Gene Summary

Gene:LTA; lymphotoxin alpha
Summary:The encoded protein, a member of the tumor necrosis factor family, is a cytokine produced by lymphocytes. The protein is highly inducible, secreted, and forms heterotrimers with lymphotoxin-beta which anchor lymphotoxin-alpha to the cell surface. This protein also mediates a large variety of inflammatory, immunostimulatory, and antiviral responses, is involved in the formation of secondary lymphoid organs during development and plays a role in apoptosis. Genetic variations in this gene are associated with susceptibility to leprosy type 4, myocardial infarction, non-Hodgkin's lymphoma, and psoriatic arthritis. Alternatively spliced transcript variants have been observed for this gene. [provided by RefSeq, Jul 2012]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Source:NCBIAccessed: 16 March, 2017


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 (1992-2017)
Graph generated 16 March 2017 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 16 March, 2017 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: LTA (cancer-related)

Stankevicius V, Vasauskas G, Noreikiene R, et al.
Extracellular Matrix-dependent Pathways in Colorectal Cancer Cell Lines Reveal Potential Targets for Anticancer Therapies.
Anticancer Res. 2016; 36(9):4559-67 [PubMed] Related Publications
BACKGROUND: Cancer cells grown in a 3D culture are more resistant to anticancer therapy treatment compared to those in a monolayer 2D culture. Emerging evidence has suggested that the key reasons for increased cell survival could be gene expression changes in cell-extracellular matrix (ECM) interaction-dependent manner.
MATERIALS AND METHODS: Global gene-expression changes were obtained in human colorectal carcinoma HT29 and DLD1 cell lines between 2D and laminin-rich (lr) ECM 3D growth conditions by gene-expression microarray analysis. The most significantly altered functional categories were revealed by Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis.
RESULTS: The microarray data revealed that 841 and 1190 genes were differentially expressed in colorectal carcinoma DLD1 and HT29 cells. KEGG analysis indicated that the most significantly altered categories were cell adhesion, mitogen-activated protein kinase and immune response.
CONCLUSION: Our results indicate altered pathways related to cancer development and progression and suggest potential ECM-regulated targets for the development of anticancer therapies.

Besusparis J, Plancoulaine B, Rasmusson A, et al.
Impact of tissue sampling on accuracy of Ki67 immunohistochemistry evaluation in breast cancer.
Diagn Pathol. 2016; 11(1):82 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Gene expression studies have identified molecular subtypes of breast cancer with implications to chemotherapy recommendations. For distinction of these types, a combination of immunohistochemistry (IHC) markers, including proliferative activity of tumor cells, estimated by Ki67 labeling index is used. Clinical studies are frequently based on IHC performed on tissue microarrays (TMA) with variable tissue sampling. This raises the need for evidence-based sampling criteria for individual IHC biomarker studies. We present a novel tissue sampling simulation model and demonstrate its application on Ki67 assessment in breast cancer tissue taking intratumoral heterogeneity into account.
METHODS: Whole slide images (WSI) of 297 breast cancer sections, immunohistochemically stained for Ki67, were subjected to digital image analysis (DIA). Percentage of tumor cells stained for Ki67 was computed for hexagonal tiles super-imposed on the WSI. From this, intratumoral Ki67 heterogeneity indicators (Haralick's entropy values) were extracted and used to dichotomize the tumors into homogeneous and heterogeneous subsets. Simulations with random selection of hexagons, equivalent to 0.75 mm circular diameter TMA cores, were performed. The tissue sampling requirements were investigated in relation to tumor heterogeneity using linear regression and extended error analysis.
RESULTS: The sampling requirements were dependent on the heterogeneity of the biomarker expression. To achieve a coefficient error of 10 %, 5-6 cores were needed for homogeneous cases, 11-12 cores for heterogeneous cases; in mixed tumor population 8 TMA cores were required. Similarly, to achieve the same accuracy, approximately 4,000 nuclei must be counted when the intratumor heterogeneity is mixed/unknown. Tumors of low proliferative activity would require larger sampling (10-12 TMA cores, or 6,250 nuclei) to achieve the same error measurement results as for highly proliferative tumors.
CONCLUSIONS: Our data show that optimal tissue sampling for IHC biomarker evaluation is dependent on the heterogeneity of the tissue under study and needs to be determined on a per use basis. We propose a method that can be applied to determine the sampling strategy for specific biomarkers, tissues and study targets. In addition, our findings highlight the benefit of high-capacity computer-based IHC measurement techniques to improve accuracy of the testing.

Cai YJ, Zheng XF, Lu CH, et al.
Effect of FUT3 gene silencing with miRNA on proliferation, invasion and migration abilities of human KATO-III gastric cancer cell line.
Cell Mol Biol (Noisy-le-grand). 2016; 62(7):15-20 [PubMed] Related Publications
This study investigated the effects of FUT3 gene expression inhibition with miRNA on the proliferation, invasion and migration abilities of KATO-III cells. KATO-III cells were transfected with plasmid pcDNA™6.2-GW/EmGFP-FUT3-miR(FUT3-miRNA) and negative control plasmid in mediation of liposome, respectively, using untransfected cells as blank controls. Forty-eight hours after transfection, FUT3 mRNA levels were tested by RT-PCR. Levels of sLeA proteins were assayed by Western blot. The effects of FUT3-miRNA on the proliferation, invasion and migration of KATO-III cells were determined by CCK8 testing and Transwell assays, respectively. Results indicate that the transfection of FUT3-miRNA may down-regulate sLeA protein expression on the surface of KATO-III cells, and significantly inhibit cell proliferation (p<0.05). As compared to the negative and blank control groups, the number of invasion and migration cells in the FUT3-miRNA group decreased significantly (each p<0.05). Experimental results indicate that the miRNA expression vector which targets the FUT3 gene can effectively inhibit the proliferation, migration and invasion abilities of KATO-III cells.

