DNMT1

Gene Summary

Gene:DNMT1; DNA (cytosine-5-)-methyltransferase 1
Aliases: AIM, DNMT, MCMT, CXXC9, HSN1E, ADCADN
Location:19p13.2
Summary:DNA (cytosine-5-)-methyltransferase 1 has a role in the establishment and regulation of tissue-specific patterns of methylated cytosine residues. Aberrant methylation patterns are associated with certain human tumors and developmental abnormalities. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2008]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:DNA (cytosine-5)-methyltransferase 1
HPRD
Source:NCBIAccessed: 16 March, 2015

Ontology:

What does this gene/protein do?
Show (22)
Pathways:What pathways are this gene/protein implicaed in?
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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.

  • Enzyme Inhibitors
  • Cancer DNA
  • Colorectal Cancer
  • Epigenetics
  • DNA Sequence Analysis
  • Small Cell Lung Cancer
  • DNA-Binding Proteins
  • DNA Methylation
  • Sulfonamides
  • Xenograft Models
  • Gene Expression Profiling
  • Radiation-Sensitizing Agents
  • U937 Cells
  • Transcriptional Activation
  • Y Chromosome
  • Western Blotting
  • Pyrimidine Nucleosides
  • RTPCR
  • Hepatocellular Carcinoma
  • Substrate Specificity
  • Estrogen Receptors
  • Cancer Gene Expression Regulation
  • Mutation
  • DNA Modification Methylases
  • Chromosome 19
  • Breast Cancer
  • Tumor Suppressor Gene
  • Apoptosis
  • Histones
  • Azacitidine
  • Cell Proliferation
  • Liver Cancer
  • Gene Silencing
  • Base Sequence
  • Neoplastic Cell Transformation
  • CpG Islands
  • DNA (Cytosine-5-)-Methyltransferase
  • Immunohistochemistry
  • Transforming Growth Factor beta
  • Neurons
Tag cloud generated 16 March, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (4)

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: DNMT1 (cancer-related)

Sofan MA, Elmasry S, Salem DA, Bazid MM
NPM1 gene mutation in Egyptian patients with cytogenetically normal acute myeloid leukemia.
Clin Lab. 2014; 60(11):1813-22 [PubMed] Related Publications
BACKGROUND: Nucleophosmin1 (NPM1) protein encoded from the NPM1 gene is a ubiquitously expressed nucleolar phoshoprotein which shuttles continuously between the nucleus and cytoplasm. NPM1 protein plays an important role in cell proliferation and apoptosis. NPM1 gene mutations at exon 12 represent the hallmark of a large sub-group of cytogenetically normal acute myeloid leukemia (CN-AML) patients worldwide.
METHODS: Genomic DNA from 53 CN-AML patients were amplified by PCR and followed by fragment analysis of post-PCR products using GeneMapper software for detection of NPM1 mutations.
RESULTS: NPM1 exon 12 mutations were found are 15/53 CN-AML patients (28.3%) including 3 of M1, 3 of M2, 5 of M4, 3 of M5, and 1 of M6 FAB subtypes. The NPM1 mutation was significantly associated with lower relapse rate (p < 0.05). The complete remission (CR) rate was significantly higher in the patients with high NPM1 mutation load (> 50%) than low NPM1 mutation load (< 50%) (87.5% vs. 28.6%; p = 0.02).
CONCLUSIONS: The aim of this study was to evaluate the NPM1 gene exon 12 mutation in Egyptian patients with CN-AML and its relation to clinical characteristics and patient outcome and survival.

Damnjanovic I, Kocic G, Najman S, et al.
Chemopreventive potential of alpha lipoic acid in the treatment of colon and cervix cancer cell lines.
Bratisl Lek Listy. 2014; 115(10):611-6 [PubMed] Related Publications
OBJECTIVES: The nuclear factor κB regulates the expression of genes involved in many processes that play a key role in the development and progression of cancer. The aim of this study was to examine the influence of the alpha lipoic acid in the chemoprevention of colon and cervix carcinoma in vitro.
BACKGROUND: In recent years, special attention has been paid to the potential chemopreventive properties of antioxidants. There are no published data on the impact of alpha lipoc acid of chemoprevention of cervix and colon cancer.
METHODS: We examined the effect of alpha lipoic acid alone or in combination with cisplatin and 5-fluorouracil on proliferation of the two cell lines, HeLa (human cervical carcinoma cells) and Caco-2 (human colon cancer cells) by MTT test. The measurement of the level of transcription factor NF-κB was also performed in the cells of both cell lines.
RESULTS: At least one of the mechanisms of the antiproliferative and/or cytotoxic effect of alpha lipoic acid on Caco-2 and HeLa cells at high concentrations, the transcription factor NF-κB, may be involved, as well as the products of transcription of genes that are under its control.
CONCLUSION: The alpha lipoic acid has proven to be a promising candidate in the combat arena against cancer (Tab. 4, Ref. 31).

Meshkat M, Tayyebi Meibodi N, Sepahi S, et al.
The frequency of human papillomaviruses in colorectal cancer samples in Mashhad, northeastern Iran.
Turk J Med Sci. 2014; 44(3):501-3 [PubMed] Related Publications
BACKGROUND/AIM: Infection with the human papillomaviruses (HPVs) is associated with the development of several cancers, including oral, esophageal, skin, lung, and cervical. However, the association of HPVs and colorectal cancers remains controversial. The aim of this study was to evaluate the association between HPV infection and paraffin-embedded colorectal tissue samples in Mashhad in the northeast of Iran.
MATERIALS AND METHODS: Paraffin-embedded tissue specimens from 111 patients with colorectal cancer were subjected to DNA extraction. The quality of extracted DNA was confirmed by amplification of a P-globin fragment using polymerase chain reaction (PCR) and GH20/PCO4 primers. PCR with GP5+/GP6+ primers was then performed on positive samples to evaluate the sequence of HPVs.
RESULTS: A total of 100 colorectal samples with positive results for the P-globin gene were analyzed. The age of patients ranged from 18 to 72 years (mean: 52). Sixty-four patients (56.7%) were male and 47 patients (43.4%) were female. One (1%) out of 100 patients with colorectal cancer was found to be positive for HPV DNA.
CONCLUSION: Results of the current study suggested that HPV infection is not common in patients with colorectal cancer in our population. We concluded that HPV types that are associated with malignant transformations do not meaningfully contribute to adenocarcinoma of the colon among our population.

