cardiac muscle cell action potential. KEGG pathway analysis showed that the upregulated DEGs were mainly enriched in cell cycle and ECM-receptor interaction and the downregulated DEGs were mainly enriched in thyroid hormone synthesis, insulin resistance, and pathways in cancer. The top 10 hub genes in the constructed PPI network were CDK1, CCNB1, TOP2A, AURKB, CCNA2, BUB1, AURKA, CDC20, MAD2L1, and BUB1B. The modules analysis showed that genes in the top 2 significant modules of PPI network were mainly associated with mitotic cell cycle and positive regulation of mitosis, respectively. CONCLUSIONS We identified a series of key genes along with the pathways that were most closely related with ATC initiation and progression. Our results provide a more detailed molecular mechanism for the development of ATC, shedding light on the potential biomarkers and therapeutic targets.

Phelps HM, Al-Jadiry MF, Corbitt NM, et al.
Molecular and epidemiologic characterization of Wilms tumor from Baghdad, Iraq.
World J Pediatr. 2018; 14(6):585-593 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
BACKGROUND: Wilms tumor (WT) is the most common childhood kidney cancer worldwide, yet its incidence and clinical behavior vary according to race and access to adequate healthcare resources. To guide and streamline therapy in the war-torn and resource-constrained city of Baghdad, Iraq, we conducted a first-ever molecular analysis of 20 WT specimens to characterize the biological features of this lethal disease within this challenged population.
METHODS: Next-generation sequencing of ten target genes associated with WT development and treatment resistance (WT1, CTNNB1, WTX, IGF2, CITED1, SIX2, p53, N-MYC, CRABP2, and TOP2A) was completed. Immunohistochemistry was performed for 6 marker proteins of WT (WT1, CTNNB1, NCAM, CITED1, SIX2, and p53). Patient outcomes were compiled.
RESULTS: Mutations were detected in previously described WT "hot spots" (e.g., WT1 and CTNNB1) as well as novel loci that may be unique to the Iraqi population. Immunohistochemistry showed expression domains most typical of blastemal-predominant WT. Remarkably, despite the challenges facing families and care providers, only one child, with combined WT1 and CTNNB1 mutations, was confirmed dead from disease. Median clinical follow-up was 40.5 months (range 6-78 months).
CONCLUSIONS: These data suggest that WT biology within a population of Iraqi children manifests features both similar to and unique from disease variants in other regions of the world. These observations will help to risk stratify WT patients living in this difficult environment to more or less intensive therapies and to focus treatment on cell-specific targets.

Liu LM, Xiong DD, Lin P, et al.
DNA topoisomerase 1 and 2A function as oncogenes in liver cancer and may be direct targets of nitidine chloride.
Int J Oncol. 2018; 53(5):1897-1912 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
The aim of the present study was to determine the role of topoisomerase 1 (TOP1) and topoisomerase 2A (TOP2A) in liver cancer (LC), and to investigate the inhibitory effect of nitidine chloride (NC) on these two topoisomerases. Immunohistochemistry (IHC) staining and microarray or RNA sequencing data mining showed markedly higher expression of TOP1 and TOP2A at the protein and mRNA levels in LC tissues compared with that in control non-tumor tissues. The prognostic values of TOP1 and TOP2A expression were also estimated based on data from The Cancer Genome Atlas. The elevated expression levels of TOP1 and TOP2A were closely associated with poorer overall survival and disease-free survival rates. When patients with LC were divided into high- and low-risk groups according to their prognostic index, TOP1 and TOP2A were highly expressed in the high-risk group. Bioinformatics analyses conducted on the co-expressed genes of TOP1 and TOP2A revealed that the topoisomerases were involved in several key cancer-related pathways, including the 'p53 pathway', 'pathway in cancer' and 'apoptosis signaling pathway'. Reverse transcription-quantitative polymerase chain reaction and IHC performed on triplicate tumor tissue samples from LC xenografts in control or NC-treated nude mice showed that NC treatment markedly reduced the protein and mRNA expression of TOP1 and TOP2A in LC tissues. Molecular docking studies further confirmed the direct binding of NC to TOP1 and TOP2A. In conclusion, the present findings indicate that TOP1 and TOP2A are oncogenes in LC and could serve as potential biomarkers for the prediction of the prognosis of patients with LC and for identification of high-risk cases, thereby optimizing individual treatment management. More importantly, the findings support TOP1 and TOP2A as potential drug targets of NC for the treatment of LC.