Al-Dhohorah T, Mashrah M, Yao Z, Huang J
Aberrant DKK3 expression in the oral leukoplakia and oral submucous fibrosis: a comparative immunohistochemical study.
Eur J Histochem. 2016; 60(2):2629 [PubMed] Free Access to Full Article Related Publications
We aimed to assess and compare the expression of Dickkopf homolog 3 (DKK3), a possible tumor suppressor gene (TSG), in oral leukoplakia (OLK) and oral submucous fibrosis (OSF) using immunohistochemistry. Seventy-five cases of normal oral mucosa (NOM), OLK, OSF, and squamous cell carcinoma (OSCC) were studied. DKK3 was expressed in all cases of NOM, OLK and OSCC. There was steady increases in the percentage of the positive cells progressing toward OSCC. The expression was localized in the cytoplasm and cell membrane of cell affected by OLK with mild dysplasia and OLK with severe dysplasia. No significant association was observed between DKK3 expression and dysplastic status of OLK. Loss of DKK3 expression was observed in 15 of 30 cases in the OSF group, which was significantly associated with histological grade of OSF (P<0.0001). The percentage of positive cells gradually declined with the increasing severity of epithelial atrophy. A significant difference (P<0.01) was observed when comparing DKK3 expression among different groups of OLK and OSF cases. DKK3 may have diverse expressions in oral premalignant lesions. Loss of DKK3 expression in dysplastic/advanced stage of OSF may imply a high risk of progression to oral cancer.

Wang Z, Liao J, Wu S, et al.
Recipient C6 rs9200 genotype is associated with hepatocellular carcinoma recurrence after orthotopic liver transplantation in a Han Chinese population.
Cancer Gene Ther. 2016; 23(6):157-61 [PubMed] Related Publications
Hepatocellular carcinoma (HCC) recurrence is one of the leading causes of death after orthotopic liver transplantation (OLT). The sixth complement component (C6) is a late-acting complement protein that participates in the assembly of the membrane attack complex, which has an indispensable role in innate and acquired immune responses, as well as cancer immune surveillance. However, studies assessing the association between C6 and HCC recurrence after OLT are scarce. This study aimed to evaluate the association of donor and recipient C6 single-nucleotide polymorphisms with the risk for HCC recurrence after OLT. A total of 71 adult patients who underwent primary LT for HCC were enrolled. HCC recurrence was observed in 26 (36.6%) patients. Ten single-nucleotide polymorphisms were genotyped and analyzed in both donor and recipient groups. Patients with the rs9200 heterozygous GA variant presented significantly higher HCC recurrence rates (54.17 vs 27.66%, P=0.028), and lower cumulative tumor-free survival and overall survival (P=0.006 and P=0.013, respectively) compared with those harboring the GG/AA genotype, in multivariate logistic regression and Cox regression analyses. The rs9200 heterozygous GA variant in C6 persisted as a statistically independent prognostic factor (P<0.05) for predicting HCC recurrence after OLT. In conclusion, recipient C6 rs9200 polymorphism is associated with HCC recurrence after OLT, and improves the predictive value of clinical models.

Suthar SK, Sharma M
Recent Developments in Chimeric NSAIDs as Anticancer Agents: Teaching an Old Dog a New Trick.
Mini Rev Med Chem. 2016; 16(15):1201-1218 [PubMed] Related Publications
Nonsteroidal anti-inflammatory drugs (NSAIDs) are one of the widely used medications all over the world, indicated for pain, fever, and inflammation. It is now well established that inflammation and cancer are closely linked with each other. Inflammatory mediators, like cyclooxygenase (COX), vascular endothelial growth factor (VEGF), tumor growth factor (TGF), fibroblast growth factor (FGF), chemokines, and cytokines and related genes, such as inhibitor of nuclear factor-kappa B kinase (IKK) and nuclear factor-kappa B (NF-κB) have been shown to be up-regulated in various cancers. Till date, numerous anticancer agents of different classes have been discovered to treat and eradicate various forms of cancer; though, limitations like cytotoxicity to normal cells and acquired tumor resistance restrict the scope of present cancer therapeutics. NSAIDs have shown to decrease the incidence, recurrence, and proliferation of various cancers, viz. colon, breast, lung, and pancreatic, etc. Therefore, the developing agents, such as NO-and H<sub>2</sub>S-releasing NSAIDs, NSAID-metal complexes, natural product-NSAID conjugates, phospho-NSAIDs, and various other NSAIDs derivatives represent the next generation therapeutics to treat both inflammation and cancer.

Valiulienė G, Treigytė G, Savickienė J, et al.
Histone modifications patterns in tissues and tumours from acute promyelocytic leukemia xenograft model in response to combined epigenetic therapy.
Biomed Pharmacother. 2016; 79:62-70 [PubMed] Related Publications
Xenograft models are suitable for in vivo study of leukemia's pathogenesis and the preclinical development of anti-leukemia agents but understanding of epigenetic regulatory mechanisms linking to adult cell functions in pathological conditions during different in vivo treatments is yet unknown. In this study, for the first time epigenetic chromatin modifications were characterized in tissues and tumours from murine xenograft model generated using the human acute promyelocytic leukemia (APL) NB4 cells engrafted in immunodeficient NOG mice. Xenografts were subjected to combined epigenetic treatment by histone deacetylase inhibitor Belinostat, histone methyltransferase inhibitor 3-DZNeaplanocin A and all-trans-retinoic acid based on in vitro model, where such combination inhibited NB4 cell growth and enhanced retinoic acid-induced differentiation to granulocytes. Xenotransplantation was assessed by peripheral blood cells counts, the analysis of cell surface markers (CD15, CD33, CD45) and the expression of certain genes (PML-RAR alpha, CSF3, G-CSFR, WT1). The combined treatment prolonged APL xenograft mice survival and prevented tumour formation. The analysis of the expression of histone marks such as acetylation of H4, trimethylation of H3K4, H3K9 and H3K27 in APL xenograft mice tumours and tissues demonstrated tissue-specific changes in the level of histone modifications and the APL prognostic mark, WT1 protein. In summary, the effects of epigenetic agents used in this study were positive for leukemia prevention and linked to a modulation of the chromatin epigenetic environment in adult tissues of malignant organism.

Stoskus M, Vaitkeviciene G, Eidukaite A, Griskevicius L
ETV6/RUNX1 transcript is a target of RNA-binding protein IGF2BP1 in t(12;21)(p13;q22)-positive acute lymphoblastic leukemia.
Blood Cells Mol Dis. 2016; 57:30-4 [PubMed] Related Publications
The oncofetal RNA-binding protein IGF2BP1 (IGF2 mRNA binding protein 1) is overexpressed in a subset of cancers and promotes cell cycle, migration and aggressive phenotype by regulating post-transcriptionally a number of key mRNAs (e. g, ACTB, CD44, CTNNB1, KRAS, MAPK4, MYC, PTEN and others). IGF2BP1 is also overexpressed in t(12;21)(p13;q22)-positive acute lymphoblastic leukemia (ALL), but the biological significance of this phenomenon has not been addressed so far. We have identified leukemia fusion gene ETV6/RUNX1 mRNA to be highly enriched in immunoprecipitated fraction of endogenous IGF2BP1 from a model cell line REH and t(12;21)(p13;q22)-positive ALL samples. Furthermore, downregulation of IGF2BP1 by two-fold has resulted in a corresponding decrease of ETV6/RUNX1 mRNA validating this transcript as a target of IGF2BP1 protein in t(12;21)(p13;q22)-positive ALL. These data infer that IGF2BP1 is a potent regulator of ETV6/RUNX1 mRNA stability and potentially link this evolutionary-highly conserved protein to cell transformation events in ETV6/RUNX1-mediated leukemogenesis of t(12;21)(p13;q22)-positive ALL.