Özdemiri M, Öznur M, Çiftçi E, et al.
Detection of kinase amplifications in gastric adenocarcinomas.
Turk J Med Sci. 2014; 44(3):461-70 [PubMed] Related Publications
AIM: To determine the incidences of copy number aberrations of receptor kinases and their relations in Turkish patients with gastric adenocarcinoma.
MATERIALS AND METHODS: The prevalence of genomic copy number aberrations of epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2)/topoisomerase IIa (TOP2A), centrosome-associated kinase aurora A (AURK A), centrosome-associated kinase aurora B (AURK B), and mesenchymal-epithelial transition factor (MET) genes and polysomies of related chromosomes were analyzed by fluorescent in situ hybridization (FISH) in tumor samples from 35 patients with gastric cancer.
RESULTS: There were 28.6%, 65.7%, 20.0%, 17.1%, 60.0%, and 45.7% cases considered FISH-positive for EGFR, MET, HER2, TOP2A, AURK A, and AURK B genes, respectively. Statistically significant associations were determined in detection of amplifications of 1) EGFR gene with chromosome 7 polysomy, 2) MET gene in nonpolysomic chromosome 7 nuclei, 3) HER2/TOP2A genes in nonpolysomic chromosome 17 nuclei, 4) coamplification of HER2/TOP2A in poorly differentiated carcinomas, and 5) AURK A gene in nonpolysomic chromosome 20 nuclei. Most of the aberrations were predominantly seen in poorly differentiated tumors, but a high rate of the amplified MET gene was also detected in moderately differentiated carcinomas.
CONCLUSION: Chromosome 7 polysomy may be responsible for EGFR gene amplifications, and we concluded that MET and AURK A genes amplifications were commonly seen aberrations in gastric adenocarcinomas and may offer information about disease progression and administration of individualized treatment for gastric cancer patients.

Şimşek H, Han Ü, Önal B, Şimişek G
The expression of EGFR, cerbB2, p16, and p53 and their relationship with conventional parameters in squamous cell carcinoma of the larynx.
Turk J Med Sci. 2014; 44(3):411-6 [PubMed] Related Publications
BACKGROUND/AIM: To investigate the expression of epidermal growth factor receptor-HER1 (EGFR), cerbB2 (HER2), p16, and p53, as well as the relationship of the expression of these genes with conventional parameters in squamous cell carcinoma (SCC) of the larynx.
MATERIALS AND METHODS: Samples from 92 cases of diagnosed laryngeal SCC between 2001 and 2011 from the Pathology Department of Ministry of Health Ankara D1şkapi Yildirinm Beyazit Teaching & Research Hospital were studied by immunohistochemistry using EGFR, cerbB2, p16, and p53 antibodies.
RESULTS: An increase in the TNM stage and pathological tumor size status correlated with an increase in EGFR and cerbB2 expression. In the cases with lymphovascular invasion, the expression was detected at a higher ratio. Cases in which high levels ofpl6 and p53 expression were observed did not show any lymphovascular invasions.
CONCLUSION: Expressions of p53 and p16 were considered to be most effective in early carcinogenesis stages of laryngeal SCC. In comparison with p53 and p16 expression levels, EGFR and cerbB2 expression levels were observed to be associated with poor prognostic parameters and were higher at later stages of laryngeal carcinogenesis development.

Bessho H, Wong B, Huang D, et al.
Inhibition of placental growth factor in renal cell carcinoma.
Anticancer Res. 2015; 35(1):531-41 [PubMed] Related Publications
BACKGROUND/AIM: Placental growth factor (PlGF) is up-regulated in major malignant diseases or following antiangiogenic therapy, although it is present in low levels under normal physiological conditions. TB403, a monoclonal antibody against PlGF, was investigated in clear cell renal cell carcinoma (ccRCC) xenografts since it has been proposed as a potential target in oncology.
MATERIALS AND METHODS: Human ccRCCs were implanted in athymic nude mice to evaluate the efficacy of TB403 and to excise xenograft tumors for molecular experiments.
RESULTS: TB403 did not significantly inhibit tumor growth in treatment-naïve or sunitinib-resistant ccRCC xenografts. Gene expression profiling resulted in over-expression of the C1orf38 gene, which induced immunoreactivity in macrophages. Angiogenesis PCR arrays showed that VEGFR-1 was not expressed in ccRCC xenografts.
CONCLUSION: PlGF blockade did not have a broad antiangiogenic efficacy; however, it might be effective on-target in VEGFR1-expressing tumors. The inhibition of VEGF pathway may induce the activity of tumor-associated-macrophages for angiogenesis escape.