Kwinta BM, Wilk A, Trofimiuk-Muldner M, et al.
The relation of pituitary adenomas invasiveness and the proliferative index measured by immunoexpression of topoisomerase IIα.
Endokrynol Pol. 2018; 69(5):530-535 [PubMed] Related Publications
INTRODUCTION: Cavernous sinus invasion by pituitary adenoma affects surgical procedure radicality and consequently the postoperative course and prognosis in pituitary adenoma treatment. The search for pituitary adenoma aggressive behaviour markers is still a matter of debate.
MATERIAL AND METHODS: This study evaluates the relation of pituitary adenoma invasiveness to the expression of topoisomerase IIα in 72 patients who underwent transsphenoidal pituitary surgery. The assessment of tumour growth was conducted according to the Hardy scale as modified by Wilson and the Knosp scale. Topoisomerase IIα expression in tumour specimens was evaluated using immunohistochemical staining.
RESULTS: There was a correlation between the Knosp scale degree and the topoisomerase IIα expression (Spearman R = 0.3611, p < 0.005). The Kruskal-Wallis H test (p = 0.0034) showed that there was a statistically significant topoisomerase IIα expression increase in tumours classified as grade E on the Hardy scale. The topoisomerase IIα expression correlated also with tumour size (Spearman R = 0.4117, p < 0.001). Higher levels of expression were observed in macroadenomas, as compared to microadenomas (p < 0.05, Mann-Whitney test). Topoisomerase IIα expression correlated with cavernous sinus invasion.
CONCLUSIONS: The topoisomerase IIα expression correlated more with invasiveness than with extensiveness, which might make it an eminently useful marker in the assessment of aggressive pituitary adenoma behaviour.

Meagher NS, Schuster K, Voss A, et al.
Does the primary site really matter? Profiling mucinous ovarian cancers of uncertain primary origin (MO-CUP) to personalise treatment and inform the design of clinical trials.
Gynecol Oncol. 2018; 150(3):527-533 [PubMed] Related Publications
OBJECTIVE: Advanced stage mucinous ovarian cancers are diagnostically and therapeutically challenging. Histotype specific trials have failed due to low recruitment after excluding non-ovarian primaries. Mucinous ovarian cancers are commonly metastatic from other sites however lack definitive diagnostic markers. We suggest a classification of mucinous ovarian cancers of uncertain primary origin 'MO-CUPs' in clinical trials. This study aims to identify drug targets to guide treatment and future trials.
METHODS: We analyzed a large de-identified, multi-platform tumor profiling dataset of MO-CUPs enriched for advanced stage and recurrent cases submitted to Caris Life Sciences. Available data included a 45-gene next-generation sequencing (NGS) panel, gene amplification of HER2 and cMET and 18 immunohistochemical (IHC) markers of drug sensitivity/resistance.
RESULTS: Mucinous tumors from 333 patients were analyzed, including 38 borderline tumors and 295 invasive cancers. The most common mutations in a subset (n = 128) of invasive cancers were KRAS (60%), TP53 (38%), PIK3CA (13%) and PTEN (9%). Borderline tumors had higher rates of BRAF mutations, and PGP and TOP2A overexpression than invasive cases. KRAS mutant invasive cancers had lower expression of thymidylate synthase (p = 0.01) and higher expression of TUBB3 (p = 0.01) than KRAS wildtype tumors.
CONCLUSIONS: To our knowledge, this is the largest series profiling mucinous ovarian cancers and almost certainly includes cases of ovarian and non-ovarian origin. Given the difficulty recruiting patients to histotype-specific trials in rare subsets of ovarian cancer, it may be more important to focus on identifying potential treatment targets and to personalise treatment and design clinical trials in MO-CUPS agnostic of primary site to overcome these issues.