Kupcinskaite-Noreikiene R, Ugenskiene R, Noreika A, et al.
Gene methylation profile of gastric cancerous tissue according to tumor site in the stomach.
BMC Cancer. 2016; 16:40 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: There is considerable information on the methylation of the promoter regions of different genes involved in gastric carcinogenesis. However, there is a lack of information on how this epigenetic process differs in tumors originating at different sites in the stomach. The aim of this study is to assess the methylation profiles of the MLH1, MGMT, and DAPK-1 genes in cancerous tissues from different stomach sites.
METHODS: Samples were acquired from 81 patients suffering stomach adenocarcinoma who underwent surgery for gastric cancer in the Lithuanian University of Health Sciences Hospital Kaunas Clinics in 2009-2012. Gene methylation was investigated with methylation-specific PCR. The study was approved by the Lithuanian Biomedical Research Ethics Committee.
RESULTS: The frequencies of methylation in cancerous tissues from the upper, middle, and lower thirds of the stomach were 11.1, 23.1, and 45.4%, respectively, for MLH1; 22.2, 30.8, and 57.6%, respectively, for MGMT; and 44.4, 48.7, and 51.5%, respectively, for DAPK-1. MLH1 and MGMT methylation was observed more often in the lower third of the stomach than in the upper third (p < 0.05). In the middle third, DAPK-1 promoter methylation was related to more-advanced disease in the lymph nodes (N2-3 compared with N0-1 [p = 0.02]) and advanced tumor stage (stage III rather than stages I-II [p = 0.05]). MLH1 and MGMT methylation correlated inversely when the tumor was located in the lower third of the stomach (coefficient, -0.48; p = 0.01). DAPK-1 and MLH1 methylation correlated inversely in tumors in the middle-third of the stomach (coefficient, -0.41; p = 0.01).
CONCLUSION: Gene promoter methylation depends on the gastric tumor location.

Yuan C, Clish CB, Wu C, et al.
Circulating Metabolites and Survival Among Patients With Pancreatic Cancer.
J Natl Cancer Inst. 2016; 108(6):djv409 [PubMed] Article available free on PMC after 01/06/2017 Related Publications
BACKGROUND: Pancreatic tumors cause changes in whole-body metabolism, but whether prediagnostic circulating metabolites predict survival is unknown.
METHODS: We measured 82 metabolites by liquid chromatography-mass spectrometry in prediagnostic plasma from 484 pancreatic cancer case patients enrolled in four prospective cohort studies. Association of metabolites with survival was evaluated using Cox proportional hazards models adjusted for age, cohort, race/ethnicity, cancer stage, fasting time, and diagnosis year. After multiple-hypothesis testing correction, a P value of .0006 or less (.05/82) was considered statistically significant. Based on the results, we evaluated 33 tagging single-nucleotide polymorphisms (SNPs) in the ACO1 gene, requiring a P value of less than .002 (.05/33) for statistical significance. All statistical tests were two-sided.
RESULTS: Two metabolites in the tricarboxylic acid (TCA) cycle--isocitrate and aconitate--were statistically significantly associated with survival. Participants in the highest vs lowest quintile had hazard ratios (HRs) for death of 1.89 (95% confidence interval [CI] = 1.06 to 3.35, Ptrend < .001) for isocitrate and 2.54 (95% CI = 1.42 to 4.54, Ptrend < .001) for aconitate. Isocitrate is interconverted with citrate via the intermediate aconitate in a reaction catalyzed by the enzyme aconitase 1 (ACO1). Therefore, we investigated the citrate to aconitate plus isocitrate ratio and SNPs in the ACO1 gene. The ratio was strongly associated with survival (P trend < .001) as was the SNP rs7874815 in the ACO1 gene (hazard ratio for death per minor allele = 1.37, 95% CI = 1.16 to 1.61, P < .001). Patients had an approximately three-fold hazard for death when possessing one or more minor alleles at rs7874851 and high aconitate or isocitrate.
CONCLUSIONS: Prediagnostic circulating levels of TCA cycle intermediates and inherited ACO1 genotypes were associated with survival among patients with pancreatic cancer.

Hu HH, Kannengiesser C, Lesage S, et al.
PARKIN Inactivation Links Parkinson's Disease to Melanoma.
J Natl Cancer Inst. 2016; 108(3) [PubMed] Related Publications
BACKGROUND: Melanoma incidence is higher in patients affected by Parkinson's disease (PD) and vice versa, but the genetic link shared by both diseases is unknown. As PARK2 is both a tumor suppressor gene and frequently mutated in young onset PD, we evaluated the role of PARK2 in melanoma predisposition and progression.
METHODS: An in-depth PARK2 gene dosage analysis and sequencing was performed on 512 French case patients and 562 healthy control patients, as well as sporadic tumors and melanoma cell lines. The frequency of genetic alterations was compared between case patients and control patients using two-sided Fisher's exact tests and odds ratio (OR) calculations. We used western blotting to determine PARKIN expression in melanocytes and melanoma cell lines and transfection followed by clonogenic assays to evaluate the effect of PARKIN expression on cellular proliferation. All statistical tests were two-sided.
RESULTS: Germline PARK2 mutations (including copy number variations, splicing, and putative deleterious missense mutations) were present in 25 case patients but only four control patients (OR = 3.95, 95% confidence interval = 1.34 to 15.75). Copy number variations (CNVs) and loss of heterozygosity were present in 60% and 74%, respectively, of primary tumors. PARKIN protein was expressed in melanocytes but not in most melanoma cell lines, and its expression decreased following melanocyte transformation by oncogenic NRAS. Re-expression of PARKIN in melanoma cell lines resulted in a drastic reduction of cell proliferation and inhibition of PARKIN in melanocytes stimulated their proliferation.
CONCLUSION: Our results show an important role for PARK2 as a tumor suppressor both in melanoma predisposition and progression, which could explain the epidemiological association of these diseases.