Gocze K, Gombos K, Kovacs K, et al.
MicroRNA expressions in HPV-induced cervical dysplasia and cancer.
Anticancer Res. 2015; 35(1):523-30 [PubMed] Related Publications
BACKGROUND/AIM: The role of oncogenic or high-risk human papillomavirus (HPV) in cervical carcinogenesis is inevitable, yet not fully understood. Detailed analysis of microRNA (miRNA) alterations occurring during high-risk HPV transformation will increase our current understanding over cervical carcinogenesis. The two main aims of the study were: (i) finding association between HPV infection characteristics and socio-demographic variables, (ii) finding an predictors of clinical outcome.
MATERIALS AND METHODS: The expression levels of different microRNAs (miR-21, miR-27a, miR-34a, miR-155, miR-196a, miR-203) were determined in formalin-fixed paraffin-embedded (FFPE) human HPV-positive cervical dysplastic and tumorous tissue samples using quantitative real-time PCR (qPCR). Sociodemographic and life-style factors were also analyzed.
RESULTS: The expression of miR-27a was significantly higher in cervical intraepithelial neoplasia (CIN)2-3 compared to CIN1 (p=0.023) and in squamous cell carcinoma (SCC) compared to CIN2-3 (p=0.033). Moreover, significantly lower levels of miR-34a were detected in CIN2-3 than in CIN1 (p=0.041) and in SCC than in CIN2-3 (p=0.021). Furthermore, we found significant differences in subjects with multiple HPV in miR-27a (p=0.015) and miR-203 (p=0.025) in CIN2-3 compared to CIN1 and miR-21 (p=0.002), mir-27a (p=0.001) and miR-34a (p=0.001) in SCC/CIN2-3. Expression of miR-27a, showing up-regulation in CIN2-3 compared to CIN1 (p=0.028) and miR-34a (down-regulated), correlated with HPV 16 positivity (CIN2-3/CIN1: p=0.027 and SCC/CIN2-3: p=0.036). MiR-34a expression was also significantly altered in connection to smoking status and presence of HPV 16.
CONCLUSION: The demand for additional, alternative molecular biomarkers with prognostic potential is strong. Evaluation of miRNA expression might be helpful to distinguish different cervical lesions and might be able to help in the prediction of HPV infection outcome.

Ramos D, Pellín-Carcelén A, Agustí J, et al.
Deregulation of glyceraldehyde-3-phosphate dehydrogenase expression during tumor progression of human cutaneous melanoma.
Anticancer Res. 2015; 35(1):439-44 [PubMed] Related Publications
BACKGROUND/AIM: Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a highly abundant housekeeping gene. GAPDH overexpression has been reported in diverse types of human cancers including cutaneous melanoma. Our goal was to quantify GAPDH mRNA and protein expression in the whole spectrum of primary and metastatic melanomas in the search for a specific role for this ubiquitous molecule during tumor progression.
MATERIALS AND METHODS: Intratumoral GAPDH mRNA expression was quantified by real-time PCR in 71 cases, including 29 primary melanomas and 42 metastatic cases. Relative expression levels in thin (≤1 mm) and thick (>1 mm) primary tumors and 'in-transit', lymph node and distant metastases were compared. Similarly, protein expression was investigated by means of immunohistochemistry. Specific exons of GAPDH were analyzed by DNA sequencing.
RESULTS: GAPDH mRNA expression was significantly up-regulated in thick melanomas when compared to primary thin melanomas. Similar differences were also encountered between metastatic melanomas when compared to lymph-node metastatic melanomas. Interestingly, GAPDH protein immunoexpression was higher in thick melanomas and distant metastases than in thin tumors and lymph node metastases, respectively. However, no specific point-mutations in GAPDH-specific exons were found in any patient.
CONCLUSION: Deregulation of GAPDH during melanoma progression was demonstrated in our series by mRNA and protein expression studies.

Nakayama S, Soejima K, Yasuda H, et al.
FOXD1 expression is associated with poor prognosis in non-small cell lung cancer.
Anticancer Res. 2015; 35(1):261-8 [PubMed] Related Publications
AIM: Clinical microarray datasets were analyzed to search for new therapeutic targets and prognostic markers of non-small cell lung cancer (NSCLC).
MATERIALS AND METHODS: Microarray datasets from 90 lung cancer specimens, were analyzed with focus on the FOXD1 gene. Levels of FOXD1 mRNA were assessed in lung cancer cell lines and these levels were correlated with survival.
RESULTS: FOXD1-knockdown led to suppression of cell proliferation. Moreover, patients with high FOXD1 expression survived for a significantly shorter time than those with low FOXD1 expression.
CONCLUSION: The expression status of FOXD1 is a novel prognostic factor and may lead to new treatment strategies for NSCLC.

Nalkiran I, Turan S, Arikan S, et al.
Determination of gene expression and serum levels of MnSOD and GPX1 in colorectal cancer.
Anticancer Res. 2015; 35(1):255-9 [PubMed] Related Publications
BACKGROUND/AIM: Oxidative stress plays a role on the development of colorectal cancer. Manganese superoxide dismutase (MnSOD) and glutathione peroxidase 1 (GPX1) are crucial in regulating oxidative balance and its stabilization. Possible mechanisms of action of these enzymes in various types of cancers require further investigation. We aimed to determine expression levels of these genes and their effects on protein levels in serum of patients with colorectal cancer.
MATERIALS AND METHODS: Expression levels of genes were determined using Real Time-Polymerase chain reaction in 35 patients with colorectal cancer. We used enzyme-linked immunosorbent assay to determine MnSOD and GPX1 levels.
RESULTS: We found significant differences in GPX1 expression between tumor and normal tissues, with a 2-fold decrease in tumor tissues (p<0.05). However, although no significant difference was found between the expression of MnSOD gene in tumor and that in normal tissues, there was a 1.13-fold change in expression. We observed no relationship between expressions of either gene and their levels in serum.
CONCLUSION: The GPX1 gene may play a critical role in the development of colorectal cancer.

Katoh S, Goi T, Naruse T, et al.
Cancer stem cell marker in circulating tumor cells: expression of CD44 variant exon 9 is strongly correlated to treatment refractoriness, recurrence and prognosis of human colorectal cancer.
Anticancer Res. 2015; 35(1):239-44 [PubMed] Related Publications
BACKGROUND/AIM: The expression of the CD44 variant exon 9 (CD44v9) was investigated in order to elucidate its significance for cancer stem cells in circulating human colorectal cancer cells (CTCs).
MATERIALS AND METHODS: After peripheral blood was drawn from patients with colorectal cancer, CTCs were collected. Using the reverse transcription-polymerase chain reaction method, we examined the relationship between expression of CD44v9 mRNA and prognosis.
RESULTS: In 60 out of 150 patients with colorectal cancer, expression of CD44v9 mRNA was positive in CTCs. In patients with stage III disease, the 5-year survival rate was 89% for patients with negative CD44v9 expression, whereas it was 52.4% in patients with positive expression (p<0.05). In patients with stage IV unresectable cancer, the 2-year survival rate was 70.1% in cases with CD44v9-negative expression and 33.3% in cases of positive expression (p<0.05).
CONCLUSION: CD44v9 mRNA in the CTCs of colorectal cancer is useful as a factor predicting recurrence, prognosis, and treatment efficacy.

