MST1

Gene Summary

Gene:MST1; macrophage stimulating 1
Aliases: MSP, HGFL, NF15S2, D3F15S2, DNF15S2
Location:3p21
Summary:The protein encoded by this gene contains four kringle domains and a serine protease domain, similar to that found in hepatic growth factor. Despite the presence of the serine protease domain, the encoded protein may not have any proteolytic activity. The receptor for this protein is RON tyrosine kinase, which upon activation stimulates ciliary motility of ciliated epithelial lung cells. This protein is secreted and cleaved to form an alpha chain and a beta chain bridged by disulfide bonds. [provided by RefSeq, Jan 2010]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:hepatocyte growth factor-like protein
HPRD
Source:NCBIAccessed: 25 June, 2015

Ontology:

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 (1990-2015)
Graph generated 25 June 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.

  • alpha-Tocopherol
  • Tumor Markers
  • Molecular Sequence Data
  • Liver Cancer
  • Young Adult
  • Xenograft Models
  • Western Blotting
  • Case-Control Studies
  • Signal Transducing Adaptor Proteins
  • Neoplasm Invasiveness
  • Two-Hybrid System Techniques
  • RT-PCR
  • Phosphorylation
  • Signal Transduction
  • Prostate Cancer
  • DNA Methylation
  • Chromosome 3
  • Messenger RNA
  • BCL2 protein
  • Transfection
  • Neoplastic Cell Transformation
  • RTPCR
  • Cell Proliferation
  • p53 Protein
  • Hepatocyte Growth Factor
  • Apoptosis
  • Promoter Regions
  • Protein-Serine-Threonine Kinases
  • Tumor Suppressor Proteins
  • Down-Regulation
  • Cancer Gene Expression Regulation
  • Nuclear Proteins
  • Proto-Oncogene Proteins
  • Amino Acid Sequence
  • Phosphoproteins
  • Hepatocellular Carcinoma
  • Tissue Array Analysis
  • Mutation
  • Proto-Oncogene Proteins c-myc
  • Immunohistochemistry
Tag cloud generated 25 June, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (2)

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: MST1 (cancer-related)

Xu Z, Chen H, Liu D, Huo J
Fibulin-1 is downregulated through promoter hypermethylation in colorectal cancer: a CONSORT study.
Medicine (Baltimore). 2015; 94(13):e663 [PubMed] Related Publications
Fibulin-1 (FBLN1) is involved in the progression of some types of cancer. However, the role of FBLN1 in colorectal cancer (CRC) has not been examined. The purpose of this study was to understand the molecular mechanisms and clinical significance of FBLN1 inactivation in CRC. The expression of FBLN1 in CRC tissues and adjacent normal tissues was analyzed by immunohistochemical analysis and quantitative real-time polymerase chain reaction (qRT-PCR). Methylation-specific polymerase chain reaction (MSP) and bisulfite sequencing PCR (BSP) were performed to examine the methylation status of the FBLN1 gene promoter. Furthermore, the methylated level of FBLN1 was analyzed with the clinicopathological characteristics. Immunohistochemical analysis and qRT-PCR analysis showed that FBLN1 protein and messenger RNA (mRNA) levels in tumor tissues were both significantly decreased compared with that in adjacent nontumor tissues. The methylation rate of FBLN1 promoter was significantly higher in CRC tissues than that in adjacent nontumor tissues (P < 0.001). In addition, the correlation between FBLN1 hypermethylation, protein expression, and overall survival (OS) was statistically significant. Our results indicated that the FBLN1 gene may be a novel candidate of tumor suppressor gene in CRC, and that promoter hypermethylation of FBLN1 is an important reason for its downregulation and is also a good predictor of OS for CRC.