Zafeer M, Mahjabeen I, Kayani MA
Increased expression of ERCC2 gene in head and neck cancer is associated with aggressive tumors: a systematic review and case-control study.
Int J Biol Markers. 2016; 31(1):e17-25 [PubMed] Related Publications
INTRODUCTION: The excision repair cross-complementation group 2 (ERCC2) ATP-dependent helicase is an essential member of the DNA repair pathway. It has been observed to be differentially expressed in different cancers, which shows its involvement in carcinogenesis.
AIM: In the present study we have tried to determine the association of expression patterns of this gene with head and neck carcinogenesis.
METHOD: We first carried out a systematic review of the available studies on the role of ERCC2 in head and neck cancer (HNC). In order to test the hypothesis that the expression patterns of XPD/ERCC2 play a critical role in HNC pathogenesis, we then conducted a population based case-control study on 81 head and neck tumor samples and adjacent normal-tissue control samples. Reverse transcriptase polymerase chain reaction (RT-PCR) and quantitative polymerase chain reaction (qPCR) were used to assess ERCC2 deregulation at the mRNA level.
RESULT: Expression analysis showed that the ERCC2 expression level was significantly upregulated (p<0.05) in HNC tissues compared with adjacent normal tissues. Furthermore, the expression pattern of ERCC2 was correlated with the expression pattern of Ki-67 and a significant correlation (r = 0.230, p<0.03) was observed between ERCC2 and Ki-67. Spearman's correlation also showed a significant correlation between ERCC2 expression and tumor stage (r = 0.271, p<0.02) and grade (r = 0.228, p<0.02) of HNC.
CONCLUSIONS: Our data suggest that deregulation of ERCC2 in HNC has the potential to predict a more aggressive cancer phenotype and may be considered a possible biomarker for improved diagnosis and prognosis of HNC.

Ger M, Kaupinis A, Nemeikaite-Ceniene A, et al.
Quantitative proteomic analysis of anticancer drug RH1 resistance in liver carcinoma.
Biochim Biophys Acta. 2016; 1864(2):219-32 [PubMed] Related Publications
UNLABELLED: Acquired resistance of tumor cells to the therapeutic treatment is a major challenge in virtually any chemotherapy. A novel anticancer agent 2,5-diaziridinyl-3-(hydroxymethyl)-6-methyl-1,4-benzoquinone (RH1) is designed to be activated by
NAD(P)H: quinone oxidoreductase, an enzyme expressed at high levels in many types of tumors. Here we investigated the potential mechanisms of acquired RH1 drug resistance in cancer cells by applying high-throughput differential quantitative proteomic analysis of the newly established RH1-resistant hepatoma cell lines. Over 400 proteins display significantly altered levels between drug-sensitive and drug-resistant cell lines. Differentially expressed proteins were clustered into more than 14 groups according to their functional annotation and protein-protein interactions. Bioinformatic analysis highlights the biological processes that might be responsible for acquired resistance to RH1. The level of several xenobiotic metabolism enzymes (total n=17) involved in RH1 activation and detoxification is decreased (Nqo1, catalase, Gst, Gsr), corresponding with the decrease in their catalytic activity. The altered biological processes also include the decrease of cell cycle positive regulators (n=15) and the increase of DNA repair proteins (n=5) as well as annexin family members (n=5) in the RH1-resistant cells. Drug-resistant hepatoma cell proteomes are also distinguished by the altered level of proteins involved in energy production and metabolism (n=55). Our data provide the basis for in-depth study of molecular mechanisms of tumor cell resistance to the promising anticancer drug RH1 enabling the further validation of protein biomarkers for the drug insusceptibility and of potential secondary pharmacological targets of RH1 resistant cells.

Eftimov T, Enchev Y, Tsekov I, et al.
JC polyomavirus in the aetiology and pathophysiology of glial tumours.
Neurosurg Rev. 2016; 39(1):47-53 [PubMed] Related Publications
Glial brain tumours with their poor prognosis, limited treatment modalities and unclear detailed pathophysiology represent a significant health concern. The purpose of the current study was to investigate and describe the possible role of the human polyomavirus JC as an underlying cancerogenic or co-cancerogenic factor in the complex processes of glial tumour induction and development. Samples from 101 patients with glial tumours were obtained during neurosurgical tumour resection. Small tissue pieces were taken from several areas of the histologically verified solid tumour core. Biopsies were used for DNA extraction and subsequent amplification reactions of sequences from the JC viral genome. Real-time polymerase chain reaction was used for detection and quantification of its non-coding control region (NCCR) and gene encoding the regulatory protein Large T antigen (LT). An average of 37.6% of all patients was found to be LT positive, whereas only 6.9% tested positive for NCCR. The analysis of the results demonstrated significant variance between the determined LT prevalence and the rate for NCCR, with a low starting copy number in all positive samples and threshold cycles in the range of 36 to 42 representing viral load in the range from 10 to 1000 copies/μl. The results most probably indicate incomplete JC viral replication. Under such conditions, mutations in the host cell genome may be accumulated due to interference of the virus with the host cell machinery, and eventually malignant transformation may occur.

Mou X, Li T, Wang J, et al.
Genetic Variation of BCL2 (rs2279115), NEIL2 (rs804270), LTA (rs909253), PSCA (rs2294008) and PLCE1 (rs3765524, rs10509670) Genes and Their Correlation to Gastric Cancer Risk Based on Universal Tagged Arrays and Fe3O4 Magnetic Nanoparticles.
J Biomed Nanotechnol. 2015; 11(11):2057-66 [PubMed] Related Publications
With the help of Fe3O4 nagnetic nanoparticles as a solid carrier and an excellent tool for separation, six SNP loci (rs2279115 of BCL2 gene, rs804270 of NEIL2 gene, rs909253 of LTA gene, rs2294008 of PSCA gene, rs3765524 and rs10509670 of PLCE1 gene) were selected to evaluate their relation to gastric cancer risk. Using two kinds of functionalized magnetic nanoparticles and universal tagged arrays, the whole operation procedure including genome DNA extraction and SNP genotyping was performed. All genotypes and allele frequencies were calculated in the cases and controls respectively to analyze their association with gastric cancer risk. Totally 200 pathological samples and 134 normal control subjects were collected. The results demonstrated that four SNP loci (rs2279115, rs804270, rs909253 and rs3765524) showed a potential association with gastric cancer risk, and the other two (rs2294008, rs10509670) possessed no difference/association among cases and controls.