Li N, Li L, Chen Y
The Identification of Core Gene Expression Signature in Hepatocellular Carcinoma.
Oxid Med Cell Longev. 2018; 2018:3478305 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
Hepatocellular carcinoma (HCC) is one of the most common malignancies, which causes serious financial burden worldwide. This study aims to investigate the potential mechanisms contributing to HCC and identify core biomarkers. The HCC gene expression profile GSE41804 was picked out to analyze the differentially expressed genes (DEGs). Gene ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were carried out using DAVID. We constructed a protein-protein interaction (PPI) network to visualize interactions of the DEGs. The survival analysis of these hub genes was conducted to evaluate their potential effects on HCC. In this analysis, 503 DEGs were captured (360 downregulated genes and 143 upregulated genes). Meanwhile, 15 hub genes were identified. GO analysis showed that the DEGs were mainly enriched in oxidative stress, cell cycle, and extracellular structure. KEGG analysis suggested the DEGs were enriched in the absorption, metabolism, and cell cycle pathway. PPI network disclosed that the top3 modules were mainly enriched in cell cycle, oxidative stress, and liver detoxification. In conclusion, our analysis uncovered that the alterations of oxidative stress and cell cycle are two major signatures of HCC. TOP2A, CCNB1, and KIF4A might promote the development of HCC, especially in proliferation and differentiation, which could be novel biomarkers and targets for diagnosis and treatment of HCC.

Li W, Liu J, Fu W, et al.
3-O-acetyl-11-keto-β-boswellic acid exerts anti-tumor effects in glioblastoma by arresting cell cycle at G2/M phase.
J Exp Clin Cancer Res. 2018; 37(1):132 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
BACKGROUND: Glioblastoma (GBM) is the most common, malignant, and lethal primary brain tumor in adults accounting for about 50% of all gliomas. Up to now, the chemotherapy approaches for GBM were limited. 3-O-acetyl-11-keto-β-boswellic acid (AKBA), the major active ingredient of the gum resin from Boswellia serrata and Boswellia carteri Birdw., was reported to inhibit the growth of many types of cancer cells; however, the underlying mechanism of its anticancer effects are still unclear.
METHODS: The effects of AKBA on cell viability and its cytotoxicity were determined using CCK8 and LDH kits respectively. The EdU-DNA synthesis assay was used to evaluate inhibition of cell proliferation by AKBA. The role of AKBA in glioblastoma cell functions such as migration/invasion, and colony formation was evaluated using transwell chambers and soft agar, respectively. Flow cytometry and western blotting were used to detect AKBA-induced apoptosis. Potential mechanisms of AKBA action were explored by RNA sequencing and the identified hub genes were validated by real-time quantitative PCR and western blotting. Finally, the in vivo anti-tumor activity of AKBA was evaluated against a human glioblastoma cell line, U87-MG, in a xenograft mouse model.
RESULTS: AKBA inhibited cell proliferation, caused the release of LDH, decreased DNA synthesis, and inhibited the migration, invasion, and colony formation of U251 and U87-MG human glioblastoma cell lines. AKBA increased apoptosis as well as the activity of caspase 3/7 and the protein expression of cleaved-caspase 3 and cleaved PARP, while decreasing mitochondrial membrane potential. RNA-sequencing analyses showed that AKBA suppressed the expression of pRB, FOXM1, Aurora A, PLK1, CDC25C, p-CDK1, cyclinB1, Aurora B, and TOP2A while increasing the expression of p21 and GADD45A. These findings were validated by qRT-PCR and western blotting. The data are consistent with a mechanism in which AKBA arrested the cell cycle in glioblastoma cells at the G2/M phase by regulating the p21/FOXM1/cyclin B1 pathway, inhibited mitosis by downregulating the Aurora B/TOP2A pathway, and induced mitochondrial-dependent apoptosis. Oral administration of AKBA (100 mg/kg) significantly suppressed the tumorigenicity of U87-MG cells in a xenograft mouse model.
CONCLUSIONS: Taken together, these results suggest that AKBA (molecular weight, 512.7 Da) might be a promising chemotherapy drug in the treatment of GBM.