Fu D, Ren C, Tan H, et al.
Sox17 promoter methylation in plasma DNA is associated with poor survival and can be used as a prognostic factor in breast cancer.
Medicine (Baltimore). 2015; 94(11):e637 [PubMed] Related Publications
Aberrant DNA methylation that leads to the inactivation of tumor suppressor genes is known to play an important role in the development and progression of breast cancer. Methylation status of cancer-related genes is considered to be a promising biomarker for the early diagnosis and prognosis of tumors. This study investigated the methylation status of the Sox17 gene in breast cancer tissue and its corresponding plasma DNA to evaluate the association of methylation levels with clinicopathological parameters and prognosis.The methylation status of the Sox17 gene promoter was evaluated with methylation-specific polymerase chain reaction (MSP) in 155 paired breast cancer tissue and plasma samples and in 60 paired normal breast tissue and plasma samples. Association of Sox17 methylation status with clinicopathological parameters was analyzed by χ tests. Overall and disease-free survival (DFS) curves were calculated using Kaplan-Meier analysis, and the differences between curves were analyzed by log-rank tests.The frequency of Sox17 gene methylation was 72.9% (113/155) in breast cancer tissues and 58.1% (90/155) in plasma DNA. Sox17 gene methylation was not found in normal breast tissues or in their paired plasma DNA. There was a significant correlation of Sox17 methylation between corresponding tumor tissues and paired plasma DNA (r = 0.688, P < 0.001). Aberrant Sox17 methylation in cancer tissues and in plasma DNA was significantly associated with the tumor node metastasis stage (P = 0.035 and P = 0.001, respectively) and with lymph node metastasis (P < 0.001 and P = 0.001, respectively). Kaplan-Meier survival curves showed that aberrant Sox17 promoter methylation in cancer tissues and plasma DNA was associated with poor DFS (P < 0.005) and overall survival (OS) (P < 0.005). Multivariate analysis showed that Sox17 methylation in plasma DNA was an independent prognostic factor in breast cancer for both DFS (P = 0.020; hazard ratio [HR] = 2.142; 95% confidence interval [CI]: 1.128-4.067) and for OS (P = 0.001; HR = 4.737; 95% CI: 2.088-10.747).Sox17 gene promoter methylation may play an important role in breast cancer progression and could be used as a prognostic biomarker to identify patients at risk of developing metastasis or recurrence after mastectomy.

Arantes LM, de Carvalho AC, Melendez ME, et al.
Validation of methylation markers for diagnosis of oral cavity cancer.
Eur J Cancer. 2015; 51(5):632-41 [PubMed] Related Publications
PURPOSE: Activation of proto-oncogenes and inactivation of tumour suppressor genes are the major genetic alterations involved in carcinogenesis. The increase in methylation at the promoter region of a tumour suppressor gene can lead to gene inactivation, selecting cells with proliferative advantage. Thus, promoter hypermethylation is considered a marker in a variety of malignant tumours, including oral cavity.
EXPERIMENTAL DESIGN: The methylation pattern of eight genes was evaluated in 40 oral cavity squamous cell carcinomas (OSCCs) and 40 saliva samples from healthy individuals by Q-MSP. Different combinations of genes were also assessed in order to identify gene panels that could better distinguish between OSCC and saliva samples.
RESULTS: CCNA1, DAPK, DCC and TIMP3 methylation were highly specific for being found in the OSCC samples. Moreover, the combination of these genes improved detection when compared with single markers, reaching values of 92.5% for sensitivity and specificity (when using the panel CCNA1, DCC, TIMP3). Moreover, DAPK, DCC and TIMP3 were hypermethylated in nearly 90% of clinically T1 and T2 cases.
CONCLUSION: The pursuing of this panel of hypermethylated genes is an important tool for the detection of individuals with OSCC. Moreover, the identification of these markers in early stages of OSCC shows the feasibility of using the panel on saliva as possible biomarkers for early diagnosis. The lack of association between the methylation status of these genes and clinical characteristics shows that they are able to distinguish OSCC cases irrespective of social and clinical factors (gender, age, human papillomavirus (HPV) status, clinical stage, vascular embolisation and perineural invasion).