Rwigemera A, Mamelona J, Martin LJ
Comparative effects between fucoxanthinol and its precursor fucoxanthin on viability and apoptosis of breast cancer cell lines MCF-7 and MDA-MB-231.
Anticancer Res. 2015; 35(1):207-19 [PubMed] Related Publications
BACKGROUND/AIM: We evaluated whether low doses of the natural carotenoid fucoxanthin and/or of its metabolite fucoxanthinol are effective against proliferation of estrogen-sensitive MCF-7 and estrogen-resistant MDA-MB-231 breast cancer cell lines.
MATERIALS AND METHODS: These cell lines were stimulated with 10 to 20 μM fucoxanthin and/or fucoxanthinol, followed by cell viability assays, Annexin V immunofluorescence to evaluate apoptosis, as well as mRNA and protein extractions for changes in nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) members' expressions and nuclear translocations.
RESULTS: Fucoxanthin and fucoxanthinol reduced the viability of MCF-7 and MDA-MB-231 cells in a time-dependent manner as a result of increased apoptosis. In both cell lines, modulatory actions of fucoxanthinol on members of the NF-κB pathway were more pronounced than that of fucoxanthin.
CONCLUSION: In MDA-MB-231 cells, fucoxanthinol reduced nuclear levels of NF-κB members' p65, p52 and RelB. Fucoxanthinol and fucoxanthin could be effective for the treatment and/or prevention of breast cancer.

Seki K, Kinashi Y, Takahashi S
Influence of p53 status on the effects of boron neutron capture therapy in glioblastoma.
Anticancer Res. 2015; 35(1):169-74 [PubMed] Related Publications
BACKGROUND/AIM: The tumor suppressor gene p53 is mutated in glioblastoma. We studied the relationship between the p53 gene and the biological effects of boron neutron capture therapy (BNCT).
MATERIALS AND METHODS: The human glioblastoma cells; A172, expressing wild-type p53, and T98G, with mutant p53, were irradiated by the Kyoto University Research Reactor (KUR). The biological effects after neutron irradiation were evaluated by the cell killing effect, 53BP1 foci assay and apoptosis induction.
RESULTS: The survival-fraction data revealed that A172 was more radiosensitive than T98G, but the difference was reduced when boronophenylalanine (BPA) was present. Both cell lines exhibited similar numbers of foci, suggesting that the initial levels of DNA damage did not depend on p53 function. Detection of apoptosis revealed a lower rate of apoptosis in the T98G.
CONCLUSION: BNCT causes cell death in glioblastoma cells, regardless of p53 mutation status. In T98G cells, cell killing and apoptosis occurred effectively following BNCT.

Boukhari A, Alhosin M, Bronner C, et al.
CD47 activation-induced UHRF1 over-expression is associated with silencing of tumor suppressor gene p16INK4A in glioblastoma cells.
Anticancer Res. 2015; 35(1):149-57 [PubMed] Related Publications
CD47, an integrin-associated protein is over-expressed in several tumors including glioblastomas. Activation of CD47 induces proliferation of human astrocytoma cells but not normal astrocytes via an Akt-dependent way. However, the pathways mediating this process are still unknown. The epigenetic integrator UHRF1 (Ubiquitin-like containing PHD and RING Finger 1) is over-expressed in various cancers and plays a vital role in the silencing of numerous tumor suppressor genes including p16(INK4A), thereby promoting cell proliferation. The aim of the present study was to investigate the role of UHRF1 and p16(INK4A) in CD47-induced effects. Herein we showed that activation of CD47 in human astrocytoma cell lines U87 and CCF- STTG1 (Grade IV), up-regulated the expression of UHRF1 with subsequent down-regulation of p16(INK4A), thus promoting cell proliferation. Blockage of CD47 using a blocking antibody down-regulated UHRF1 expression, accompanied by a re-expression of p16(INK4A), conducting to decreased cell proliferation in both cancer cell lines. Neither CD47 activation nor its blocking has any effect on UHRF1/p16(INK4A) expression in normal human astrocytes. Depletion of CD47 in the U87 cell line resulted in down-regulation of UHRF1. We also found that CD47 activated the inflammatory genes IL-6, IL-7 and MCP-1 by a NF-κB-dependent mechanism in human astrocytoma but not in normal astrocytes. In conclusion, the present findings indicate that CD47 activation increases expression of UHRF1 and suggest, for the first time, that CD47 regulates the epigenetic code by targeting UHRF1. This could represent a new pathway towards cell proliferation and metastasis.

Shinden Y, Akiyoshi S, Ueo H, et al.
Diminished expression of MiR-15a is an independent prognostic marker for breast cancer cases.
Anticancer Res. 2015; 35(1):123-7 [PubMed] Related Publications
BACKGROUND/AIM: MiR-15a targets Cyclin E1 (CCNE1), which regulates the cell cycle and promotes cell proliferation and progression. Herein, we investigated the clinicopathological significance of miR-15a as a prognostic marker in breast cancer (BC) cases.
MATERIALS AND METHODS: We collected primary tumor samples of 230 BC cases, including 68 triple-negative cases. The expression levels of miR-15a in primary tumors were measured by qRT-PCR assay.
RESULTS: Low expression of miR-15a in primary tumors was significantly correlated with shorter disease-free survival (p=0.0012) and overall survival (p=0.005) compared to the high miR-15a expression in triple-negative BC cases. Multivariate analysis indicated that low miR-15a expression was an independent prognostic factor for overall survival [RR=2.56(1.03-7.18), p=0.04].
CONCLUSION: MiR-15a expression levels could be a promising biological and prognostic marker for overall survival especially in triple-negative BC cases.

