TOP1

Gene Summary

Gene:TOP1; topoisomerase (DNA) I
Aliases: TOPI
Location:20q12-q13.1
Summary:This gene encodes a DNA topoisomerase, an enzyme that controls and alters the topologic states of DNA during transcription. This enzyme catalyzes the transient breaking and rejoining of a single strand of DNA which allows the strands to pass through one another, thus altering the topology of DNA. This gene is localized to chromosome 20 and has pseudogenes which reside on chromosomes 1 and 22. [provided by RefSeq, Jul 2008]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:DNA topoisomerase 1
HPRD
Source:NCBIAccessed: 16 March, 2015

Ontology:

What does this gene/protein do?
Show (22)

Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 16 March 2015 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 16 March, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (7)

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: TOP1 (cancer-related)

Zavalishina LE, Danilova NV, Matsionis AE, Pavlenko IA
[Specific features of gene amplification on the long arm of chromosome 17 in different molecular genetic subtypes of breast cancer].
Arkh Patol. 2014 Mar-Apr; 76(2):8-12 [PubMed] Related Publications
The frequency of gene amplification and coamplification of HER2/neu, TOP2A and the centromeric region of chromosome 17 (CEP17) was examined in 265 breast cancer (BC) cases belonging to different molecular genetic subgroups. Luminal B breast cancer was found to be characterized by the increased probability of coamplifications (CEP17 and HER/neu, HER2/neu, and TOP2A) on chromosome 17. At the same time, the amplification of just three loci on one chromosome is a rare event and encountered in 17% of luminal B breast cancer cases (or 1.1% of all BC cases). That of HER2/neu in conjunction with elevated CEP17 count is statistically significantly more rarely accompanied by deletion of TOP2A rather than its amplification. The findings suggest that there are different amplification mechanisms in different BC molecular genetic subgroups.

Min W, Wang B, Li J, et al.
The expression and significance of five types of miRNAs in breast cancer.
Med Sci Monit Basic Res. 2014; 20:97-104 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: This study aimed to investigate the expression and significance of 5 types of miRNAs in breast cancer to provide a theoretical and practical foundation for using these miRNAs in the diagnosis and treatment of breast cancer, thereby improving medical services.
MATERIAL/METHODS: Stem-loop real-time RT-PCR was used to detect the expression levels of miR-145, miR-21, miR-10b, miR-125a, and miR-206 in 35 cases of breast cancer and adjacent normal breast tissues, and to analyze the relationship of miRNAs expression with clinicopathological features of breast cancer. The expression levels of estrogen receptor (ER) and progesterone receptor (PR) were examined by immunohistochemistry. Fluorescence in situ hybridization was used for the detection of HER-2 and TOP 2A.
RESULTS: The expression levels of miR-145, miR-125a, and miR-206 in breast cancer were lower than those in adjacent normal tissues. MiR-145 was negatively correlated with tumor size, lymph node metastasis, ER, HER-2, and TOP 2A (P<0.05), regardless of age, menstruation, and PR. MiR-125a was correlated with negative node status, negative HER-2 status (P<0.05), whereas tumor size, age, menstruation, ER, and PR were independent factors. MiR-206 expression was correlated with negative ER status, negative PR status, and negative HER-2 status (P<0.05), regardless of age, menstruation, lymph node metastasis, and TOP 2A. MiR-21 and miR-10b expression in breast cancer tissues was significantly higher than that in adjacent tissues (P<0.05). MiR-21 in post-menstrual patients with lymph node metastasis was highly expressed (P<0.05), and had no correlations with tumor size, ER, PR, and TOP 2A expression. MiR-10b expression was positively correlated with breast cancer tumor size, lymph node metastasis, and TOP 2A status (P<0.05), but had no correlations with age, menstruation, ER, PR, and HER-2.
CONCLUSIONS: MiR-145, miR-21, miR-10b, miR-125a, and miR-206 may play important roles in breast cancer development and invasion.

Fu Y, Zhou S, Liu Y, et al.
The cytotoxicity of benzaldehyde nitrogen mustard-2-pyridine carboxylic acid hydrazone being involved in topoisomerase IIα inhibition.
Biomed Res Int. 2014; 2014:527042 [PubMed] Free Access to Full Article Related Publications
The antitumor property of iron chelators and aromatic nitrogen mustard derivatives has been well documented. Combination of the two pharmacophores in one molecule in drug designation is worth to be explored. We reported previously the syntheses and preliminary cytotoxicity evaluation of benzaldehyde nitrogen mustard pyridine carboxyl acid hydrazones (BNMPH) as extended study, more tumor cell lines (IC50 for HepG2: 26.1 ± 3.5 μM, HCT-116: 57.5 ± 5.3 μM, K562: 48.2 ± 4.0 μM, and PC-12: 19.4 ± 2.2 μM) were used to investigate its cytotoxicity and potential mechanism. In vitro experimental data showed that the BNMPH chelating Fe(2+) caused a large number of ROS formations which led to DNA cleavage, and this was further supported by comet assay, implying that ROS might be involved in the cytotoxicity of BNMPH. The ROS induced changes of apoptosis related genes, but the TFR1 and NDRG1 metastatic genes were not obviously regulated, prompting that BNMPH might not be able to deprive Fe(2+) of ribonucleotide reductase. The BNMPH induced S phase arrest was different from that of iron chelators (G1) and alkylating agents (G2). BNMPH also exhibited its inhibition of human topoisomerase IIα. Those revealed that the cytotoxic mechanism of the BNMPH could stem from both the topoisomerase II inhibition, ROS generation and DNA alkylation.

Miura JT, Johnston FM, Thomas J, et al.
Molecular profiling in gastric cancer: examining potential targets for chemotherapy.
J Surg Oncol. 2014; 110(3):302-6 [PubMed] Related Publications
BACKGROUND AND OBJECTIVES: Current NCCN guidelines recommend epirubicin (E), cisplatin (C), and 5-fluorouracil (F) as a first-line therapeutic approach for operable gastric adenocarcinoma (GC). Molecular profiling (MP) was used to evaluate the expression of chemotherapy targeted biomarkers associated with ECF therapy and other first-line cytotoxic regimens for GC.
METHODS: GC specimens were analyzed by immunohistochemistry (IHC) for TOP2A, TS, ERCC1, PGP, and TOPO1 expression (Caris Life Sciences, Phoenix, AZ) from 2009 to 2012.
RESULTS: A total of 230 GC specimens were analyzed. The median age of patients was 61 (IQR: 50-72) years with the majority being male (n = 139, 60%). IHC actionable targets included: 60% (n = 138) high TOP2A, 55% (n = 127) negative ERCC1, and 63% (n = 145) negative TS, indicating potential benefit from E, C, and F, respectively. Simultaneous expression analysis demonstrated only 24% (n = 55) of patients had gene expression levels that suggested uniform sensitivity to ECF. Biomarker results of 6.5% (n = 15) of patients revealed a potential complete lack of sensitivity to first-line ECF.
CONCLUSIONS: MP of GC has the potential to define patients who would derive the greatest benefit from current therapies. Prospective controlled studies are required to validate the role of biomarkers in the management of GC patients.