Kanekiyo S, Iizuka N, Tsunedomi R, et al.
Preoperative serum methylation signature as prognostic tool after curative hepatectomy in patients with hepatocellular carcinoma.
Anticancer Res. 2015; 35(2):997-1007 [PubMed] Related Publications
AIM: This study aimed to investigate the relationship between prognosis after curative hepatectomy and serum methylation signature (SMS), defined by methylation levels of six specific genes (cyclin D2, Ras association (RalGDS/AF-6) domain family member 1, serine peptidase inhibitor Kunitz type 2, cystic fibrosis transmembrane conductance regulator, brain abundant membrane attached signal protein 1, and steroid-5-alpha-reductase alpha polypeptide 2).
PATIENTS AND METHODS: Serum samples were collected preoperatively from 125 patients with hepatocellular carcinoma associated with hepatitis C virus infection who underwent curative hepatectomy. We measured the methylation levels of the preceding six genes. We defined the methylation of three genes or more in the serum as SMS-positive in this study. We investigated the prognosis of SMS-positive patients.
RESULTS: SMS-positive patients exhibited significantly shorter disease-free survival (DFS) and overall survival (OS) than SMS-negative patients (p=0.0002 and p<0.0001, respectively). Multivariate analysis showed that SMS positivity was an independent risk factor for shorter DFS (hazard ratio (HR)=2.182; p<0.001) and OS (HR=4.198; p<0.001).
CONCLUSION: SMS is useful as a prognostic predictor in patients with hepatocellular carcinoma after curative hepatectomy.

Zhou C, Qin Y, Xie Z, et al.
NPTX1 is a novel epigenetic regulation gene and associated with prognosis in lung cancer.
Biochem Biophys Res Commun. 2015; 458(2):381-6 [PubMed] Related Publications
BACKGROUND: CpG island hypermethylation of gene promoters is a well-known mechanism of epigenetic regulation of tumor related-genes and is directly linked to lung carcinogenesis. Alterations in the pattern of methylation of the NPTX1 gene have not yet been studied in detail in human lung cancer.
METHODS: Methylation-specific PCR (MSP) and bisulfite sequencing PCR (BSP) were used to analyze promoter methylation status, and real-time quantitative reverse transcription-PCR (qRT-PCR) examined mRNA levels. Subsequently, we compared the methylation profile of NPTX1 in samples of neoplastic and non-neoplastic lung tissue taken from the same patients by using quantitative methylation specific PCR (QMSP).
RESULTS: CpG island hypermethylation in promoter of NPTX1 was confirmed in lung cancer cell lines. A significant increase in NPTX1 methylation was identified in lung cancer specimens compared to adjacent noncancerous tissues and that it was negatively correlated with its mRNA expression. The overall survival time among patients carrying methylated NPTX1 tumors was significantly shorter as compared to those with unmethylated NPTX1 tumors (P = 0.011). Moreover, methylation of NPTX1 gene was found to be an independent prognostic factor for poor overall survival based on multivariate analysis models (p = 0.021), as was age ≥60 years old (p = 0.012) and TNM stage (p < 0.001).
CONCLUSIONS: These results suggest that NPTX1 hypermethylation and consequent mRNA changes might be an important molecular mechanism in lung cancer. Epigenetic alterations in NPTX1 may serve as potential diagnostic and prognostic biomarkers in lung cancer.