Ferguson SD, Zheng S, Xiu J, et al.
Profiles of brain metastases: Prioritization of therapeutic targets.
Int J Cancer. 2018; 143(11):3019-3026 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
We sought to compare the tumor profiles of brain metastases from common cancers with those of primary tumors and extracranial metastases in order to identify potential targets and prioritize rational treatment strategies. Tumor samples were collected from both the primary and metastatic sites of nonsmall cell lung cancer, breast cancer and melanoma from patients in locations worldwide, and these were submitted to Caris Life Sciences for tumor multiplatform analysis, including gene sequencing (Sanger and next-generation sequencing with a targeted 47-gene panel), protein expression (assayed by immunohistochemistry) and gene amplification (assayed by in situ hybridization). The data analysis considered differential protein expression, gene amplification and mutations among brain metastases, extracranial metastases and primary tumors. The analyzed population included: 16,999 unmatched primary tumor and/or metastasis samples: 8,178 nonsmall cell lung cancers (5,098 primaries; 2,787 systemic metastases; 293 brain metastases), 7,064 breast cancers (3,496 primaries; 3,469 systemic metastases; 99 brain metastases) and 1,757 melanomas (660 primaries; 996 systemic metastases; 101 brain metastases). TOP2A expression was increased in brain metastases from all 3 cancers, and brain metastases overexpressed multiple proteins clustering around functions critical to DNA synthesis and repair and implicated in chemotherapy resistance, including RRM1, TS, ERCC1 and TOPO1. cMET was overexpressed in melanoma brain metastases relative to primary skin specimens. Brain metastasis patients may particularly benefit from therapeutic targeting of enzymes associated with DNA synthesis, replication and/or repair.

Hashimoto Y, Penas-Prado M, Zhou S, et al.
Rethinking medulloblastoma from a targeted therapeutics perspective.
J Neurooncol. 2018; 139(3):713-720 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
INTRODUCTION: Medulloblastoma is an aggressive but potentially curable central nervous system tumor that remains a treatment challenge. Analysis of therapeutic targets can provide opportunities for the selection of agents.
METHODS: Using multiplatform analysis, 36 medulloblastomas were extensively profiled from 2009 to 2015. Immunohistochemistry, next generation sequencing, chromogenic in situ hybridization, and fluorescence in situ hybridization were used to identify overexpressed proteins, immune checkpoint expression, mutations, tumor mutational load, and gene amplifications.
RESULTS: High expression of MRP1 (89%, 8/9 tumors), TUBB3 (86%, 18/21 tumors), PTEN (85%, 28/33 tumors), TOP2A (84%, 26/31 tumors), thymidylate synthase (TS; 80%, 24/30 tumors), RRM1 (71%, 15/21 tumors), and TOP1 (63%, 19/30 tumors) were found in medulloblastoma. TOP1 was found to be enriched in metastatic tumors (90%; 9/10) relative to posterior fossa cases (50%; 10/20) (p = 0.0485, Fisher exact test), and there was a positive correlation between TOP2A and TOP1 expression (p = 0.0472). PD-1 + T cell tumor infiltration was rare, PD-L1 tumor expression was uncommon, and TML was low, indicating that immune checkpoint inhibitors as a monotherapy should not necessarily be prioritized for therapeutic consideration based on biomarker expression. Gene amplifications such as those of Her2 or EGFR were not found. Several unique mutations were identified, but their rarity indicates large-scale screening efforts would be necessary to identify sufficient patients for clinical trial inclusion.
CONCLUSIONS: Therapeutics are available for several of the frequently expressed targets, providing a justification for their consideration in the setting of medulloblastoma.