Smith NA, Byl JA, Mercer SL, et al.
Etoposide quinone is a covalent poison of human topoisomerase IIβ.
Biochemistry. 2014; 53(19):3229-36 [PubMed] Article available free on PMC after 28/04/2015 Related Publications
Etoposide is a topoisomerase II poison that is utilized to treat a broad spectrum of human cancers. Despite its wide clinical use, 2-3% of patients treated with etoposide eventually develop treatment-related acute myeloid leukemias (t-AMLs) characterized by rearrangements of the MLL gene. The molecular basis underlying the development of these t-AMLs is not well understood; however, previous studies have implicated etoposide metabolites (i.e., etoposide quinone) and topoisomerase IIβ in the leukemogenic process. Although interactions between etoposide quinone and topoisomerase IIα have been characterized, the effects of the drug metabolite on the activity of human topoisomerase IIβ have not been reported. Thus, we examined the ability of etoposide quinone to poison human topoisomerase IIβ. The quinone induced ~4 times more enzyme-mediated DNA cleavage than did the parent drug. Furthermore, the potency of etoposide quinone was ~2 times greater against topoisomerase IIβ than it was against topoisomerase IIα, and the drug reacted ~2-4 times faster with the β isoform. Etoposide quinone induced a higher ratio of double- to single-stranded breaks than etoposide, and its activity was less dependent on ATP. Whereas etoposide acts as an interfacial topoisomerase II poison, etoposide quinone displayed all of the hallmarks of a covalent poison: the activity of the metabolite was abolished by reducing agents, and the compound inactivated topoisomerase IIβ when it was incubated with the enzyme prior to the addition of DNA. These results are consistent with the hypothesis that etoposide quinone contributes to etoposide-related leukemogenesis through an interaction with topoisomerase IIβ.

Shi X, Wu S, Yang Y, et al.
AQP5 silencing suppresses p38 MAPK signaling and improves drug resistance in colon cancer cells.
Tumour Biol. 2014; 35(7):7035-45 [PubMed] Related Publications
It is known that aquaporin 5 (AQP5) may represent a novel therapeutic target for treating colon cancer (CC), but whether AQP5 plays a role in the regulation of multidrug resistance (MDR) of colon cancer still remains unclear. In the present study, AQP5 and P-glycoprotein (P-gp), glutathione S-transferase-π (GST-π), topoisomerase II (TOPO II), and thymidylate synthase (TS) were checked in CC and adjacent cancer tissues; AQP5-siRNA was applied to silencing AQP5 in CC cell line HT-29, 5-fluorouracil (5-FU), and cisplatin (DDP) added on cells, and sulforhodamine B (SRB) was used; fluorescence real-time quantitative RT-PCR and Western blot were employed to detect changes in multidrug resistance factor and expression mitogen-activated protein kinase (MAPK) signaling pathway in HT-29. The results showed that AQP5 is significantly induced in cancer tissues than that in adjacent cancer tissues. The expression of AQP5 is positively correlated with drug resistance factors, as demonstrated by the increased expressions of P-gp, GST-π, and TOPO II in CC tissues compared to that in adjacent cancer tissues. Conversely, knockdown of AQP5 in HT-29 human colon cancer cells increased inhibition rates of cancer chemotherapeutic drugs such as 5-FU and DDP. The improved efficacies of chemotherapeutic drugs are associated with the decreased expression of P-gp, GST-π, and TOPO II. In addition, phosphorylation of p38 MAPK was increased by knockdown of AQP5 in HT-29 cells while phosphorylation and expression of extracellular signal-regulated kinase (ERK), c-jun N-terminal kinase (JNK), and Protein kinase B (AKT) were not affected. P38 MAPK inhibitor increased the drug sensitivity of HT-29 cells in a similar way as AQP5-siRNAs do. So these results indicate that AQP5 is associated with drug resistance of colon cancer, and that the AQP5-P38 MAPK pathway may represent a potential drug target to improve drug resistance of colon cancer cells.

Fasching PA, Weihbrecht S, Haeberle L, et al.
HER2 and TOP2A amplification in a hospital-based cohort of breast cancer patients: associations with patient and tumor characteristics.
Breast Cancer Res Treat. 2014; 145(1):193-203 [PubMed] Related Publications
Gene amplification is an important factor for altered gene expression in breast cancers. TOP2A-amplification often occurs concomitantly with HER2 amplification, and it has been suggested to be predictive for the response to anthracycline chemotherapy. This study assessed the correlation between HER2 status and TOP2A co-amplification, the possible association of TOP2A single-nucleotide polymorphisms with the frequency of this co-amplification as well as confirmation of association with outcome. HER2 and TOP2A amplification were analyzed in a tissue microarray from a clinical cohort study. Additionally, a common genetic variant (rs13695) in the TOP2A gene was genotyped in germline DNA. HER2 gene amplification was compared with HER2-IHC findings assessed during clinical routine work, and the association between all the biomarkers analyzed and the clinical outcome was determined. As an exploratory aim, rs13695 genotypes were compared with TOP2A amplification status. HER2 amplification was seen in 101 of 628 (16.1 %) and TOP2A amplification in 32 (5.1 %) cancers. No TOP2A amplification occurred without HER2 co-amplification. HER2 amplification was found in 8, 13.6, and 55.1 % of patients with HER2-IHC 0/1+, 2+, and 3+ tumors, respectively. HER2-IHC was not associated with an effect on the prognosis, but HER2-FISH was. There was an association between the rs13695 genotype and TOP2A amplification status (P = 0.03). Although there was a significant correlation between HER2 status determined by IHC and HER2 by FISH, only HER2 gene amplification status by FISH was correlated with outcome indicating greater utility for FISH in routine clinical settings.