Guo Y, Shu L, Zhang C, et al.
Curcumin inhibits anchorage-independent growth of HT29 human colon cancer cells by targeting epigenetic restoration of the tumor suppressor gene DLEC1.
Biochem Pharmacol. 2015; 94(2):69-78 [PubMed] Related Publications
Colorectal cancer remains the most prevalent malignancy in humans. The impact of epigenetic alterations on the development of this complex disease is now being recognized. The dynamic and reversible nature of epigenetic modifications makes them a promising target in colorectal cancer chemoprevention and treatment. Curcumin (CUR), the major component in Curcuma longa, has been shown as a potent chemopreventive phytochemical that modulates various signaling pathways. Deleted in lung and esophageal cancer 1 (DLEC1) is a tumor suppressor gene with reduced transcriptional activity and promoter hypermethylation in various cancers, including colorectal cancer. In the present study, we aimed to investigate the inhibitory role of DLEC1 in anchorage-independent growth of the human colorectal adenocarcinoma HT29 cells and epigenetic regulation by CUR. Specifically, we found that CUR treatment inhibited colony formation of HT29 cells, whereas stable knockdown of DLEC1 using lentiviral short hairpin RNA vector increased cell proliferation and colony formation. Knockdown of DLEC1 in HT29 cells attenuated the ability of CUR to inhibit anchorage-independent growth. Methylation-specific polymerase chain reaction (MSP), bisulfite genomic sequencing, and methylated DNA immunoprecipitation revealed that CUR decreased CpG methylation of the DLEC1 promoter in HT29 cells after 5 days of treatment, corresponding to increased mRNA expression of DLEC1. Furthermore, CUR decreased the protein expression of DNA methyltransferases and subtypes of histone deacetylases (HDAC4, 5, 6, and 8). Taken together, our results suggest that the inhibitory effect of CUR on anchorage-independent growth of HT29 cells could, at least in part, involve the epigenetic demethylation and up-regulation of DLEC1.

Li Z, Zhang G, Li D, et al.
Methylation-associated silencing of miR-495 inhibit the migration and invasion of human gastric cancer cells by directly targeting PRL-3.
Biochem Biophys Res Commun. 2015; 456(1):344-50 [PubMed] Related Publications
Phosphatase of regenerating liver-3 (PRL-3) is believed to be associated with cell motility, invasion, and metastasis. Our previous work found that PRL-3 is highly overexpressed in gastric cancer (GC) tissue with peritoneal metastasis and directly involved in the pathogenesis of GC peritoneal metastasis. Moreover, we further found that the down-regulation of endogenous miR-495 expression plays a causative role in over expression of PRL-3 in GC peritoneal metastasis. However, the molecular regulation mechanisms by which endogenous miR-495 expression is down-regulated and PRL-3 promotes GC peritoneal metastasis remain to be clearly elucidated. Some studies have shown that the promoter methylation is closely related to the miRNA gene expression. Therefore, in present study, based on our previous findings, we will analysis whether DNA methylation is a major cause of the down-expression of endogenous miR-495, which results in PRL-3 overexpression in GC peritoneal metastasis. Methylation specific PCR (MSP) and sodium bisulfite sequencing method (BSP) detected miR-495 gene promoter methylation status. We treated GC cell lines with 5-Aza-2'-deoxycytidine (5-Aza-dC) to make the gene promoter methylation inactivation. By treating with 5-Aza-dC the migration and invasion of GC cells were significantly inhibited. And the miR-495 was overexpressing, corresponds to the mRNA and protein levels of PRL-3 were reduced, the ability of invasion and metastasis was inhibited. This study suggest that miR-495 have tumor suppressor properties and are partially silenced by DNA hypermethylation in GC, will provide new strategies for prevention and treatment of GC peritoneal metastasis.