Merlano MC, Denaro N, Vivenza D, et al.
p16 cutoff in head and neck squamous cell carcinoma: correlation between tumor and patient characteristics and outcome.
Int J Biol Markers. 2016; 31(1):e44-52 [PubMed] Related Publications
BACKGROUND: p16 has been indicated as a suitable surrogate biomarker of HPV infection. The prognosis of p16-positive oropharynx tumors (OTs) of squamous cell carcinoma (SCC) histology is better than that of p16-negative tumors.
METHODS: We analyzed 209 samples of head and neck SCC to establish a predictive cutoff for p16 and determine the role of p16 positivity in OTs versus non-OTs. We compared the outcomes of tumors harboring any percentage of p16-positive cells (≥1%) with those of p16-negative OTs. We then considered 3 cutoffs (10%, 50% and 70% positive cells) to evaluate the outcome of OTs/non-OTs with similar p16 expression and p16-positive versus p16-negative tumors stratified by patient age.
RESULTS: p16-negative tumors among OTs and non-OTs were 29% and 49%, respectively (p = 0.0054). The cumulative distribution showed that the positive values were located around 2 focus points: 2% and 96%. Subgroup analysis showed that only OTs occurred in young patients (aged <65 years) and that there was a ≥70% gain in survival in cases with p16-positive cells.
CONCLUSIONS: p16 positivity influences outcome only in young patients and OTs (p = 0.048).

Demidenko R, Razanauskas D, Daniunaite K, et al.
Frequent down-regulation of ABC transporter genes in prostate cancer.
BMC Cancer. 2015; 15:683 [PubMed] Article available free on PMC after 01/06/2017 Related Publications
BACKGROUND: ATP-binding cassette (ABC) transporters are transmembrane proteins responsible for the efflux of a wide variety of substrates, including steroid metabolites, through the cellular membranes. For better characterization of the role of ABC transporters in prostate cancer (PCa) development, the profile of ABC transporter gene expression was analyzed in PCa and noncancerous prostate tissues (NPT).
METHODS: TaqMan Low Density Array (TLDA) human ABC transporter plates were used for the gene expression profiling in 10 PCa and 6 NPT specimens. ABCB1 transcript level was evaluated in a larger set of PCa cases (N = 78) and NPT (N = 15) by real-time PCR, the same PCa cases were assessed for the gene promoter hypermethylation by methylation-specific PCR.
RESULTS: Expression of eight ABC transporter genes (ABCA8, ABCB1, ABCC6, ABCC9, ABCC10, ABCD2, ABCG2, and ABCG4) was significantly down-regulated in PCa as compared to NPT, and only two genes (ABCC4 and ABCG1) were up-regulated. Down-regulation of ABC transporter genes was prevalent in the TMPRSS2-ERG-negative cases. A detailed analysis of ABCB1 expression confirmed TLDA results: a reduced level of the transcript was identified in PCa in comparison to NPT (p = 0.048). Moreover, the TMPRSS2-ERG-negative PCa cases showed significantly lower expression of ABCB1 in comparison to NPT (p = 0.003) or the fusion-positive tumors (p = 0.002). Promoter methylation of ABCB1 predominantly occurred in PCa and was rarely detected in NPT (p < 0.001).
CONCLUSIONS: The study suggests frequent down-regulation of the ABC transporter genes in PCa, especially in the TMPRSS2-ERG-negative tumors.

Fernandes MT, Ghezzo MN, Silveira AB, et al.
Lymphotoxin-β receptor in microenvironmental cells promotes the development of T-cell acute lymphoblastic leukaemia with cortical/mature immunophenotype.
Br J Haematol. 2015; 171(5):736-51 [PubMed] Related Publications
Lymphotoxin-mediated activation of the lymphotoxin-β receptor (LTβR; LTBR) has been implicated in cancer, but its role in T-cell acute lymphoblastic leukaemia (T-ALL) has remained elusive. Here we show that the genes encoding lymphotoxin (LT)-α and LTβ (LTA, LTB) are expressed in T-ALL patient samples, mostly of the TAL/LMO molecular subtype, and in the TEL-JAK2 transgenic mouse model of cortical/mature T-ALL (Lta, Ltb). In these mice, expression of Lta and Ltb is elevated in early stage T-ALL. Surface LTα1 β2 protein is expressed in primary mouse T-ALL cells, but only in the absence of microenvironmental LTβR interaction. Indeed, surface LT expression is suppressed in leukaemic cells contacting Ltbr-expressing but not Ltbr-deficient stromal cells, both in vitro and in vivo, thus indicating that dynamic surface LT expression in leukaemic cells depends on interaction with its receptor. Supporting the notion that LT signalling plays a role in T-ALL, inactivation of Ltbr results in a significant delay in TEL-JAK2-induced leukaemia onset. Moreover, young asymptomatic TEL-JAK2;Ltbr(-/-) mice present markedly less leukaemic thymocytes than age-matched TEL-JAK2;Ltbr(+/+) mice and interference with LTβR function at this early stage delayed T-ALL development. We conclude that LT expression by T-ALL cells activates LTβR signalling in thymic stromal cells, thus promoting leukaemogenesis.

Erfani E, Roudi R, Rakhshan A, et al.
Comparative expression analysis of putative cancer stem cell markers CD44 and ALDH1A1 in various skin cancer subtypes.
Int J Biol Markers. 2016; 31(1):e53-61 [PubMed] Related Publications
INTRODUCTION: Skin cancers, particularly melanoma, are initiated and maintained by a subpopulation of tumor cells expressing stemness markers that are called cancer stem cells (CSCs). This study aimed to evaluate the expression levels and clinicopathological significance of the putative CSC markers CD44 and ALDH1A1 in patients with skin cancer.
METHODS: The expression levels of CD44 and ALDH1A1 were investigated in 107 skin cancer specimens including 58 (54%) basal cell carcinomas (BCC), 37 (35%) squamous cell carcinomas (SCC), and 12 (11%) melanomas using the tissue microarray (TMA) technique. The correlation of the expression levels of these markers and clinicopathological parameters was then analyzed.
RESULTS: The expression levels of CD44 and ALDH1A1 were significantly higher in melanoma patients than patients with SCC or BCC (p<0.001 and p = 0.002, respectively). A higher level of CD44 expression was more often found in melanoma tumor cells with a higher rate of recurrence (p = 0.029) and in SCC cases with ulceration (p = 0.01), while there was no significant correlation between ALDH1A1 expression and other clinicopathological parameters. Similarly, coexpression of CD44 and ALDH1A1 (CD44high/ALDH1A1high) was significantly observed in melanoma samples (p<0.001).
CONCLUSIONS: These findings suggest that a CD44high/ALDH1A1high phenotype in melanoma and a CD44high phenotype in SCC can be considered candidates for targeted therapy of skin cancers aiming at CSCs.