Sherman-Baust CA, Kuhn E, Valle BL, et al.
A genetically engineered ovarian cancer mouse model based on fallopian tube transformation mimics human high-grade serous carcinoma development.
J Pathol. 2014; 233(3):228-37 [PubMed] Article available free on PMC after 01/07/2015 Related Publications
Recent evidence suggests that ovarian high-grade serous carcinoma (HGSC) originates from the epithelium of the fallopian tube. However, most mouse models are based on the previous prevailing view that ovarian cancer develops from the transformation of the ovarian surface epithelium. Here, we report the extensive histological and molecular characterization of the mogp-TAg transgenic mouse, which expresses the SV40 large T-antigen (TAg) under the control of the mouse müllerian-specific Ovgp-1 promoter. Histological analysis of the fallopian tubes of mogp-TAg mice identified a variety of neoplastic lesions analogous to those described as precursors to ovarian HGSC. We identified areas of normal-appearing p53-positive epithelium that are similar to 'p53 signatures' in the human fallopian tube. More advanced proliferative lesions with nuclear atypia and epithelial stratification were also identified that were morphologically and immunohistochemically reminiscent of human serous tubal intraepithelial carcinoma (STIC), a potential precursor of ovarian HGSC. Beside these non-invasive precursor lesions, we also identified invasive adenocarcinoma in the ovaries of 56% of the mice. Microarray analysis revealed several genes differentially expressed between the fallopian tube of mogp-TAg and wild-type (WT) C57BL/6. One of these genes, Top2a, which encodes topoisomerase IIα, was shown by immunohistochemistry to be concurrently expressed with elevated p53 and was specifically elevated in mouse STICs but not in the surrounding tissues. TOP2A protein was also found elevated in human STICs, low-grade and high-grade serous carcinoma. The mouse model reported here displays a progression from normal tubal epithelium to invasive HGSC in the ovary, and therefore closely simulates the current emerging model of human ovarian HGSC pathogenesis. This mouse therefore has the potential to be a very useful new model for elucidating the mechanisms of serous ovarian tumourigenesis, as well as for developing novel approaches for the prevention, diagnosis and therapy of this disease.

Tabarestani S, Ghaderian SM, Rezvani H, et al.
Prognostic and predictive value of copy number alterations in invasive breast cancer as determined by multiplex ligation-dependent probe amplification.
Cell Oncol (Dordr). 2014; 37(2):107-18 [PubMed] Related Publications
BACKGROUND: Breast cancer is a leading cause of morbidity and mortality in women worldwide. About 70 % of breast cancers are estrogen receptor (ER) positive. Blocking estrogen action by tamoxifen has been the treatment of choice in ER positive breast cancers for more than 30 years. In the past, several studies have revealed associations between gene copy number alterations and responsiveness to tamoxifen therapy, but so far no single gene copy number alteration could completely explain the response variation observed between individual breast cancer patients. Here, we set out to perform a simultaneous analysis of copy number alterations of several genes involved in the prognosis and response to therapy by multiplex ligation-dependent probe amplification (MLPA).
METHODS: A case-control study was designed encompassing 170 non-metastatic ER positive breast cancer patients (case group = 85, control group = 85). All patients in the control group had received standard adjuvant tamoxifen treatment for 5 years without any evidence of recurrence. Patients in the case group had experienced early recurrences while receiving tamoxifen treatment. 76 % of the patients of the case group and 73 % of the patients of the control group had received anthracycline-based adjuvant chemotherapy. Gene copy number alterations detected by MLPA in both groups were compared.
RESULTS: Amplification of CCND1 (OR = 3.13; 95 % CI = 1.35 to 7.26; p = 0.006) and TOP2A (OR = 3.05; 95 % CI = 1.13 to 8.24; p = 0.022) were significantly more prevalent in the case group, compared to the control group. In a multivariate analysis CCND1 (p = 0.01) and TOP2A (p = 0.041) amplifications remained significant predictors of recurrence.
CONCLUSIONS: Our results indicate that CCND1 amplification may serve as a useful biomarker for hormone responsiveness, and that TOP2A amplification may serve as a useful prognostic biomarker.

Latorre E, Castiglioni I, Gatto P, et al.
Loss of protein kinase Cδ/HuR interaction is necessary to doxorubicin resistance in breast cancer cell lines.
J Pharmacol Exp Ther. 2014; 349(1):99-106 [PubMed] Related Publications
The protein kinase Cδ (PKCδ) interacts with and phosphorylates HuR, dictating its functionality. We show here that the genotoxic stimulus induced by doxorubicin triggers PKCδ interaction with HuR and leads to HuR phosphorylation on serines 221 and 318 and cytoplasmic translocation. This series of events is crucial to elicit the death pathway triggered by doxorubicin and is necessary to promote HuR function in post-transcriptional regulation of gene expression, because genetic ablation of PKCδ caused the inability of HuR to bind its target mRNAs, topoisomerase IIα (TOP2A) included. In in vitro select doxorubicin-resistant human breast cancer cell lines upregulating the multidrug resistance marker ABCG2, PKCδ, and HuR proteins were coordinately downregulated together with the doxorubicin target TOP2A protein whose mRNA was HuR-regulated. Therefore, we show here that PKCδ, HuR, and TOP2A constitute a network mediating doxorubicin efficacy in breast cancer cells. The importance of these molecular events in cancer therapy is suggested by their being profoundly suppressed in cells selected for doxorubicin resistance.

Engstrøm MJ, Ytterhus B, Vatten LJ, et al.
TOP2A gene copy number change in breast cancer.
J Clin Pathol. 2014; 67(5):420-5 [PubMed] Article available free on PMC after 01/07/2015 Related Publications
AIMS: The clinical significance of TOP2A as a prognostic marker has not been clarified. The aims of this study were to investigate the frequency of TOP2A copy number change; to correlate TOP2A with HER2 status, hormone receptor (HR) status and molecular subtype, and further to explore differences in breast cancer-specific survival according to TOP2A and HER2.
METHODS: In this study, TOP2A, HER2 and chromosome 17 copy number were assessed in 670 cases of breast cancer using in situ hybridisation techniques. Gene to chromosome ratios ≥2 were classified as amplification. TOP2A deletion (gene to chromosome ratio ≤0.8) or monosomy (only one signal for both gene and chromosome in more than 75% of nuclei) were classified as gene loss.
RESULTS: A strong association between TOP2A change and HR and HER2 status was found. During the first 5 years after diagnosis, the risk of death from breast cancer was significantly higher for cases with HER2 amplification irrespective of TOP2A status.
CONCLUSIONS: TOP2A copy number change was strongly associated with HR and HER2 status and as a prognostic marker TOP2A is probably of limited value.