Serenaite I, Daniunaite K, Jankevicius F, et al.
Heterogeneity of DNA methylation in multifocal prostate cancer.
Virchows Arch. 2015; 466(1):53-9 [PubMed] Related Publications
Most prostate cancer (PCa) cases are multifocal, and separate foci display histological and molecular heterogeneity. DNA hypermethylation is a frequent alteration in PCa, but interfocal heterogeneity of these changes has not been extensively investigated. Ten pairs of foci from multifocal PCa and 15 benign prostatic hyperplasia (BPH) samples were obtained from prostatectomy specimens, resulting altogether in 35 samples. Methylation-specific PCR (MSP) was used to evaluate methylation status of nine tumor suppressor genes (TSGs), and a set of selected TSGs was quantitatively analyzed for methylation intensity by pyrosequencing. Promoter sequences of the RASSF1 and ESR1 genes were methylated in all paired PCa foci, and frequent (≥75 %) DNA methylation was detected in RARB, GSTP1, and ABCB1 genes. MSP revealed different methylation status of at least one gene in separate foci in 8 out of 10 multifocal tumors. The mean methylation level of ESR1, GSTP1, RASSF1, and RARB differed between the paired foci of all PCa cases. The intensity of DNA methylation in these TSGs was significantly higher in PCa cases than in BPH (p < 0.001). Hierarchical cluster analysis revealed a divergent methylation profile of paired PCa foci, while the foci from separate cases with biochemical recurrence showed similar methylation profile and the highest mean levels of DNA methylation. Our findings suggest that PCa tissue is heterogeneous, as between paired foci differences in DNA methylation status were found. Common epigenetic profile of recurrent tumors can be inferred from our data.

Liang L, He H, Lv R, et al.
Preliminary mechanism on the methylation modification of Dkk-1 and Dkk-3 in hepatocellular carcinoma.
Tumour Biol. 2015; 36(2):1245-50 [PubMed] Related Publications
Wnt/β-catenin signaling pathway, having a crucial role in regulating diverse cellular processes, can be a new therapeutic target in cancer. To investigate the role of Dkk-1 (Dickkopf-1) and Dkk-3 in tumors and cirrhoses of the liver tissue in hepatocellular carcinoma (HCC), tissues from 38 patients with HCC resections including 5 patients who underwent hemangioma surgery of adjacent tumor tissues at the same time were obtained. Tissues were divided into three groups (nonfibrosis, cirrhosis, and carcinoma) through hematoxylin-eosin (HE) staining. Methylation-specific polymerase chain reaction (PCR) (MSP) measured the methylation status, and reverse transcription-PCR tested the messenger RNA (mRNA) levels, and immunohistochemical analysis provided levels of protein expression. The methylation detection rate of Dkk-1 and Dkk-3 was the highest (P < 0.05) and the mRNA levels of Dkk-1 and Dkk-3 were the lowest (P < 0.05) in the carcinoma tissues. The mRNA levels of β-catenin were significantly higher in the carcinoma tissue than the other tissues (P < 0.05). The expression of Dkk-1 and Dkk-3 was significantly higher in the carcinoma tissues than the other tissues (P < 0.05); but the β-catenin expression was the highest (P < 0.05). Compared with the control, the mRNA levels of β-catenin in the Dkk-1 and Dkk-3 silencing cells increased 5.34 (P < 0.05) and 3.5 times (P > 0.05). After the interference of 5-aza-2'-deoxycytidine, the mRNA levels of Dkk-1 and Dkk-3 significantly increased 58.9 and 59.3 times (P < 0.0001), and the mRNA levels of β-catenin decreased 6.02 times (P < 0.05). In the process of HCC, the abnormal activity of Wnt/β-catenin signaling may be associated with the methylation of Dkk-1 and Dkk-3.

Dong W, Shen R, Cheng S
Reduction of TIP30 in esophageal squamous cell carcinoma cells involves promoter methylation and microRNA-10b.
Biochem Biophys Res Commun. 2014; 453(4):772-7 [PubMed] Related Publications
TIP30 is a putative tumor suppressor that can promote apoptosis and inhibit angiogenesis. However, the role of TIP30 in esophageal squamous cell carcinoma (ESCC) biology has not been investigated. Immunohistochemistry was used to investigate the expression of TIP30 in 70 ESCC. Hypermethylation of TIP30 was evaluated by the methylation specific PCR (MSP) method in ESCC (tumor and paired adjacent non-tumor tissues). Lost expression of TIP30 was observed in 50 of 70 (71.4%) ESCC. 61.4% (43 of 70) of primary tumors analyzed displayed TIP30 hypermethylation, indicating that this aberrant characteristic is common in ESCC. Moreover, a statistically significant inverse association was found between TIP30 methylation status and expression of the TIP30 protein in tumor tissues (p=0.001). We also found that microRNA-10b (miR-10b) targets a homologous DNA region in the 3'untranslated region of the TIP30 gene and represses its expression at the transcriptional level. Reporter assay with 3'UTR of TIP30 cloned downstream of the luciferase gene showed reduced luciferase activity in the presence of miR-10b, providing strong evidence that miR-10b is a direct regulator of TIP30. These results suggest that TIP30 expression is regulated by promoter methylation and miR-10b in ESCC.