Lloyd MC, Szekeres K, Brown JS, Blanck G
Class II transactivator expression in melanoma cells facilitates T-cell engulfment.
Anticancer Res. 2015; 35(1):25-9 [PubMed] Related Publications
BACKGROUND/AIM: Melanoma cells express high levels of HLA class II, cell surface antigen-presenting proteins, which is an anomalous phenotype among solid tumors. There has never been a satisfying explanation for how this HLA class II-positive phenotype is related to tumor development. Lugini and colleagues demonstrated that melanoma cells have the capacity to engulf T-cells. We considered the possibility that this capacity could be dependent on HLA class II expression.
MATERIALS AND METHODS: We co-cultured melanoma and CD4-positive, labeled, Jurkat-C T-cells. The melanoma cells were transformed with an expression vector for CIITA, the obligate HLA class II gene transactivator. We then assayed for the transfer of label to the melanoma cells.
RESULTS: CIITA expression facilitated engulfment of the T-cell material but not material from B-cells.
CONCLUSION: The results suggest a possible mechanism for HLA class II-positive melanoma cells in blunting an anti-tumor response and suggest a possible target for melanoma therapy.

Kizilay F, Kalemci MS, Şimşir A, et al.
The place of androgen receptor gene mutation analysis in the molecular diagnosis of prostate cancer and genotype-phenotype relationship.
Turk J Med Sci. 2014; 44(2):261-6 [PubMed] Related Publications
AIM: To determine the relationship between androgen receptor (AR) gene polymorphism and prostate cancer in our society.
MATERIALS AND METHODS: Thirty-nine patients diagnosed with prostate cancer and 34 benign prostatic hyperplasia (BPH) patients who were diagnosed in 2010 met the study criteria. The inclusion criteria included patients whose diagnosis was confirmed with a biopsy, with the presence of adequate pathologic material for review, between the ages of 40 and 80, and who were healthy men without a family history of prostate cancer. The exclusion criteria excluded men diagnosed with another cancer and those who had kin with a history of prostate cancer. A direct DNA sequencing method was utilized for detection of polymorphisms.
RESULTS: CAG repeat length varied from 13 to 28 (mean: 21.67) for the BPH group and 12 to 28 (mean: 21.74) for the prostate cancer group. Prostate-specific antigen (PSA) density and the androgen receptor (AR) CAG repeat had a statistically significant negative correlation in the BPH group. A statistically significant difference was associated between AR CAG repeat and PSA density.
CONCLUSION: Randomized prospective studies should be planned with larger patient and control groups and with more variables, which may open new horizons in prostate cancer screening and early detection.

Paquet ER, Hallett MT
Absolute assignment of breast cancer intrinsic molecular subtype.
J Natl Cancer Inst. 2015; 107(1):357 [PubMed] Related Publications
BACKGROUND: Massively parallel gene expression profiling has provided a more objective, molecular-level characterization of breast cancer subtypes. Several bioinformatics tools are available to infer patient subtype from a gene expression profile including the well-studied PAM50. The specific algorithmic methods used in these tools require access to a broad patient dataset. The choice of subtype for an individual is determined relative to all other patients across the panel, making subtypes heavily dependent on the composition of the dataset. Our aim was to develop a bioinformatics approach assigning absolute breast cancer subtypes, independent of dataset composition.
METHODS: Using a dataset of 4924 breast cancer patients, we defined a new bioinformatics approach: Absolute Intrinsic Molecular Subtyping (AIMS) that assigns subtype from a gene expression profile for an individual sample without the need for a large, diverse, and normalized dataset. We evaluated the agreement of AIMS with PAM50 and compared subtype assignment and prognostic value of the subtypes. We assessed AIMS' robustness using a benchmark set of tests including subtype reproducibility between technologies, gene removal, and normal gene expression contamination, and compared it with PAM50. All statistical tests, except where noted, were two-sided.
RESULTS: AIMS vastly agreed with PAM50, with 76% and 77% agreement for cross validation and the test set, respectively, and the prognostic capacity of the intrinsic subtypes was preserved. AIMS is fully stable, and its absolute nature enables its use on a wide range of datasets and technologies, including RNA-seq.
CONCLUSIONS: The instability of a breast cancer subtyping scheme like PAM50 could have important consequences in clinical management of patients. AIMS is a fully stable and robust subtyping scheme that recapitulates PAM50.

van Kruchten M, de Vries EF, Arts HJ, et al.
Assessment of estrogen receptor expression in epithelial ovarian cancer patients using 16α-18F-fluoro-17β-estradiol PET/CT.
J Nucl Med. 2015; 56(1):50-5 [PubMed] Related Publications
UNLABELLED: The estrogen receptor α (ERα) is expressed in approximately 70% of ovarian cancer tumors. PET of tumor ERα expression with the tracer 16α-(18)F-fluoro-17β-estradiol ((18)F-FES) may be valuable to select ovarian cancer patients for endocrine therapy. The aim of this study was to evaluate the feasibility of (18)F-FES PET to determine tumor ERα expression noninvasively in epithelial ovarian cancer patients.
METHODS: (18)F-FES PET/CT was performed shortly before cytoreductive surgery. Tumor (18)F-FES uptake was quantified for all lesions 10 mm or greater on CT and expressed as maximum standardized uptake value. (18)F-FES PET/CT findings were compared with histology and immunohistochemistry for ERα, ERβ, and progesterone receptor. Receptor expression was scored semiquantitatively using H-scores (percentage of positive tumor cells × staining intensity). The optimum threshold to discriminate ER-positive and -negative lesions was determined by receiver-operating-characteristic analysis.
RESULTS: In the 15 included patients with suspected ovarian cancer, 32 measurable lesions greater than 10 mm were present on CT. Tumor (18)F-FES uptake could be quantified for 28 lesions (88%), and 4 lesions were visible but nonquantifiable because of high uptake in adjacent tissue. During surgery, histology was obtained of 23 of 28 quantified lesions (82%). Quantitative (18)F-FES uptake correlated with the semiquantitative immunoscore for ERα (ρ = 0.65, P < 0.01) and weakly with progesterone receptor expression (ρ = 0.46, P = 0.03) and was not associated with ERβ expression (ρ = 0.21, P = 0.33). The optimum threshold to discriminate ERα-positive and ERα-negative lesions was a maximum standardized uptake value greater than 1.8, which provided a 79% sensitivity, 100% specificity, and area under the curve of 0.86 (95% confidence interval, 0.70-1.00). In 2 of 7 patients with cytology/histology available at primary diagnosis and at debulking surgery, immunohistochemical ERα expression had changed over time. (18)F-FES PET was in accordance with histology at debulking surgery but not at primary diagnosis, indicating that (18)F-FES PET could provide reliable information about current tumor ERα status.
CONCLUSION: (18)F-FES PET/CT can reliably assess ERα status in epithelial ovarian cancer tumors and metastases noninvasively. Evaluation of the predictive value of (18)F-FES PET/CT for endocrine therapy in epithelial ovarian cancer patients is warranted.