Cai TY, Liu XW, Zhu H, et al.
Tirapazamine sensitizes hepatocellular carcinoma cells to topoisomerase I inhibitors via cooperative modulation of hypoxia-inducible factor-1α.
Mol Cancer Ther. 2014; 13(3):630-42 [PubMed] Related Publications
Topoisomerase I inhibitors are a class of anticancer drugs with a broad spectrum of clinical activity. However, they have limited efficacy in hepatocellular cancer. Here, we present in vitro and in vivo evidence that the extremely high level of hypoxia-inducible factor-1α (HIF-1α) in hepatocellular carcinoma is intimately correlated with resistance to topoisomerase I inhibitors. In a previous study conducted by our group, we found that tirapazamine could downregulate HIF-1α expression by decreasing HIF-1α protein synthesis. Therefore, we hypothesized that combining tirapazamine with topoisomerase I inhibitors may overcome the chemoresistance. In this study, we investigated that in combination with tirapazamine, topoisomerase I inhibitors exhibited synergistic cytotoxicity and induced significant apoptosis in several hepatocellular carcinoma cell lines. The enhanced apoptosis induced by tirapazamine plus SN-38 (the active metabolite of irinotecan) was accompanied by increased mitochondrial depolarization and caspase pathway activation. The combination treatment dramatically inhibited the accumulation of HIF-1α protein, decreased the HIF-1α transcriptional activation, and impaired the phosphorylation of proteins involved in the homologous recombination repair pathway, ultimately resulting in the synergism of these two drugs. Moreover, the increased anticancer efficacy of tirapazamine combined with irinotecan was further validated in a human liver cancer Bel-7402 xenograft mouse model. Taken together, our data show for the first time that HIF-1α is strongly correlated with resistance to topoisomerase I inhibitors in hepatocellular carcinoma. These results suggest that HIF-1α is a promising target and provide a rationale for clinical trials investigating the efficacy of the combination of topoisomerase I inhibitors and tirapazamine in hepatocellular cancers.

Gao R, Das BB, Chatterjee R, et al.
Epigenetic and genetic inactivation of tyrosyl-DNA-phosphodiesterase 1 (TDP1) in human lung cancer cells from the NCI-60 panel.
DNA Repair (Amst). 2014; 13:1-9 [PubMed] Article available free on PMC after 01/07/2015 Related Publications
Tyrosyl-DNA-phosphodiesterase 1 (TDP1) repairs 3'-blocking DNA lesions by catalytically hydrolyzing the tyrosyl-DNA-phosphodiester bond of trapped topoisomerase I (Top1) cleavage complexes (Top1cc). It also removes 3'-blocking residues derived from oxidative damage or incorporation of chain terminating anticancer and antiviral nucleosides. Thus, TDP1 is regarded as a determinant of resistance to Top1 inhibitors and chain terminating nucleosides, and possibly of genomic stability. In the 60 cell lines of the NCI Developmental Therapeutic Anticancer Screen (the NCI-60), whose whole genome transcriptome and mutations have recently been characterized, we discovered two human lung cancer cell lines deficient for TDP1 (NCI_H522 and HOP_62). HOP_62 shows undetectable TDP1 mRNA and NCI_H522 bears a homozygous deleterious mutation of TDP1 at a highly conserved amino acid residue (K292E). Absence of TDP1 protein and lack of TDP1 catalytic activity were demonstrated in cell lysates from both cell lines. Lack of TDP1 expression in HOP_62 was shown to be due to TDP1 promoter hypermethylation. Our study provides insights into the possible inactivation of TDP1 in cancers and its relationship to cellular response to Top1-targeted drugs. It also reveals two TDP1 knockout lung cancer cell lines for further TDP1 functional analyses.

Silva G, Fachin AL, Beleboni RO, et al.
In vitro action of flavonoids in the canine malignant histiocytic cell line DH82.
Molecules. 2013; 18(12):15448-63 [PubMed] Related Publications
Cancer is commonly diagnosed in dogs over the age of 10 and is a leading cause of death due to the lack of effective drugs. Flavonoids possess antioxidant, anti-inflammatory and anticarcinogenic properties and have been studied as chemopreventive agents in human cancer therapy. However, the literature on dogs is sparse. In this study, we analyzed the effect of nine flavonoids on cell viability, DNA damage and topoisomerase IIa/IIb gene expression in a canine tumor cell line (DH82). Apigenin, luteolin, trans-chalcone and 4-methoxychalcone showed the highest degree of cytotoxicity in the absence of considerable DNA damage, whereas genistein exhibited low cytotoxicity but induced a high level of DNA damage. These five flavonoids inhibited topoisomerase IIa and IIb gene expression to variable extents and with variable specificity. Genistein exerted a lower inhibitory effect on the two topoisomerases than luteolin and apigenin. trans-Chalcone and 4-methoxychalcone exerted greater inhibition of topoisomerase IIa expression than topoisomerase IIb. The differences in the effects between genistein and luteolin and apigenin might be explained by the position of ring B, whereas the more specific effect of chalcones on topoisomerase IIa might be due to their open chain structure.

Mikulová V, Cabiňaková M, Janatková I, et al.
Detection of circulating tumor cells during follow-up of patients with early breast cancer: Clinical utility for monitoring of therapy efficacy.
Scand J Clin Lab Invest. 2014; 74(2):132-42 [PubMed] Related Publications
INTRODUCTION: Circulating tumor cells (CTCs) detection prior to and during therapy is considered as an independent and strong prognostic marker. The present study was designed to isolate and characterize CTCs in peripheral blood of an early breast cancer (BC) patient as a biomarker for monitoring treatments efficacy.
MATERIALS AND METHODS: In total, 54 early breast cancer patients undergoing neoadjuvant and/or adjuvant chemotherapy regimens were enrolled into a prospective study. CTC detection in blood was performed by AdnaTest BreastCancer(™) (AdnaGen AG, Germany), which is based on the detection of EpCAM, HER2 and MUC1 specific transcripts in enriched CTC-lysates. Additionally, cDNA from isolated CTCs and PBMC was used for qPCR gene expression analysis of TOP1, TOP2A, CTSD, ST6, CK19 and reference gene actin.
RESULTS: We found that CTCs can be detected in the peripheral blood of approximately 31% of early stage breast cancer patients. The presence of CTCs was detected in 36% ER positive, 32% PR positive and 30% HER2 positive patients. We found no correlation between CTCs and tumor size, tumor grade, histological grade and receptor status. Only 7% of all patients remained CTCs positive after adjuvant therapy. Gene expression analysis revealed a particular heterogeneity of the studied genes.
CONCLUSIONS: In conclusion, CTC detection may be a promising early marker of disease progression potentially enhancing the difficult therapeutic decisions. Further studies should, however, clearly demonstrate its utility for both the prediction of outcome and monitoring the effect of treatment.