Ren F, Wang DB, Li T, et al.
Identification of differentially methylated genes in the malignant transformation of ovarian endometriosis.
J Ovarian Res. 2014; 7:73 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Key roles for epigenetic mechanisms in tumorigenesis are well accepted, while the relationship between gene methylation and malignant transformation of ovarian endometriosis (EMS) was seldom reported. In this study, we aimed to screen for aberrantly methylated genes associated with the malignant transformation of ovarian EMS and to preliminarily verify the reliability of screened results by detecting the methylation status and protein expression of the candidate gene in a larger scale of formaldehyde-fixed and paraffin-embedded (FFPE) samples.
METHODS: Methylated CpG island amplification coupled with representational difference analysis (MCA-RDA) was performed on 3 couples of endometriosis-associated ovarian carcinoma (EAOC) fresh samples to identify differentially methylated candidate genes related to malignant transformation of ovarian EMS; Methylation-specific PCR (MSP) and immunohistochemistry were performed in 30 EAOC samples to detected the methylation status and protein expression of RASSF2 gene to verify the reliability of MCA-RDA results.
RESULTS: Nine differentially methylated genes were obtained by MCA-RDA as candidate genes for malignant transformation of EMS; Methylation frequency of RASSF2 in the neoplastic tissues of EAOC group was higher than that in the ectopic endometria (p < 0.05). While protein expression of RASSF2 in the neoplastic tissues was lower than that in the ectopic endometria of the EAOC group (p < 0.05) Absence of protein expression of RASSF2 was significantly correlated with the promoter methylation of the gene (p < 0.05).
CONCLUSIONS: RASSF2, RUNX3, GSTZ1, CYP2A, GBGT1, NDUFS1, SPOCK2, ADAM22, and TRIM36 were candidate genes for malignant transformation of ovarian EMS and epigenetic inactivation of RASSF2 by promoter hypermethylation is an early event in malignant transformation of ovarian EMS. The screen results were reliable and worthy of further study.

Kordi-Tamandani DM, Davani SK, Baranzehi T, Hemati S
Analysis of promoter methylation, polymorphism and expression profile of cytotoxic T-lymphocyte-associated antigen-4 in patients with gastric cancer.
J Gastrointestin Liver Dis. 2014; 23(3):249-53 [PubMed] Related Publications
BACKGROUND AND AIM: Cytotoxic T lymphocyte-associated antigen-4 (CTLA4) is a crucial immune-checkpoint receptor regulating T-cell activation. The current study was carried out to evaluate the function of CTLA4 gene in patients with gastric cancer.
METHODS: The methylation of CTLA4 gene promoter was evaluated by methylation-specific polymerase chain reaction (MSP) technique using 85 paraffin-embedded gastric cancer tissue samples and normal tissue on the tumor margins as control tissue samples. Expression analysis was performed on paraffin-embedded tissue samples (25 each of cancerous and normal tissues) using Real-time PCR.
RESULTS: Statistically significant differences were observed between the tumor and margin-cell areas with respect to promoter methylation status (OR = 4.829, 95% CI: 2.46-9.48, p < 0.001) and CTLA4 expression profile (mean +/- SD = 7.56 +/- 17.35, p = 0.04).
CONCLUSION: To the best of our knowledge, the current study is the first one highlighting the association between promoter hypermethylation of CTLA4 gene, decreased CTLA4 expression, and increased risk of gastric cancer.