Everson RG, Hashimoto Y, Freeman JL, et al.
Multiplatform profiling of meningioma provides molecular insight and prioritization of drug targets for rational clinical trial design.
J Neurooncol. 2018; 139(2):469-478 [PubMed] Related Publications
INTRODUCTION: Surgery and radiation therapy are the standard treatment options for meningiomas, but these treatments are not always feasible. Expression profiling was performed to determine the presence of therapeutic actionable biomarkers for prioritization and selection of agents.
METHODS: Meningiomas (n = 115) were profiled using a variety of strategies including next-generation sequencing (592-gene panel: n = 14; 47-gene panel: n = 94), immunohistochemistry (n = 8-110), and fluorescent and chromogenic in situ hybridization (n = 5-70) to determine mutational and expression status.
RESULTS: The median age of patients in the cohort was 60 years, with a range spanning 6-90 years; 52% were female. The most frequently expressed protein markers were EGFR (93%; n = 44), followed by PTEN (77%; n = 110), BCRP (75%; n = 8), MRP1 (65%, n = 23), PGP (62%; n = 84), and MGMT (55%; n = 97). The most frequent mutation among all meningioma grades occurred in the NF2 gene at 85% (11/13). Recurring mutations in SMO and AKT1 were also occasionally detected. PD-L1 was expressed in 25% of grade III cases (2/8) but not in grade I or II tumors. PD-1 + T cells were present in 46% (24/52) of meningiomas. TOP2A and thymidylate synthase expression increased with grade (I = 5%, II = 22%, III = 62% and I = 5%, II = 23%, III = 47%, respectively), whereas progesterone receptor expression decreased with grade (I = 79%, II = 41%, III = 29%).
CONCLUSION: If predicated on tumor expression, our data suggest that therapeutics directed toward NF2 and TOP2A could be considered for most meningioma patients.

Matsumoto A, Hayashida T, Takahashi M, et al.
Antitumor effect of lapatinib and cytotoxic agents by suppression of E2F1 in HER2‑positive breast cancer.
Mol Med Rep. 2018; 18(1):958-964 [PubMed] Related Publications
The human epidermal growth factor receptor 2 (HER2)‑targeting agent, lapatinib, combined with oral fluoropyrimidine capecitabine, has been previously demonstrated to be an effective treatment option for patients with trastuzumab‑resistant HER2‑positive metastatic breast cancer. To investigate the molecular mechanisms associated with the interactions between lapatinib and capecitabine, the effect of treatment with lapatinib and phosphatidylinositol‑4,5‑bisphosphate 3‑kinase (PI3K) inhibitors on the expression of E2F transcription factor 1 (E2F1) and thymidylate synthase (TS), which is associated with an increased response to 5‑fluorouracil (5‑FU)‑based chemotherapy, was determined in HER2‑positive breast cancer cells. The results of reverse transcription‑quantitative polymerase chain reaction demonstrated that administration of lapatinib and PI3K inhibitors decreased the mRNA expression of TS and E2F1, a transcription factor that promotes TS gene expression, in SKBR3 and T47D cell lines. Furthermore, treatment with lapatinib and PI3K inhibitors also suppressed the mRNA expression of ribonucleotide reductase M1 subunit (RRM1), an important determinant of gemcitabine resistance, and DNA topoisomerase II‑α (TOP2A), a molecular target of anthracyclines, in SKBR3 and T47D cell lines. Western blot analysis further demonstrated that the phosphorylation of Akt was inhibited by lapatinib, and the results of the MTT assay revealed that the combination of lapatinib with either 5‑FU or gemcitabine demonstrated synergistic antitumor effects, whereas a combinatory treatment of lapatinib with epirubicin, a typical anthracycline drug, exhibited antagonistic antitumor effects in HER2‑positive breast cancer cells. These results indicate that the synergistic antitumor effects exhibited by combinatory treatment of lapatinib with capecitabine may be induced via the suppression of E2F1‑mediated TS expression.