Supernat A, Łapińska-Szumczyk S, Majewska H, et al.
A multimarker qPCR platform for the characterisation of endometrial cancer.
Oncol Rep. 2014; 31(2):1003-13 [PubMed] Related Publications
The molecular background of endometrial cancer (EC) has not been fully elucidated. In the present study, we developed a quantitative PCR (qPCR) platform to examine the gene dosages of the potential molecular markers MGB1, TOP2A, ERBB1-4, MYC, CCND1, ESR1 and PI3K. The platform was applied in samples collected from 157 EC patients (stage I-IV) to verify its clinical utility and to examine the diagnostic and prognostic significance of the analysed biomarkers. The gene dosage pattern of the ERBB family and its downstream effectors PI3K and MYC showed particularly strong correlations with clinicopathological data. The ERBB PI3K/Akt pathway was upregulated in 31 (20%) of 156 cases. Activation of the ERBB PI3K/Akt pathway was positively correlated with a higher stage (p=0.001), higher grade (p=0.001), histological type II disease (p=0.0003) and metastases (p=0.02). The implemented hierarchical clustering revealed that cluster 2 was characterised by high copy numbers of the studied genes. Cluster 2 was associated with shorter overall survival (p=0.05). The platform was found to be a fast and simple method for direct analysis of the genes involved in uterine carcinogenesis, making it feasible for EC biology characterisation.

Smith KA, Cowell IG, Zhang Y, et al.
The role of topoisomerase II beta on breakage and proximity of RUNX1 to partner alleles RUNX1T1 and EVI1.
Genes Chromosomes Cancer. 2014; 53(2):117-28 [PubMed] Related Publications
Rearrangements involving the RUNX1 gene account for approximately 15% of balanced translocations in therapy-related acute myeloid leukemia (t-AML) patients and are one of the most common genetic abnormalities observed in t-AML. Drugs targeting the topoisomerase II (TOP2) enzyme are implicated in t-AML; however, the mechanism is not well understood and to date a single RUNX1-RUNX1T1 t-AML breakpoint junction sequence has been published. Here we report an additional five breakpoint junction sequences from t-AML patients with the RUNX1- RUNX1T1 translocation. Using a leukemia cell line model, we show that TOP2 beta (TOP2B) is required for induction of RUNX1 chromosomal breaks by the TOP2 poison etoposide and that, while TOP2 alpha (TOP2A) and TOP2B proteins are both present on RUNX1 and RUNX1T1 chromatin, only the TOP2B enrichment reached significance following etoposide exposure at a region on RUNX1 where translocations occur. Furthermore, we demonstrate that TOP2B influences the separation between RUNX1 and two translocation partners (RUNX1T1 and EVI) in the nucleus of lymphoid cells. Specifically, we identified a TOP2B-dependent increase in the number of nuclei displaying juxtaposed RUNX1 and RUNX1T1 loci following etoposide treatment.

Rolle CE, Kanteti R, Surati M, et al.
Combined MET inhibition and topoisomerase I inhibition block cell growth of small cell lung cancer.
Mol Cancer Ther. 2014; 13(3):576-84 [PubMed] Article available free on PMC after 01/07/2015 Related Publications
Small cell lung cancer (SCLC) is a devastating disease, and current therapies have not greatly improved the 5-year survival rates. Topoisomerase (Top) inhibition is a treatment modality for SCLC; however, the response is short lived. Consequently, our research has focused on improving SCLC therapeutics through the identification of novel targets. Previously, we identified MNNG HOS transforming gene (MET) to be overexpressed and functional in SCLC. Herein, we investigated the therapeutic potential of combinatorial targeting of MET using SU11274 and Top1 using 7-ethyl-10-hydroxycamptothecin (SN-38). MET and TOP1 gene copy numbers and protein expression were determined in 29 patients with limited (n = 11) and extensive (n = 18) disease. MET gene copy number was significantly increased (>6 copies) in extensive disease compared with limited disease (P = 0.015). Similar TOP1 gene copy numbers were detected in limited and extensive disease. Immunohistochemical staining revealed a significantly higher Top1 nuclear expression in extensive (0.93) versus limited (0.15) disease (P = 0.04). Interestingly, a significant positive correlation was detected between MET gene copy number and Top1 nuclear expression (r = 0.5). In vitro stimulation of H82 cells revealed hepatocyte growth factor (HGF)-induced nuclear colocalization of p-MET and Top1. Furthermore, activation of the HGF/MET axis enhanced Top1 activity, which was abrogated by SU11274. Combination of SN-38 with SU11274 dramatically decreased SCLC growth as compared with either drug alone. Collectively, these findings suggest that the combinatorial inhibition of MET and Top1 is a potentially efficacious treatment strategy for SCLC.

Sayed-Ahmed MM, Hafez MM, Al-Shabanah OA, et al.
Increased expression of biological markers as potential therapeutic targets in Saudi women with triple-negative breast cancer.
Tumori. 2013 Jul-Aug; 99(4):545-54 [PubMed] Related Publications
AIMS AND BACKGROUND: Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer that lacks the expression of hormone receptors and human epidermal growth factor receptor 2 (HER2). Although TNBC represents only 15% of all types of breast cancer, it accounts for a large number of metastatic cases and deaths. Because of the high metastatic rate and both local and systemic recurrence associated with TNBC, extensive research efforts are actively looking for target therapies to effectively treat this aggressive disease. Accordingly, this study has been initiated to investigate the differential expression of biological markers in TNBC and non-TNBC Saudi women that might be utilized as potential targeted therapy and/or predict the sensitivity to currently available therapeutic regimens.
METHODS AND STUDY DESIGN: Two hundred formalin-fixed, paraffin-embedded (FFPE) breast cancer tissues were selected and divided into 3 groups: benign breast tissues (20), TNBC tissues (80) and non-TNBC tissues (100). Expression of mRNA in FFPE tissues was analyzed using real-time polymerase chain reaction (RT-PCR) for the following genes: poly (ADP-ribose) polymerase 1 (PARP-1), topoisomerase 2A (TOPO-2A), vascular endothelial growth factor (VEGF), C-MYC, basic fibroblast growth factor (bFGF), matrix metalloproteinases (MMP-2 and MMP-9), human epidermal growth factor 1 (HER1) and multidrug resistance (MDR) genes.
RESULTS: In the TNBC group, expression of PARP-1, TOPO-2A, HER1, C-MYC, VEGF, bFGF and MMP-2 showed a highly significant increase compared to the non-TNBC group.
CONCLUSIONS: The results of this study suggest that (1) TNBC patients will benefit more from TOPO-2A inhibitors as well as antiangiogenic and antimetastatic therapies; (2) inhibition of these target genes is emerging as one of the most exciting and promising targeted therapeutic strategies to treat TNBC in which the intended targets are DNA repair, tumor angiogenesis and metastasis.