Deng J, Liang H, Ying G, et al.
Clinical significance of the methylated cytosine-phosphate-guanine sites of protocadherin-10 promoter for evaluating the prognosis of gastric cancer.
J Am Coll Surg. 2014; 219(5):904-13 [PubMed] Related Publications
BACKGROUND: Protocadherin-10 (PCDH10) has been identified as a tumor suppressor gene in multiple carcinomas. In this study, we intended to elucidate the clinical applicability of the methylation of CpG sites of PCDH10 promoter for prognostic prediction in gastric cancer (GC).
STUDY DESIGN: Qualitative and quantitative detections of PCDH10 promoter methylation were performed with methylation-specific polymerase chain reaction (MSP) and bisulphite genomic sequencing, respectively. The methylated statuses of 27 cytosine-phosphate-guanine (CpG) sites in PCDH10 promoter were detected in a series of 458 GC tissues to supply precise information of prognostic prediction. Associations between molecular, clinicopathologic, and survival data were analyzed.
RESULTS: Protocadherin-10 promoter methylation was found in 91.92% in all patients. Gastric cancer patients with 5 or more methylated CpG sites of PCDH10 promoter was significantly associated with poorer survival (p = 0.038). Meanwhile, methylation of combined CpG (-115, -108, -13, and +3) sites was also identified to provide elaborate survival discrimination for GC patients (p = 0.044). On multivariate survival analysis, methylation of combined CpG (-115, -108, -13, and +3) sites (hazard ratio [HR] = 1.255; p = 0.049) was identified to be an independent prognostic indicator of GC, as were N stage and T stage. Additionally, the methylation of combined CpG (-115, -108, -13, and +3) sites had smaller Akaike information criterion (AIC) and Bayesian information criterion (BIC) values than the other 2 independent predictors of the survival. Ultimately, we demonstrated that the methylation of combined CpG (-115, -108, -13, and +3) sites was negatively associated with PCDH10 expression in GC tissues.
CONCLUSIONS: The methylated CpG sites of PCDH10 promoter had significant applicability for clinical evaluation of the prognosis of GC.

Pinto JT, Krasnikov BF, Alcutt S, et al.
Kynurenine aminotransferase III and glutamine transaminase L are identical enzymes that have cysteine S-conjugate β-lyase activity and can transaminate L-selenomethionine.
J Biol Chem. 2014; 289(45):30950-61 [PubMed] Article available free on PMC after 07/11/2015 Related Publications
Three of the four kynurenine aminotransferases (KAT I, II, and IV) that synthesize kynurenic acid, a neuromodulator, are identical to glutamine transaminase K (GTK), α-aminoadipate aminotransferase, and mitochondrial aspartate aminotransferase, respectively. GTK/KAT I and aspartate aminotransferase/KAT IV possess cysteine S-conjugate β-lyase activity. The gene for the former enzyme, GTK/KAT I, is listed in mammalian genome data banks as CCBL1 (cysteine conjugate beta-lyase 1). Also listed, despite the fact that no β-lyase activity has been assigned to the encoded protein in the genome data bank, is a CCBL2 (synonym KAT III). We show that human KAT III/CCBL2 possesses cysteine S-conjugate β-lyase activity, as does mouse KAT II. Thus, depending on the nature of the substrate, all four KATs possess cysteine S-conjugate β-lyase activity. These present studies show that KAT III and glutamine transaminase L are identical enzymes. This report also shows that KAT I, II, and III differ in their ability to transaminate methyl-L-selenocysteine (MSC) and L-selenomethionine (SM) to β-methylselenopyruvate (MSP) and α-ketomethylselenobutyrate, respectively. Previous studies have identified these seleno-α-keto acids as potent histone deacetylase inhibitors. Methylselenol (CH3SeH), also purported to have chemopreventive properties, is the γ-elimination product of SM and the β-elimination product of MSC catalyzed by cystathionine γ-lyase (γ-cystathionase). KAT I, II, and III, in part, can catalyze β-elimination reactions with MSC generating CH3SeH. Thus, the anticancer efficacy of MSC and SM will depend, in part, on the endogenous expression of various KAT enzymes and cystathionine γ-lyase present in target tissue coupled with the ability of cells to synthesize in situ either CH3SeH and/or seleno-keto acid metabolites.