Wen P, Chidanguro T, Shi Z, et al.
Identification of candidate biomarkers and pathways associated with SCLC by bioinformatics analysis.
Mol Med Rep. 2018; 18(2):1538-1550 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
Small cell lung cancer (SCLC) is one of the highly malignant tumors and a serious threat to human health. The aim of the present study was to explore the underlying molecular mechanisms of SCLC. mRNA microarray datasets GSE6044 and GSE11969 were downloaded from Gene Expression Omnibus database, and the differentially expressed genes (DEGs) between normal lung and SCLC samples were screened using GEO2R tool. Functional and pathway enrichment analyses were performed for common DEGs using the DAVID database, and the protein‑protein interaction (PPI) network of common DEGs was constructed by the STRING database and visualized with Cytoscape software. In addition, the hub genes in the network and module analysis of the PPI network were performed using CentiScaPe and plugin Molecular Complex Detection. Finally, the mRNA expression levels of hub genes were validated in the Oncomine database. A total of 150 common DEGs with absolute fold‑change >0.5, including 66 significantly downregulated DEGs and 84 upregulated DEGs were obtained. The Gene Ontology term enrichment analysis suggested that common upregulated DEGs were primarily enriched in biological processes (BPs), including 'cell cycle', 'cell cycle phase', 'M phase', 'cell cycle process' and 'DNA metabolic process'. The common downregulated genes were significantly enriched in BPs, including 'response to wounding', 'positive regulation of immune system process', 'immune response', 'acute inflammatory response' and 'inflammatory response'. Kyoto Encyclopedia of Genes and Genomes pathway analysis identified that the common downregulated DEGs were primarily enriched in the 'complement and coagulation cascades' signaling pathway; the common upregulated DEGs were mainly enriched in 'cell cycle', 'DNA replication', 'oocyte meiosis' and the 'mismatch repair' signaling pathways. From the PPI network, the top 10 hub genes in SCLC were selected, including topoisomerase IIα, proliferating cell nuclear antigen, replication factor C subunit 4, checkpoint kinase 1, thymidylate synthase, minichromosome maintenance protein (MCM) 2, cell division cycle (CDC) 20, cyclin dependent kinase inhibitor 3, MCM3 and CDC6, the mRNA levels of which are upregulated in Oncomine SCLC datasets with the exception of MCM2. Furthermore, the genes in the significant module were enriched in 'cell cycle', 'DNA replication' and 'oocyte meiosis' signaling pathways. Therefore, the present study can shed new light on the understanding of molecular mechanisms of SCLC and may provide molecular targets and diagnostic biomarkers for the treatment and early diagnosis of SCLC.

Zhang L, Huang Y, Ling J, et al.
Screening and function analysis of hub genes and pathways in hepatocellular carcinoma via bioinformatics approaches.
Cancer Biomark. 2018; 22(3):511-521 [PubMed] Related Publications
BACKGROUND: Liver carcinoma is a major cause of cancer-related death worldwide. Up to date, the mechanisms of liver cancerigenesis and development have not been fully understood. Multi-genes and pathways were involved in the tumorigenesis of liver cancer.
OBJECTIVE: The aim of the present study was to screen key genes and pathways in liver cancerigenesis and development by using bioinformatics methods.
METHODS: A dataset GSE64041 were retrieved from GEO database and the differentially expressed genes (DEGs) were screened out. Then the DEG functions were annotated by gene ontology (GO) and pathway enrichment analysis, respectively. The hub genes were further selected by protein-protein interaction (PPI) analysis. Afterwards, the mRNA and protein expressions as well as the prognostic values of the hub genes were assessed.
RESULTS: As a result, 208 up-regulated and 82 down-regulated genes were screened out. These DEGs were mainly enriched in cell cycle and metabolism-related pathways. Through PPI analysis, TOP2A, PRDM10, CDK1, AURKA, BUB1, PLK1, CDKN3, NCAPG, BUB1B and CCNA2 were selected as hub genes, which were all over-expressed in liver cancers relative to those in normal tissues, respectively. Among them, PLK1 and CCNA2 were suggested to be prognostic factors for liver carcinoma.
CONCLUSION: In conclusion, the present study identified several hub genes, and cell cycle and metabolism-related pathways that may play critical roles in the tumorigenesis of liver cancer. Future validation laboratory experiments are required to confirm the results.