Xu M, Qiang F, Gao Y, et al.
Evaluation of a novel functional single-nucleotide polymorphism (rs35010275 G>C) in MIR196A2 promoter region as a risk factor of gastric cancer in a Chinese population.
Medicine (Baltimore). 2014; 93(26):e173 [PubMed] Related Publications
Single-nucleotide polymorphisms (SNPs) in microRNAs (miRNAs) have been suggested to influence the occurrence and progression of cancer through altering the expression and biological function of miRNAs. The aim of this study was to investigate whether the potential functional SNPs in MIR196A2 promoter had effect on the susceptibility to gastric cancer (GC) in a Chinese population.We conducted a 2-stage case-control study (753 cases and 854 controls in testing set; 940 cases and 1061 controls in validation set) to evaluate the association between 2 potential functional SNPs in MIR196A2 promoter (rs12304647 A>C and rs35010275 G>C) and GC risk. The luciferase reporter assay and electrophoretic mobility shift assay were used to examine the functionality of the important polymorphism.We found that the rs35010275 C allele was significantly associated with the decreased risk of GC (adjusted odds ratio = 0.85, 95% confidence interval = 0.77-0.94) in the combined case-control studies. The miR-196a expression levels in GC tissues were significantly higher than that in corresponding adjacent normal tissues (P < 0.001). Besides, each allele of rs35010275 displayed completely opposite effects to influence the transcription activity of MIR196A2 promoter via recruiting different transcription factors or complexes.The functional rs35010275 G>C polymorphism in MIR196A2 promoter was significantly associated with miR-196a expression and influenced the genetic susceptibility to GC.

Langhe R, Norris L, Saadeh FA, et al.
A novel serum microRNA panel to discriminate benign from malignant ovarian disease.
Cancer Lett. 2015; 356(2 Pt B):628-36 [PubMed] Related Publications
Ovarian cancer is the seventh most common cancer in women and the most frequent cause of gynaecological malignancy-related mortality in women. Currently, no standardized reliable screening test exists. MicroRNA profiling has allowed the identification of signatures associated with diagnosis, prognosis and response to treatment of human tumours. The aim of this study was to determine if a microRNA signature could distinguish between malignant and benign ovarian disease. A training set of 5 serous ovarian carcinomas and 5 benign serous cystadenomas were selected for the initial experiments. The validation set included 20 serous ovarian carcinomas and 20 benign serous cystadenomas. The serum/plasma focus microRNA Exiqon panel was used for the training set. For the validation set a pick and mix Exiqon panel, which focuses on microRNAs of interest was used. A panel of 4 microRNAs (let-7i-5p, miR-122, miR-152-5p and miR-25-3p) was significantly down regulated in cancer patients. These microRNAs target WNT signalling, AKT/mTOR and TLR-4/MyD88, which have previously been found to play a role in ovarian carcinogenesis and chemoresistance. let-7i-5p, miR-122, miR-152-5p and miR-25-3p could act as diagnostic biomarkers in ovarian cancer.

Mehta A, Patel D, Rosenberg A, et al.
Hyperparathyroidism-jaw tumor syndrome: Results of operative management.
Surgery. 2014; 156(6):1315-24; discussion 1324-5 [PubMed] Article available free on PMC after 01/12/2015 Related Publications
BACKGROUND: Hyperparathyroidism-jaw tumor syndrome (HPT-JT) is a rare, autosomal-dominant disease secondary to germline-inactivating mutations of the tumor suppressor gene HRPT2/CDC73. The aim of the present study was to determine the optimal operative approach to parathyroid disease in patients with HPT-JT.
METHODS: A retrospective analysis of clinical and genetic features, parathyroid operative outcomes, and disease outcomes in 7 unrelated HPT-JT families.
RESULTS: Seven families had 5 distinct germline HRPT2/CDC73 mutations. Sixteen affected family members (median age, 30.7 years) were diagnosed with primary hyperparathyroidism (PHPT). Fifteen of the 16 patients underwent preoperative tumor localization studies and uncomplicated bilateral neck exploration at initial operation; all were in biochemical remission at most recent follow-up. Of these patients, 31% had multiglandular involvement; 37.5% of the patients developed parathyroid carcinoma (median overall survival, 8.9 years; median follow-up, 7.4 years). Long-term follow-up showed that 20% of patients had recurrent PHPT.
CONCLUSION: Given the high risk of malignancy and multiglandular involvement in our cohort, we recommend bilateral neck exploration and en bloc resection of parathyroid tumors suspicious for cancer and life-long postoperative follow-up.