Schrama D, Hesbacher S, Angermeyer S, et al.
Serine 220 phosphorylation of the Merkel cell polyomavirus large T antigen crucially supports growth of Merkel cell carcinoma cells.
Int J Cancer. 2016; 138(5):1153-62 [PubMed] Related Publications
Merkel cell polyomavirus (MCPyV) is regarded as a major causal factor for Merkel cell carcinoma (MCC). Indeed, tumor cell growth of MCPyV-positive MCC cells is dependent on the expression of a truncated viral Large T antigen (LT) with an intact retinoblastoma protein (RB)-binding site. Here we determined the phosphorylation pattern of a truncated MCPyV-LT characteristically for MCC by mass spectrometry revealing MCPyV-LT as multi-phospho-protein phosphorylated at several serine and threonine residues. Remarkably, disruption of most of these phosphorylation sites did not affect its ability to rescue knockdown of endogenous T antigens in MCC cells indicating that phosphorylation of the respective amino acids is not essential for the growth promoting function of MCPyV-LT. However, alteration of serine 220 to alanine completely abolished the ability of MCPyV-LT to support proliferation of MCC cells. Conversely, mimicking the phosphorylated state by mutation of serine 220 to glutamic acid resulted in a fully functional LT. Moreover, MCPyV-LT(S220A) demonstrated reduced binding to RB in co-immunoprecipitation experiments as well as weaker induction of RB target genes in MCC cells. In conclusion, we provide evidence that phosphorylation of serine 220 is required for efficient RB inactivation in MCC and may therefore be a potential target for future therapeutic approaches.

Ling Y, Li Q, Yang H, et al.
Loss of heterozygosity in thyroid hormone receptor beta in invasive breast cancer.
Tumori. 2015 Sep-Oct; 101(5):572-7 [PubMed] Related Publications
BACKGROUND: Loss of heterozygosity (LOH) on chromosome arm 3p, where the gene of thyroid hormone receptor beta (THRB) is located, has been reported in breast cancer. Although some studies performed in vitro have suggested that THRB could act as a tumor suppressor in breast cancer development, there is still no unequivocal evidence to support this.
METHODS: To determine the role of LOH in breast tumor development, the LOH of THRB and its proximal microsatellite markers D3S1293, D3S3659, D3S3700, D3S2307 and D3S2336 was investigated in a genomic region spanning ~3.3 Mb in tumor specimens and in corresponding normal tissues of 74 invasive breast cancer patients. The association was analyzed between LOH in microsatellite markers and clinicopathological characteristics.
RESULTS: LOH was detected in D3S1293 (36.7%), THRB (59.4%), D3S3659 (37.5%) and D3S3700 (55.2%) among the informative cases, while LOH was not detected in D3S2307 and D3S2336. Cases exhibited LOH of 52.8%-71.4% if any 2 markers were combined and analyzed out of the first 4 microsatellite markers. LOH in THRB was associated with negative estrogen receptor (ER), negative progesterone receptor (PR), both negative estrogen receptor and progesterone receptor (HR) and human epidermal growth factor receptor-2 (HER2) and lymph node metastasis (p = 0.0001, p = 0.005, p = 0.001 and p = 0.018). The association with negative PR in LOH in THRB and/or D3S1293 was pronounced (p<0.0001). LOH in D3S3700 showed an association with lymph node metastasis (p = 0.014). This association was enhanced if D3S3700 was combined with THRB or D3S3659 (p = 0.0004, p = 0.0002).
CONCLUSIONS: LOH in THRB and its proximal microsatellite markers may play a role in tumorigenesis and development in invasive breast cancer.

Cheng S, Zheng J, Zhu J, et al.
PD-L1 gene polymorphism and high level of plasma soluble PD-L1 protein may be associated with non-small cell lung cancer.
Int J Biol Markers. 2015; 30(4):e364-8 [PubMed] Related Publications
BACKGROUND: PD-1 and its ligand PD-L1 belong to the co-inhibition molecules, which can downregulate immune responses. The PD-L1 polymorphism and the level of soluble PD-L1 (sPD-L1) were investigated in non-small cell lung cancer (NSCLC).
METHODS: A total of 288 NSCLC patients and 300 controls were enrolled. An A/C polymorphism at position 8923 in the PD-L1 gene was genotyped using the polymerase chain reaction-restriction fragment length polymorphism method.
RESULTS: The prevalence of the 8923C allele was significantly higher in NSCLC patients than controls (10.2% versus 5.3%, p = 0.002, odds ratio 2.03, 95% confidence interval 1.30-3.17; data were adjusted for age and sex). NSCLC patients also showed increased plasma levels of sPD-L1 compared to controls (1.92 ng/mL versus 0.91 ng/mL, p<0.001). Furthermore, lung adenocarcinoma patients had higher sPD-L1 levels than patients with squamous cell carcinoma (p<0.01). However, no association was observed between the different genetic variants and plasma concentrations of sPD-L1.
CONCLUSIONS: The PD-L1 8923A/C polymorphism could be associated with increased susceptibility to NSCLC. Plasma levels of sPD-L1 are significantly increased in NSCLC patients, especially those with adenocarcinoma.