Gao HY, Wang W, Luo XG, et al.
Screening of prognostic risk microRNAs for acute myeloid leukemia.
Hematology. 2018; 23(10):747-755 [PubMed] Related Publications
Objectives This study aimed to investigate the risk miRNAs (microRNAs) for AML (acute myeloid leukemia) prognosis and related regulatory mechanisms. Methods MiRNA and gene expression data, as well as clinical data of 176 patients were first downloaded from TCGA. Then miRNAs and genes significantly affecting the survival time based on KM survival curve were identified using Log Rank test. Next, COX proportional-hazard regression analysis was performed to screen the risk miRNAs (P-value < 0.05). Common genes from survival analysis and predicted by miRWalk were used to construct the miRNA regulatory network with the risk miRNAs. Finally, a protein-protein interaction (PPI) network was constructed, as well as functional annotation and pathway enrichment analysis. Results The survival analysis revealed 33 miRNAs and 1,377 genes significantly affecting the survival time. HR values of nine miRNAs (up-regulated hsa-mir-606, 520a, 137, 362, 599, 600, 202, 639and down-regulated 502) were either >1 or <1. The miRNA regulatory network contained 477 nodes and 944 edges. The top ten genes of the constructed PPI network were EGFR, EIF4G1, REL, TOP1, COL14A1, HDAC3, MRPL49, PSMA2, TOP2A and VCAM1 successively. According to pathway enrichment analysis, 6 KEGG pathways and 6 REACTOME pathways were obtained respectively. Conclusion Up-regulated hsa-mir-520a, 599, 606, 137 and 362 may increase the prognostic risk for AML patients via regulating the expression of corresponding target genes, especially COL14A1, HDAC3, REL, EGFR, PSMA2, EIF4G1, MRPL49 and TOP1.

Hsu JM, Xia W, Hsu YH, et al.
STT3-dependent PD-L1 accumulation on cancer stem cells promotes immune evasion.
Nat Commun. 2018; 9(1):1908 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
Enriched PD-L1 expression in cancer stem-like cells (CSCs) contributes to CSC immune evasion. However, the mechanisms underlying PD-L1 enrichment in CSCs remain unclear. Here, we demonstrate that epithelial-mesenchymal transition (EMT) enriches PD-L1 in CSCs by the EMT/β-catenin/STT3/PD-L1 signaling axis, in which EMT transcriptionally induces N-glycosyltransferase STT3 through β-catenin, and subsequent STT3-dependent PD-L1 N-glycosylation stabilizes and upregulates PD-L1. The axis is also utilized by the general cancer cell population, but it has much more profound effect on CSCs as EMT induces more STT3 in CSCs than in non-CSCs. We further identify a non-canonical mesenchymal-epithelial transition (MET) activity of etoposide, which suppresses the EMT/β-catenin/STT3/PD-L1 axis through TOP2B degradation-dependent nuclear β-catenin reduction, leading to PD-L1 downregulation of CSCs and non-CSCs and sensitization of cancer cells to anti-Tim-3 therapy. Together, our results link MET to PD-L1 stabilization through glycosylation regulation and reveal it as a potential strategy to enhance cancer immunotherapy efficacy.