Perrino CM, Hucthagowder V, Evenson M, et al.
Genetic alterations in renal cell carcinoma with rhabdoid differentiation.
Hum Pathol. 2015; 46(1):9-16 [PubMed] Related Publications
Renal cell carcinoma with rhabdoid differentiation (RCC-R) in adult patients is an aggressive variant of renal cancer with no known specific genetic alterations. The aim of this study was to characterize genome-wide genetic aberrations in RCC-R via utilization of high-density single-nucleotide polymorphism (SNP) arrays. We identified 20 cases of RCC-R, which displayed both clear cell renal cell carcinoma and rhabdoid histomorphologic components. DNA was extracted from formalin-fixed, paraffin-embedded tissue (from clear cell renal cell carcinoma and RCC-R areas from each case) and subjected to high-density SNP array assay. Genetic aberrations present in 10% of cases were considered significant. In areas with clear cell histomorphology, gains were most commonly observed in chromosomes 5q (66.7%, 10/15), 7 (46.7%, 7/15), and 8q (46.7%, 7/15); and losses were most commonly identified in chromosomes 14 (60%, 9/15), 8p (46.7%, 7/15), and 22 (46.7%, 7/15). In areas with rhabdoid differentiation, gains were most commonly observed in chromosome 7 (58.8%, 10/17); and losses were most commonly identified in chromosomes 9 (70.6%, 12/17), 14 (58.8%, 10/17), 4 (52.9%, 9/17), and 17p (52.9%, 9/17). Rhabdoid cells shared many chromosomal abnormalities and exhibited a greater number of copy number variations in comparison with coexisting clear cells. Loss of 11p was specific for rhabdoid differentiation, with loss found in 29.4% of rhabdoid components compared with 0% of clear cell areas. The greater number of overall genetic alterations in the rhabdoid cells and the shared genetic background between rhabdoid and clear cell areas suggest genetic evolution of the rhabdoid cells that correlates with histomorphologic progression.

Huang B, Li H, Huang L, et al.
Clinical significance of microRNA 138 and cyclin D3 in hepatocellular carcinoma.
J Surg Res. 2015; 193(2):718-23 [PubMed] Related Publications
BACKGROUND: MicroRNA 138 (miR-138) is recently shown to inhibit tumor growth and block cell cycle arrest of hepatocellular carcinoma (HCC) by targeting cyclin D3 (CCND3). The aim of this study was to investigate the clinical significance of miR-138 and CCND3 in human HCC, which remains unclear.
METHODS: Quantitative real-time polymerase chain reaction analysis was performed to detect the expression levels of miR-138 and CCND3 messenger RNA (mRNA) in 180 self-pairs of HCC and noncancerous liver tissues.
RESULTS: Compared with noncancerous liver tissues, the expression levels of miR-138 in HCC tissues were significantly downregulated (P < 0.001), whereas the expression levels of CCND3 mRNA in HCC tissues were significantly upregulated (P < 0.001). There was a negative correlation between miR-138 and CCND3 mRNA expression in HCC tissues (r = -0.56, P = 0.02). Additionally, statistical analysis showed that the combined miR 138 downregulation and CCND3 upregulation (miR-138-low-CCND3-high) was significantly associated with the advanced tumor-node-metastasis stage (P = 0.008) and the presence of portal vein invasion (P = 0.008) and lymph node metastasis (P = 0.01). More importantly, a significant trend was identified between the combined expression of miR-138-low-CCND3-high in HCC and worsening clinical prognosis. Multivariate survival analysis further recognized miR-138-low-CCND3-high expression as an independent prognostic factor for patients with HCC.
CONCLUSIONS: Our data suggest that the combined expression of miR-138 and its direct target CCND3 may be correlated with significant characteristics of HCC. MiR-138 downregulation and CCND3 upregulation maybe concurrently associated with prognosis in patients with HCC.

Fan LQ, Li Y, Zhao Q, et al.
Comparative proteomics in gastric cancer cell line BGC823 after ZNF139 gene inhibited with RNA interference.
Hepatogastroenterology. 2014; 61(134):1822-9 [PubMed] Related Publications
BACKGROUND/AIMS: Zinc finger protein 139 (ZNF139) gene is proved play an important role in gastric cancer. Aim of this study is to identify changes of proteins after ZNF139 gene was inhibited in gastric cancer cell line BGC823.
METHODS: siRNA-specific ZNF139 was synthesized and transfected into BGC823; 2-D fluorescence difference gel electrophoresis (2-D DIGE) and liquid chromatography-mass spectrometry (LC-MS) were applied to screen, identify differentially expressed proteins, and function of these proteins was analyzed; Western blot method was applied to verify the identified proteins.
RESULTS: ZNF139 expression in siRNA transfected cancer cell BGC823 decreased significantly. Results of 2-D DIGE showed eight differential protein spots, of which seven were identified with LC-MS, including switches associated protein 70, far upstream element binding protein 1, heat shock protein 60, annexin A7, small ubiquitin-like modifier 1 activating enzyme, chaperonin-containing tail-less complex protein 1 and annexin A2. These proteins were found to be associated with proliferation, apoptosis, invasion, metastasis, adhesion of gastric cancer cells with bioinformatic analysis. Western blot analysis confirmed that expressions of these proteins in BGC823 were consistent with the proteomic results.
CONCLUSIONS: ZNF139 gene may influence the biological behavior of gastric cancer cells in many ways by regulating multiple proteins.

Yunqiao L, Vanke H, Jun X, Tangmeng G
MicroRNA-206, down-regulated in hepatocellular carcinoma, suppresses cell proliferation and promotes apoptosis.
Hepatogastroenterology. 2014 Jul-Aug; 61(133):1302-7 [PubMed] Related Publications
BACKGROUND/AIMS: MicroRNA-206 has been proven down-regulated in many human malignancies and correlated with tumor progression. However, the expression and functions of miR-206 in hepatocellular carcinoma (HCC) are still unclear. The aim of this study was to explore the effects of miR-206 in HCC tumorigenesis and development.
METHODOLOGY: The expression levels of miR-206 were quantified by qRT-PCR in 147 surgically resected HCC and matched adjacent non-cancerous tissues, and correlated with clinicopathological factors. MTT, flow cytometric assay, and Transwell invasion and migration assays were used to test the proliferation, apoptosis, invasion, and migration of HepG2 HCC cells transfected with miR-206 mimics or negative control (NC) RNA-oligonucleotides.
RESULTS: MiR-206 expression was significantly downregulated in HCC compared with matched non-cancerous liver tissues. Low level of miR-206 was associated with poor tumor differentiation, multiple tumor nodes, lymph node metastasis, and advanced TNM stage. In addition, transfection of miR-206 mimics in HepG2 cells was able to reduce cell proliferation, invasion, and migration, and promote cell apoptosis.
CONCLUSIONS: These findings demonstrate that miRNA-206 could not only be useful as a novel biomarker but also serve as a potential target for gene therapy of HCC.