Tang Y, Zhou X, Ji J, et al.
High expression levels of miR-21 and miR-210 predict unfavorable survival in breast cancer: a systemic review and meta-analysis.
Int J Biol Markers. 2015; 30(4):e347-58 [PubMed] Related Publications
BACKGROUND: MicroRNAs (miRNAs) have been emerging as valuable prognostic biomarkers of breast cancer. We therefore summarized recent research into miRNAs involved in human breast cancer and, further, completed a meta-analysis to predict the role of specific miRNAs in the survival of breast cancer patients.
METHODS: Studies were identified by searching PubMed, Embase and Web of Science. Descriptive characteristics for studies were described, and an additional meta-analysis for specific miRNAs was performed. Pooled hazard ratios (HRs) and their corresponding 95% confidence intervals (CIs) were calculated.
RESULTS: A total of 41 articles including 27 types of miRNAs were found regarding prognostic biomarkers for breast cancer survival, of which, micRNA-21 (miR-21) was the most-studied specific miRNA that appeared repeatedly among the selected classifiers. For the studies evaluating miR-21's association with clinical outcomes, the median HR in the studies was 2.32 (interquartile range [IQR] = 1.04-3.40), and the pooled HR suggested that high expression of miR-21 has a negative impact on overall survival (OS; HR = 1.46, 95% CI, 1.25-1.70; p<0.05) and disease/recurrence-free survival in breast cancer (HR = 1.49, 95% CI, 1.17-1.90; p<0.01). We also found that higher expression levels of miR-210 significantly predicted poorer outcome, with median HR in the reported studies of 4.07 (IQR = 1.54-4.43) and a pooled HR of 2.94 (95% CI, 2.08-4.17; p<0.05).
CONCLUSIONS: These results indicate that miRNAs show promising associations with prognosis in breast cancer. Moreover, specific miRNAs such as miR-21 and miR-210 can predict poor survival rates in breast cancer patients.

Borutinskaitė V, Navakauskienė R
The Histone Deacetylase Inhibitor BML-210 Influences Gene and Protein Expression in Human Promyelocytic Leukemia NB4 Cells via Epigenetic Reprogramming.
Int J Mol Sci. 2015; 16(8):18252-69 [PubMed] Article available free on PMC after 01/06/2017 Related Publications
Today, cancer is understood as an epigenetic as well as genetic disease. The main epigenetic hallmarks of the cancer cell are DNA methylation and histone modifications. Proteins such as histone deacetylases (HDACs) that cause modifications of histones and other proteins can be targets for novel anticancer agents. Recently, interest in compounds that can inhibit HDACs increased, and now there are many HDACs inhibitors (HDACIs) available with different chemical structures, biological and biochemical properties; hopefully some of them will succeed, probably in combination with other agents, in cancer therapies. In our study we focused on the novel HDACI-BML-210. We found that BML-210 (N-phenyl-N'-(2-Aminophenyl)hexamethylenediamide) inhibits the growth of NB4 cells in dose- and time-dependent manner. In this study we also examined how expression and activity of HDACs are affected after leukemia cell treatment with BML-210. Using a mass spectrometry method we identified proteins that changed expression after treatment with BML-210. We prepared RT-PCR analysis of these genes and the results correlated with proteomic data. Based on these and other findings from our group, we suggest that HDACIs, like BML-210, can be promising anticancer agents in promyelocytic leukemia treatment.

Miltiadous O, Sia D, Hoshida Y, et al.
Progenitor cell markers predict outcome of patients with hepatocellular carcinoma beyond Milan criteria undergoing liver transplantation.
J Hepatol. 2015; 63(6):1368-77 [PubMed] Related Publications
BACKGROUND & AIMS: In patients with hepatocellular carcinoma (HCC), liver transplantation (LT) is an excellent therapy if tumor characteristics are within the Milan criteria. We aimed to define genomic features enabling to identify HCC patients beyond Milan criteria who have acceptable transplant outcomes.
METHODS: Among 770 consecutive HCC patients transplanted between 1990 and 2013, 132 had tumors exceeding Milan criteria on pathology and were enrolled in the study; 44% of the patients satisfied the 'up-to-7 rule' [7=sum of the size of the largest tumor and the number of tumors]. Explant tumors were assessed for genomic signatures and immunohistochemical markers associated with poor outcome.
RESULTS: At a median follow-up of 88months, 64 patients had died and 45 recurred; the 5-year overall survival (OS) and recurrence rates were 57% and 35%, respectively. Cytokeratin 19 (CK19) gene signature was independently associated with recurrence [Hazard ratio (HR)=2.95, p<0.001], along with tumor size (HR=3.37, p=0.023) and presence of satellites (HR=2.98, p=0.001). S2 subclass signature was independently associated with poor OS (HR=3.18, p=0.001), along with tumor size (HR=5.06, p<0.001) and up-to-7 rule (HR=2.50, p=0.002). Using the presence of progenitor cell markers (either CK19 or S2 signatures) patients were classified into poor prognosis (n=58; 5-year recurrence 53%, survival 45%) and good prognosis (n=74; 5-year recurrence 19%, survival 67%) (HR=3.16, p<0.001 for recurrence, and HR=1.72, p=0.04 for OS).
CONCLUSIONS: HCC patients transplanted beyond Milan criteria without gene signatures of progenitor markers (CK19 and S2) achieved survival rates similar as those within Milan criteria. Once prospectively validated, these markers may support a limited expansion of LT indications.

Fazi B, Felsani A, Grassi L, et al.
The transcriptome and miRNome profiling of glioblastoma tissues and peritumoral regions highlights molecular pathways shared by tumors and surrounding areas and reveals differences between short-term and long-term survivors.
Oncotarget. 2015; 6(26):22526-52 [PubMed] Article available free on PMC after 01/06/2017 Related Publications
Glioblastoma multiforme (GBM) is the most common and deadliest primary brain tumor, driving patients to death within 15 months after diagnosis (short term survivors, ST), with the exception of a small fraction of patients (long term survivors, LT) surviving longer than 36 months. Here we present deep sequencing data showing that peritumoral (P) areas differ from healthy white matter, but share with their respective frankly tumoral (C) samples, a number of mRNAs and microRNAs representative of extracellular matrix remodeling, TGFβ and signaling, of the involvement of cell types different from tumor cells but contributing to tumor growth, such as microglia or reactive astrocytes. Moreover, we provide evidence about RNAs differentially expressed in ST vs LT samples, suggesting the contribution of TGF-β signaling in this distinction too. We also show that the edited form of miR-376c-3p is reduced in C vs P samples and in ST tumors compared to LT ones. As a whole, our study provides new insights into the still puzzling distinction between ST and LT tumors, and sheds new light onto that "grey" zone represented by the area surrounding the tumor, which we show to be characterized by the expression of several molecules shared with the proper tumor mass.