Yuan JM, Mao WM, Luo J, et al.
[Effect of miRNA-106a expression on the prognosis of patients with esophageal squamous cell carcinoma].
Zhonghua Zhong Liu Za Zhi. 2013; 35(8):590-4 [PubMed] Related Publications
OBJECTIVE: To study the expression of miRNA-106a gene in esophageal squamous cell carcinoma (ESCC) and its association with clinicopathological features and prognosis of ESCC patients.
METHODS: Real-time fluorescence quantitative polymerase chain reaction (PCR) assay was used to determine the expression of miRNA-106a gene in esophageal cancer tissue and corresponding normal mucosa of 81 cases. Immunohistochemical technique was applied to detect the expression of p53, human epidermal growth factor receptor 2 (HER-2), DNA topoisomerase II (Topo II) and multidrug resistance-associated protein (MRP). The association of miRNA-106a expression with clinicopathological features, expression of related proteins, and prognosis of the patients was analyzed.
RESULTS: Among the 81 cases, under-expression of miRNA-106a gene was found in 48 cases (59.3%), normal expression in 22 cases (27.2%), and overexpression in 11 cases (13.6%). The expression of miRNA-106 gene was significantly associated with lymph node metastasis, pathological stage, and nerve invasion (all P < 0.05), significantly associated with expression of p53 (P = 0.006), and not significantly associated with expressions of HER-2, Topo II and MRP proteins (all P > 0.05). The expression of miRNA-106a gene was also significantly associated with progression-free survival (PFS, P = 0.032), but not significantly with overall survival (OS, P = 0.486). The results of Cox multivariate regression analysis showed that the PFS of ESCC patients was significantly correlated with lymph node metastasis (P = 0.029), but not correlated with the age, gender, tumor length, T stage, degree of differentiation, nerve invasion, and miRNA-106a expression (all P > 0.05).
CONCLUSIONS: In esophageal squamous cell carcinomas, the miRNA-106a gene is under-expressed, with tumor suppressor function, and may be regarded as a biological marker to assess the prognosis in patients with esophageal squamous cell carcinoma.

García-Caballero T, Prieto O, Vázquez-Boquete A, et al.
Dual-colour CISH is a reliable alternative to FISH for assessment of topoisomerase 2-alpha amplification in breast carcinomas.
Breast Cancer Res Treat. 2014; 143(1):81-9 [PubMed] Related Publications
Anthracyclines are among the most powerful antineoplastic drugs available for breast cancer treatment. Although HER2 amplification has been postulated to predict anthracycline benefit, numerous reports have demonstrated that HER2/TOP2A co-amplification is the clinically useful predictive marker of response to anthracyclines. The standard technique to evaluate gene status for target therapy selection is fluorescence in situ hybridization (FISH), but this technique has some disadvantages. Dual-colour chromogenic in situ hybridization (CISH) is an extension of the FISH protocol that allows bright-field microscopy and thus represents a user-friendly alternative to FISH. In order to evaluate whether dual-colour CISH is a reliable alternative to FISH in determining TOP2A gene amplification and to determine the frequency with which TOP2A and HER2 were co-amplified, we analysed 100 invasive breast cancer specimens (70 consecutive and 30 HER2-amplified samples) using tissue microarrays. Thus, a 99 % agreement was found between TOP2A status determined by dual-colour CISH and FISH, as well as a high degree of correlation in TOP2A ratios using both techniques. TOP2A gene amplification was present in 8.6 % of the 70 consecutive samples studied, all of which were HER2-amplified. Co-amplification of TOP2A was observed in 46.5 % of the additional 30 HER2-amplified samples (no TOP2A amplification was seen in non-amplified HER2 samples). We conclude that dual-colour CISH represents an excellent alternative to FISH for determination of TOP2A gene status in invasive breast cancer. Our results showing TOP2A amplification only in HER2-amplified cases also add to the evidence that TOP2A determination should be restricted to those cases.

Yu C, Liu SL, Qi MH, Zou X
Cinnamaldehyde/chemotherapeutic agents interaction and drug-metabolizing genes in colorectal cancer.
Mol Med Rep. 2014; 9(2):669-76 [PubMed] Related Publications
Cinnamaldehyde is an active monomer isolated from the stem bark of Cinnamomum cassia, a traditional oriental medicinal herb, which is known to possess marked antitumor effects in vitro and in vivo. The aim of the present study was to examine the potential advantages of using cinnamaldehyde in combination with chemotherapeutic agents commonly used in colorectal carcinoma (CRC) therapy, as well as to investigate the effect of cinnamaldehyde on chemotherapeutic-associated gene expression. The synergistic interaction of cinnamaldehyde and chemotherapeutic agents on human CRC HT-29 and LoVo cells was evaluated using the combination index (CI) method. The double staining with Annexin V conjugated to fluorescein-isothiocyanate and phosphatidylserine was employed for apoptosis detection. The expression of drug-metabolizing genes, including excision repair cross‑complementing 1 (ERCC1), orotate phosphoribosyltransferase (OPRT), thymidylate synthase (TS), breast cancer susceptibility gene 1 (BRCA1) and topoisomerase 1 (TOPO1), all in HT-29 and LoVo cells, with or without the addition of cinnamaldehyde, was examined by quantitative polymerase chain reaction (PCR). Cinnamaldehyde had a synergistic effect on the chemotherapeutic agents cytotoxicity in HT-29 and LoVo cells. In addition, cinnamaldehyde suppressed BRCA1, TOPO1, ERCC1 and TS mRNA expression, except for OPRT expression, which was markedly upregulated. Our findings indicate that cinnamaldehyde appears to be a promising candidate as an adjuvant in combination therapy with 5-fluorouracil (5-FU) and oxaliplatin (OXA), two chemotherapeutic agents used in CRC treatment. The possible mechanisms of its action may involve the regulation of drug‑metabolizing genes.