Koev IG, Feodorova YN, Kazakova MH, et al.
Glioblastoma multiforme classified as mesenchymal subtype.
Folia Med (Plovdiv). 2014 Jul-Sep; 56(3):215-9 [PubMed] Related Publications
INTRODUCTION: Recently, researchers have been considering as adverse prognostic factors in primary glioblastomas not only clinical indicators but also various cellular, genetic and immunological markers. The aim of the present article was to report a case of primary glioblastoma multiforme with poor survival in a patient after surgical intervention, and to determine the unfavorable prognostic markers.
CASE REPORT: We present a 71-year-old man with histologically verified glioblastoma multiforme and a postoperative survival of 48 days. The patient did not receive any radiotherapy and adjuvant therapy with temozolomide because of the short survival. Serum and transcription levels of TNF-α, CD44, YKL-40 and IL-6 were determined by molecular-biological and immunological analyses. We found very high transcription levels of the genes CD44, YKL-40 and IL-6, increased gene expression of TNF-α, and elevated serum concentrations of TNF-α, YKL-40 and IL-6 and reduced serum concentration of CD44.
CONCLUSION: Molecular-biological and immunological analyses support the hypothesis that glioblastoma multiforme is presented by a heterogeneous group of glial tumors with different clinical course and prognosis. The high expression levels of TNF-α, CD44, YKL-40, and IL-6 indicate that the tumor can be categorized as mesenchymal subtype of glioblastoma multiforme, which accounts for the rapid clinical course and lethal outcome of the condition.

Lange M, Żawrocki A, Nedoszytko B, et al.
Does the aberrant expression of CD2 and CD25 by skin mast cells truly correlate with systemic involvement in patients presenting with mastocytosis in the skin?
Int Arch Allergy Immunol. 2014; 165(2):104-10 [PubMed] Related Publications
BACKGROUND: Neoplastic mast cells involving the bone marrow (BMMCs) of patients with mastocytosis display an aberrant expression of CD25 and/or CD2 antigens. The aim of this study was to determine the frequency of CD2 and CD25 expression on skin mast cells (sMCs) of patients with mastocytosis in the skin at the early stage of the disease. Furthermore, the usefulness of the phenotypic profile of sMCs for the diagnosis of systemic mastocytosis (SM) was evaluated.
METHODS: The 52 adults included in the study were diagnosed with mastocytosis strictly according to the criteria of the World Health Organization. CD117, CD2 and CD25 antigen expression on sMCs was detected by immunohistochemistry. The presence of the KIT D816V mutation in the BM was analyzed using allele-specific PCR.
RESULTS: The presence of CD2- or CD25-positive sMCs was detected in 57.1% of cutaneous mastocytosis (CM) and 90.3% of SM cases (p = 0.008). In all mastocytosis patients, CD2 expression on sMCs was more frequent than CD25 expression (67.3 and 38.5%, respectively). Moreover, CD2 expression on sMCs was more frequent in SM than in CM cases (p = 0.02). The presence of one of the aberrant sMC antigens was detected in 84.2% of patients with the KIT D816V mutation in the BM. A positive correlation between densities of CD25- and CD117-positive sMCs was found in SM patients (r = 0.46, p = 0.009).
CONCLUSIONS: Although sMCs displayed immunoreactivity for one of the neoplastic antigens in the majority of SM patients, the aberrant CD2 and/or CD25 expression on sMCs is not as indicative of SM as the BMMC immunophenotype.

Chaudhry MS, Karadimitris A
Role and regulation of CD1d in normal and pathological B cells.
J Immunol. 2014; 193(10):4761-8 [PubMed] Related Publications
CD1d is a nonpolymorphic, MHC class I-like molecule that presents phospholipid and glycosphingolipid Ags to a subset of CD1d-restricted T cells called invariant NKT (iNKT) cells. This CD1d-iNKT cell axis regulates nearly all aspects of both the innate and adaptive immune responses. Expression of CD1d on B cells is suggestive of the ability of these cells to present Ag to, and form cognate interactions with, iNKT cells. In this article, we summarize key evidence regarding the role and regulation of CD1d in normal B cells and in humoral immunity. We then extend the discussion to B cell disorders, with emphasis on autoimmune disease, viral infection, and neoplastic transformation of B lineage cells, in which CD1d expression can be altered as a mechanism of immune evasion and can have both diagnostic and prognostic importance. Finally, we highlight current and future therapeutic strategies that aim to target the CD1d-iNKT cell axis in B cells.

Choi YW, Kim HJ, Kim YH, et al.
B-RafV600E inhibits sodium iodide symporter expression via regulation of DNA methyltransferase 1.
Exp Mol Med. 2014; 46:e120 [PubMed] Article available free on PMC after 01/12/2015 Related Publications
B-RafV600E mutant is found in 40-70% of papillary thyroid carcinoma (PTC) and has an important role in the pathogenesis of PTC. The sodium iodide symporter (NIS) is an integral plasma membrane glycoprotein that mediates active iodide transport into the thyroid follicular cells, and B-RafV600E has been known to be associated with the loss of NIS expression. In this study, we found that B-RafV600E inhibited NIS expression by the upregulation of its promoter methylation, and that specific regions of CpG islands of NIS promoter in B-RafV600E harboring PTC were highly methylated compared with surrounding normal tissue. Although DNA methyltransferase 3a and 3b (DNMT3a,3b) were not increased by B-RafV600E, DNMT1 expression was markedly upregulated in PTC and B-RafV600E expressing thyrocytes. Furthermore, DNMT1 expression was upregulated by B-RafV600E induced NF-κB activation. These results led us to conclude that NIS promoter methylation, which was induced by B-RafV600E, is one of the possible mechanisms involved in NIS downregulation in PTC.

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