Simanaviciene V, Popendikyte V, Gudleviciene Z, Zvirbliene A
Different DNA methylation pattern of HPV16, HPV18 and HPV51 genomes in asymptomatic HPV infection as compared to cervical neoplasia.
Virology. 2015; 484:227-33 [PubMed] Related Publications
Epigenetic alterations of human papillomavirus (HPV) genome play an important role in virus life cycle and carcinogenic progression. The aim of the current study was to investigate the correlation between the grade of cervical pathology and DNA methylation status within the L1 gene and the long control region (LCR) of HPV16, HPV18 and HPV51. HPV genomes were analyzed using bisulfite DNA modification procedure with the subsequent amplification of target DNA regions and sequencing. A collection of 202 cervical specimens was analyzed: 157 HPV16-positive specimens, 21 HPV18-positive specimens and 24 HPV51-positive specimens. This study revealed that methylation of CpG was significantly more prevalent in L1 gene as compared to LCR region of all three studied HPV types and the degree of DNA methylation level correlated with the severity of cervical neoplasia. An increased DNA methylation level of HPV16 promoter region in case of cervical cancer was determined.

Han H, Xue-Franzén Y, Miao X, et al.
Early growth response gene (EGR)-1 regulates leukotriene D4-induced cytokine transcription in Hodgkin lymphoma cells.
Prostaglandins Other Lipid Mediat. 2015; 121(Pt A):122-30 [PubMed] Related Publications
Classical Hodgkin lymphoma (cHL) has a unique pathological feature characterized by a minority of malignant Hodgkin Reed-Sternberg (H-RS) cells surrounded by numerous inflammatory cells. Cysteinyl-leukotrienes (CysLTs) are produced by eosinophils, macrophages and mast cells in the HL tumor microenvironment. In the present study we have explored the signal transduction pathways leading to leukotriene (LT) D4 induced expression of cytokines in the Hodgkin lymphoma cell line L1236 and KM-H2. Stimulation of L1236 and KM-H2 cells with LTD4 led to a concentration- and time-dependent increase at the transcriptional level of tumor necrosis factor-alpha (TNF-α), interleukin (IL)-6, IL-8, chemokine (C-C motif) ligand 3 (CCL3) and CCL4. The expression of several transcription factors was induced upon stimulation of Hodgkin cell lines with LTD4. Among these, EGR-1 was required for cytokine production. Inhibition of EGR-1 expression using shEGR-1 transduced by lentivirus led to suppression of the expression of TNF-α and IL-6. The effect of LTD4 on the expression of transcription factors and cytokines were also blocked by the specific CysLT1 receptor antagonist zafirlukast. These results demonstrate that EGR-1 plays a critical role in LTD4-induced cytokine transcription in Hodgkin cell lines.

Korobeinikova E, Myrzaliyeva D, Ugenskiene R, et al.
The prognostic value of IL10 and TNF alpha functional polymorphisms in premenopausal early-stage breast cancer patients.
BMC Genet. 2015; 16:70 [PubMed] Article available free on PMC after 01/06/2017 Related Publications
BACKGROUND: Interleukin-10 and tumor necrosis factor α play an important role in breast carcinogenesis. Genes, encoding those two cytokines, contain single nucleotide polymorphisms, which are associated with differential levels of gene transcription. This study analyzes single nucleotide polymorphisms in interleukin 10 and tumor necrosis factor α genes and their contribution to breast cancer phenotype, lymph node status and survival in a group of young Lithuanian women with early-stage breast cancer patients.
RESULTS: We genotyped 100 premenopausal Eastern European (Lithuanian) patients with stage I-II breast cancer, ≤ 50 years old at the time of diagnosis, for interleukin 10 -592A > C, -819C > T and -1082A > G and tumor necrosis factor α -308G > A single nucleotide polymorphisms in the gene promoter region. We used the polymerase chain reaction, namely a restriction fragment length polymorphism method, for a SNP analysis. All genotypes were in Hardy-Weinberg equilibrium and had the same distribution as the HapMap CEU population. Holders of IL10 -592A > C heterozygous IL10 -592 AC genotype had a higher probability of estrogen receptor positive breast cancer phenotype than homozygous variants (P = 0.017). Phased ACC haplotype of IL10 polymorphisms was associated with younger age of diagnosis (P = 0.017). Of all the tested single nucleotide polymorphisms, only TNFα -308G > A has revealed a prognostic capability for breast cancer survival. GA genotype carriers, compared to GG, showed a significant disadvantage in progression-free survival (P = 0.005, adjusted hazard ratio (HR) = 4.631, 95 % confidence interval (CI) = 1.587 - 13.512), metastasis-free survival (P = 0.010, HR = 4.708, 95 % CI = 1.445 - 15.345) and overall survival (P = 0.037, HR = 4.829, 95 % CI = 1.098 - 21.243).
CONCLUSIONS: According to our data, IL10 -1082A > G, -819 T > C, -592A > C polymorphisms and phased haplotypes have not revealed a prognostic value for breast cancer. On the contrary, the TNFα -308 polymorphism might modulate the risk and contribute to the identification of patients at a higher risk of breast cancer recurrence, metastasis and worse overall survival among young Lithuanian early-stage breast cancer patients.

Meng X, Xiao C, Zhao Y, et al.
Meta-analysis of microarrays: diagnostic value of microRNA-21 as a biomarker for lung cancer.
Int J Biol Markers. 2015; 30(3):e282-5 [PubMed] Related Publications
BACKGROUND: MicroRNA-21 (miR-21) has previously been demonstrated as a potential biomarker in diagnosis of various human tumors. This meta-analysis was performed to evaluate the possibility of miR-21 as a biomarker for early detection of lung cancer.
METHODS: Relevant lung cancer-related miRNA microarray datasets were collected from the NCBI Gene Expression Omnibus (GEO) database and EBI ArrayExpress database up to February 2014. Quality control of the output data was estimated using Limma package and ExiMiR package in R. Standardized mean difference (SMD) with 95% confidence intervals (CIs) from selected datasets was pooled. Heterogeneity was assessed using Cochran's Q test and the I2 statistic, and a p value <0.0.05 or I2 >50% was defined as significant heterogeneity. Furthermore, sensitivity analysis was conducted to evaluate the stability of the pooled results. Four miRNA datasets (GSE24704, GSE17681, GSE27486 and GSE40738) from blood samples were selected, including 153 lung cancer patients and 109 healthy people.
RESULTS: The pooled results generated by random-effects model revealed that no significant difference was observed between case and control groups (SMD = 0.58; 95% CI, -0.04 to 1.19; p = 0.07) with significant heterogeneity (p = 0.0032, I2 = 78.2%; p = 0.06). Sensitivity analysis indicated that the results of the meta-analysis were stable.
CONCLUSIONS: MiR-21 expression levels in whole blood and peripheral blood cells did not show significant differences between lung cancer patients and healthy controls, and it might be ineffective to measure miR-21 expression to achieve an early diagnosis of lung cancer.

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