Nygård SB, Christensen IJ, Nielsen SL, et al.
Assessment of the topoisomerase I gene copy number as a predictive biomarker of objective response to irinotecan in metastatic colorectal cancer.
Scand J Gastroenterol. 2014; 49(1):84-91 [PubMed] Related Publications
OBJECTIVE: DNA topoisomerase I is a putative biomarker of irinotecan efficacy with clinical associations previously demonstrated at the protein level. The purpose of the present study was to perform the first clinical investigation of the association between the DNA topoisomerase I gene (TOP1) copy number and objective response following irinotecan treatment in patients with metastatic colorectal cancer.
MATERIALS AND METHODS: Formalin-fixed, paraffin-embedded tumor samples from 78 patients, who received irinotecan monotherapy in second line, were included. TOP1 was assessed by fluorescence in situ hybridization using a technically validated dual-probe combination that hybridizes to TOP1, located at 20q12-q13.1, and to the centromere region of chromosome 20 (CEN-20). In univariate logistic regression models, the TOP1 signal count per cell and the TOP1/CEN-20 ratio were associated with objective response, which was evaluated according to RECIST v.1.1.
RESULTS: Gain of TOP1 was identified in 52.6% and 37.2% using the following cutoff values: TOP1 signal count per cell ≥3.6 and TOP1/CEN-20 ≥1.5, respectively. A borderline significant association (Odds ratio (OR): 1.62; p = 0.07) between a stepwise increase in the TOP1 signal count and objective response was demonstrated. In relation to the applied cutoff values, nonsignificant associations with objective response were identified for the TOP1 signal count (OR: 2.41; p = 0.23) and for the TOP1/CEN-20 ratio (OR: 2.05; p = 0.30).
CONCLUSIONS: Despite limitations of the study the positive associations between TOP1 and objective response suggest that further analysis in larger tumor material, preferably in a randomized setting, is highly warranted.

Bertozzi D, Marinello J, Manzo SG, et al.
The natural inhibitor of DNA topoisomerase I, camptothecin, modulates HIF-1α activity by changing miR expression patterns in human cancer cells.
Mol Cancer Ther. 2014; 13(1):239-48 [PubMed] Related Publications
DNA topoisomerase I (Top1) inhibition by camptothecin derivatives can impair the hypoxia-induced cell transcriptional response. In the present work, we determined molecular aspects of the mechanism of camptothecin's effects on hypoxia-inducible factor-1α (HIF-1α) activity in human cancer cells. In particular, we provide evidence that low concentrations of camptothecin, without interfering with HIF-1α mRNA levels, can reduce HIF-1α protein expression and activity. As luciferase assays demonstrated the involvement of the HIF-1α mRNA 3' untranslated region in camptothecin-induced impairment of HIF-1α protein regulation, we performed microarray analysis to identify camptothecin-induced modification of microRNAs (miRNA) targeting HIF-1α mRNA under hypoxic-mimetic conditions. The selected miRNAs were then further analyzed, demonstrating a role for miR-17-5p and miR-155 in HIF-1α protein expression after camptothecin treatments. The present findings establish miRNAs as key factors in a molecular pathway connecting Top1 inhibition and human HIF-1α protein regulation and activity, widening the biologic and molecular activity of camptothecin derivatives and the perspective for novel clinical interventions.

Kolar Z, Burdova A, Jamaspishvili T, et al.
Relation of ETS transcription factor family member ERG, androgen receptor and topoisomerase 2β expression to TMPRSS2-ERG fusion status in prostate cancer.
Neoplasma. 2014; 61(1):9-16 [PubMed] Related Publications
Fusion of TMPRSS2 with ERG in prostate cells is determined by double-strand DNA breaks induced by androgen signaling and transcription stress. The enzyme topoisomerase 2β (TOP2B) mediating DNA processing, plays an important role in DNA cleavage. The aim of this study was to analyse expression of AR, TOP2B and ERG in relation to TMPRSS2-ERG gene rearrangement and relevant clinicopathological characteristics in prostate cancer (CaP). Immunohistochemical staining and FISH were used for investigation. ERG expression in prostate cell lesions positively correlated with levels of TMPRSS2-ERG fusion gene (p<0.0001). The most significant co-expression of ERG was found with AR in CaP (p=0.001). Significantly more frequent co-expression of ERG was also revealed with TOP2B (p=0.028). ERG protein expression did not correlate with CaP differentiation status as we found no significant differences in ERG expression for different Gleason categories. We demonstrated a statistically significant positive correlation between the percentage of cells with fusion gene TMPRSS2-ERG in CaP and metastatic potential of tumors (p=0.011). Besides these positive corelations of AR with ERG (p=0.001) and TOP2B with ERG (p=0.028), we also demonstrated a significant co-expression of AR with TOP2B (p=0.007) in CaP. There was a statistically significant increase in the TOP2B H-index in locally advanced CaP in comparison with localized tumors (p=0.046). ERG expression correlates with occurrence of TMPRSS2-ERG fusion and with AR-driven malignant transformation. The results indicate that detection of the TMPRSS2-ERG fusion gene and parallel immunohistochemical examination of AR, TOP2B and ERG has diagnostic significance and may be useful in assessing the biological character of the prostate cancer as well as selecting the best treatment.

Chen G, Jundong GU, Chen J, et al.
Association between clinical pathology and multiple genes mRNA expression in Chinese patients with NSCLC.
J Cancer Res Ther. 2013; 9 Suppl 2:S98-100 [PubMed] Related Publications
OBJECTIVE: The aim of this study was to evaluate whether there was an association between pathology type and ERCC1, BRCA1, RRM1, TUBB3, STMN1, TOP2A and epidermal growth factor receptor (EGFR) messenger ribonucleic acid (mRNA) expression level in Chinese patients with non-small cell lung carcinoma (NSCLC).
MATERIALS AND METHODS: mRNA expression level of these genes was analyzed in 181 cancer tissues by using xTAG-step liquid-chip array. The mRNA expression level of the seven genes was evaluated in association with the clinical pathology type.
RESULTS: The average mRNA expression level of the seven genes were ERCC1 (1.02 ± 0.03), BRCA1 (0.15 ± 0.04), RRM1 (0.19 ± 0.05), TUBB3 (0.31 ± 0.06), STMN1 (2.78 ± 0.42), TOP2A (3.04 ± 0.42) and EGFR (0.58 ± 0.09), respectively in Chinese patients with NSCLC. The mRNA expression level of ERCC1, STMN1 and TOP2A genes were statistical different with different pathology type (p(a) < 0.05); STMN1 and TOP2A genes mRNA expression were much higher in squamous cell lung carcinoma than that in non-squamous cell lung carcinoma (p(a) < 0.05). And ERCC1 gene expression was much lower in squamous cell carcinoma than that in non-squamous cell carcinoma (p(a) < 0.05).
CONCLUSION: mRNA expression level of STMN1, TOP2A and ERCC1 were correlated with the clinical pathology type.