Litviakov N, Tsyganov M, Larionova I, et al.
Expression of M2 macrophage markers YKL-39 and CCL18 in breast cancer is associated with the effect of neoadjuvant chemotherapy.
Cancer Chemother Pharmacol. 2018; 82(1):99-109 [PubMed] Related Publications
PURPOSE: High activity of enzyme TOP2a in tumor cells is known to be associated with sensitivity to anthracycline chemotherapy, but 20% of such patients do not show clinical response. Tumor microenvironment, including tumor-associated macrophages (TAM), is an essential factor defining the efficiency of chemotherapy. In the present study, we analyzed the expression of M2 macrophage markers, YKL-39 and CCL18, in tumors of breast cancer patients received anthracycline-based NAC.
METHODS: Patients were divided into two groups according to the level of doxorubicin sensitivity marker TOP2a: DOX-Sense and DOX-Res groups. Expression levels of TOR2a, CD68, YKL-39 and CCL18 genes were analyzed by qPCR, the amplification of TOR2a gene locus was assessed by the microarray assay. Clinical and pathological responses to neoadjuvant chemotherapy were assessed.
RESULTS: We found that the average level of TOP2a expression in patients of DOX-Sense group was almost 10 times higher than in patients of DOX-Res group, and the expression of CD68 was 3 times higher in the DOX-Sense group compared to DOX-Res group. We demonstrated that expression levels of M2-derived cytokines but not the amount of TAM is indicative for clinical and pathological chemotherapy efficacy in breast cancer patients. Out of 8 patients from DOX-Sense group who did not respond to neoadjuvant chemotherapy (NAC), 7 patients had M2+ macrophage phenotype (YKL-39
CONCLUSIONS: Thus, we showed that in patients with breast cancer who received anthracycline-containing NAC the absence of clinical response is associated with the presence of M2+ macrophage phenotype (YKL-39-CCL18 + or YKL-39 + CCL18-) based on TOP2a overexpression data.

Wang J, Tian Y, Chen H, et al.
Key signaling pathways, genes and transcription factors associated with hepatocellular carcinoma.
Mol Med Rep. 2018; 17(6):8153-8160 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
The purpose of the present study was to investigate the underlying molecular mechanism of hepatocellular carcinoma (HCC) using bioinformatics approaches. The microarray dataset GSE64041 was downloaded from the Gene Expression Omnibus database, which included 60 tumor liver samples and 60 matched control samples. Differentially expressed genes (DEGs) between HCC and control groups were identified. Then functional enrichment analyses, protein‑protein interaction (PPI) network, sub‑network and integrated transcription factor (TF)‑microRNA (miRNA)‑target network analyses were performed for these DEGs. A total of 378 DEGs were obtained, including 101 upregulated and 277 downregulated DEGs. In addition, functional enrichment analysis for DEGs in the sub‑network revealed 'cell division' and 'cell cycle' as key Gene Ontology (GO) terms and pathways. Topoisomerase (DNA) IIα (TOP2A) and integrin subunit α2 (ITGA2) were hub nodes in the PPI network. TOP2A, cyclin dependent kinase 1 (CDK1) and polo like kinase 1 (PLK1) were revealed to be hub nodes in the sub‑network. Finally, 4 TFs including forkhead box M1 (FOXM1), E2F transcription factor 4 (E2F4), SIN3 transcription regulator family member A (SIN3A) and transcription factor 7 like 1 (TCF7L1) were obtained through integrated network analysis. TOP2A, ITGA2, PLK1 and CDK1 may be key genes involved in HCC development. 'Cell division' and 'cell cycle' were indicated to act as key GO terms and Kyoto Encyclopedia of Genes and Genomes pathways in HCC. In addition, FOXM1, TCF7L1, E2F4 and SIN3A were revealed to be key TFs associated with HCC.

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