Nygård SB, Christensen IJ, Smith DH, et al.
Underpinning the repurposing of anthracyclines towards colorectal cancer: assessment of topoisomerase II alpha gene copy number alterations in colorectal cancer.
Scand J Gastroenterol. 2013; 48(12):1436-43 [PubMed] Related Publications
OBJECTIVE. We propose a repurposing strategy where anthracyclines are reintroduced to a subgroup of patients with metastatic colorectal cancer with the highest likelihood of response. In breast cancer, DNA topoisomerase II alpha gene (TOP2A) alterations predict incremental benefit of anthracyclines, but this association has not been investigated in colorectal cancer. Frequency analysis of TOP2A gene alterations in colorectal cancer and the association with prognosis are evaluated and the challenges of using a TOP2A/CEN-17 FISH probe combination are addressed. MATERIAL AND METHODS. Formalin-fixed, paraffin-embedded material from 154 stage III colorectal cancer patients included in the RANX05 clinical trial was retrospectively assessed for TOP2A gene alterations using FISH. The TOP2A/CEN-17 ratio as well as the TOP2A gene copy number alone was used to define gene alterations and associations between gene status and outcomes were analyzed. RESULTS. TOP2A gene gain was a frequent finding with 9.8 % having a total of ≥4 TOP2A copies per cell. According to the TOP2A/CEN-17 ratio, 10.5 % had TOP2A gene gain. Polysomy or gain of the centromere region of chromosome-17 was not as frequent as reported in breast cancer. No prognostic characteristic of TOP2A was identified. CONCLUSION. TOP2A gene gain is present in numbers relevant to identify a subgroup of patients who may benefit from anthracycline therapy. Based on the present findings, we will initiate a prospective clinical trial designed to evaluate this hypothesis in patients with metastatic colorectal cancer who have failed 5-fluorouracil and oxaliplatin chemotherapy.

Moretti E, Desmedt C, Biagioni C, et al.
TOP2A protein by quantitative immunofluorescence as a predictor of response to epirubicin in the neoadjuvant treatment of breast cancer.
Future Oncol. 2013; 9(10):1477-87 [PubMed] Related Publications
AIM: Anthracyclines are commonly used in breast cancer, although they lack validated predictive biomarkers. We explored the interaction between TOP2A protein by quantitative immunofluorescence (QIF) and anthracycline sensitivity.
PATIENTS & METHODS: Patients with estrogen receptor-negative breast cancer received neoadjuvant epirubicin. Pretreatment biopsies were analyzed using AQUA(®). Total, cytoplasmic (C) and nuclear (N) TOP2A protein concentrations were expressed as QIF scores and compared with pathologic complete response (pCR), TOP2A by immunohistochemistry, TOP2A mRNA, TOP2A and HER2 gene status, and Ki-67 level.
RESULTS: In total, 76 cases were assessable. C, N, and total scores did not correlate with pCR, or other markers. The N:C ratio differed significantly by HER2 status. No pCRs occurred in patients in the lowest N:C quartile.
CONCLUSION: Although no relevant correlation between TOP2A QIF scores and pCR was found, N:C ratio may have a negative predictive role, and may merit further exploration in a multifactorial predictive model that includes tumor and host factors.

Wang N, Zhu M, Tsao SW, et al.
MiR-23a-mediated inhibition of topoisomerase 1 expression potentiates cell response to etoposide in human hepatocellular carcinoma.
Mol Cancer. 2013; 12(1):119 [PubMed] Article available free on PMC after 01/07/2015 Related Publications
BACKGROUND: microRNAs have been shown to regulate the chemosensitivity of cancer cells. The aim of this study is to investigate the role and mechanism of mir-23a in enhancing the anti-tumor effect of topoisomerase 2A (TOP2A) poison etoposide in human hepatocellular carcinoma (HCC).
METHODS: The anti-tumor effect of chemotherapeutic agents in HCC cells were examined in vitro and in vivo xenograft model. Expression of mRNA and miRNAs were determined by quantitative real-time PCR. Protein expression was analyzed by immunoblotting.
RESULTS: Overexpression of mir-23a could significantly potentiate the in vitro and in vivo anti-tumor effect of etoposide; however, ectopic expression of miR-23a fails to sensitize HCC cells to 5-fluorouracil treatment, indicating the miR-23a-induced cancer cell hypersensitivity in chemotherapy is TOP2A-specific though miR-23a overexpression could not directly up-regulate TOP2A expression. Topoisomerase 1(TOP1) is down-regulated in miR-23a-overexpressed HCC cells. MiR-23a could directly bind to 3'untranslated region of TOP1 mRNA, and suppress the corresponding protein expression and inhibition of miR-23a further arguments the expression of TOP1. MiR-23a was up-regulated during DNA damage in cancer cells in line with the p53 expression. Up-regulation of p53 induces mir-23a expression, while suppression of p53 inhibits miR-23a in HCC cells.
CONCLUSION: Our study sheds light on the role of miR-23a as a potential target in regulating chemosensitivity of HCC cells.

Saw J, Curtis DJ, Hussey DJ, et al.
The fusion partner specifies the oncogenic potential of NUP98 fusion proteins.
Leuk Res. 2013; 37(12):1668-73 [PubMed] Article available free on PMC after 01/07/2015 Related Publications
NUP98 is among the most promiscuously translocated genes in hematological diseases. Among the 28 known fusion partners, there are two categories: homeobox genes and non-homeobox genes. The homeobox fusion partners are well-studied in animal models, resulting in HoxA cluster overexpression and hematological disease. The non-homeobox fusion partners are less well studied. We created transgenic animal models for three NUP98 fusion genes (one homeobox, two non-homeobox), and show that in this system, the NUP98-homeobox fusion promotes self-renewal and aberrant gene expression to a significantly greater extent. We conclude that homeobox partners create more potent NUP98 fusion oncogenes than do non-homeobox partners.

Disclaimer: This site is for educational purposes only; it can not be used in diagnosis or treatment.

Cite this page: Cotterill SJ. TOP1 gene, Cancer Genetics Web: http://www.cancer-genetics.org/TOP1.htm Accessed:

Creative Commons License
This page in Cancer Genetics Web by Simon Cotterill is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License.
Note: content of abstracts copyright of respective publishers - seek permission where appropriate.

 [Home]    Page last revised: 16 March, 2015     Cancer Genetics Web, Established 1999