Hagrass HA, Pasha HF, Ali AM
Estrogen receptor alpha (ERα) promoter methylation status in tumor and serum DNA in Egyptian breast cancer patients.
Gene. 2014; 552(1):81-6 [PubMed] Related Publications
BACKGROUND: Status of DNA methylation is one of the most common molecular alterations in human neoplasia. Because it is possible to detect these epigenetic alterations in the bloodstream of patients, we investigated the aberrant DNA methylation status of estrogen receptor alpha (ERα) in patient pretherapeutic sera and tissue.
MATERIALS AND METHODS: In this case control study the patient series consisted of 120 sporadic primary breast cancer cases and 100 patients with benign breast lesion. ER3, ER4, and ER5 primers were used for methylation-specific polymerase chain reaction (MSP) to analyze the CpG methylation of promoter region of ERα gene. Correlation between ER3, ER4, and ER5 methylation and clinicopathological characteristics of the patients was investigated.
RESULT: The methylation status of ER3, ER4 and ER5 was 65%, 26.7% and 61.7% in tissue respectively and 57.5%, 21.7% and 55.8% in serum respectively. The concordance between tumor and serum DNA methylation was 80%, 72% and 92% for ER3, ER4 and ER5 respectively.
CONCLUSIONS: This study demonstrated the potential utility of serum DNA methylation of ERα gene promoter as a non-invasive diagnostic and/or prognostic marker in patients with breast cancer.

Lin YL, Xie PG, Ma JG
Aberrant methylation of CDH13 is a potential biomarker for predicting the recurrence and progression of non muscle invasive bladder cancer.
Med Sci Monit. 2014; 20:1572-7 [PubMed] Article available free on PMC after 07/11/2015 Related Publications
BACKGROUND: CDH13 is a novel tumor suppressor gene often inactivated by aberrant promoter methylation in human cancers. Previous studies have shown that CDH13 methylation correlated with advanced disease and poor prognosis in non-muscle invasive bladder cancer (NMIBC). The aim of the current study was to investigate the correlations between CDH13 methylation and disease recurrence as well as progression of NMIBC.
MATERIAL AND METHODS: The methylation status of CDH13 in 178 NMIBC samples and 38 normal bladder epithelial tissues was examined by methylation-specific PCR (MSP), and then correlated with clinicopathological features.
RESULTS: We found that CDH13 methylation occurs frequently in NMIBC, and significantly correlates with high grade, advanced stage, larger tumor size, and tumor recurrence and progression. Moreover, patients with methylated CDH13 exhibited significantly shorter recurrence-free survival (P<0.0001) and progression-free survival (P=0.0060) than patients with unmethylated CDH13. In addition, a multivariate Cox proportional hazard model analysis suggests that CDH13 methylation is an independent predictor for the recurrence (P=0.0043) and progression (P=0.0016) of NMIBC after initial transurethral resection.
CONCLUSIONS: Our findings demonstrate that CDH13 methylation is a frequent event in NMIBC, and is associated with unfavorable tumor features. It should be used as an independent predictor for the recurrence and progression of NMIBC, and may be useful for the design of individualized therapeutic modalities.

Kanemoto M, Shirahata M, Nakauma A, et al.
Prognostic prediction of glioblastoma by quantitative assessment of the methylation status of the entire MGMT promoter region.
BMC Cancer. 2014; 14:641 [PubMed] Article available free on PMC after 07/11/2015 Related Publications
BACKGROUND: O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation is reported to be a prognostic and predictive factor of alkylating chemotherapy for glioblastoma patients. Methylation specific PCR (MSP) has been most commonly used when the methylation status of MGMT is assessed. However, technical obstacles have hampered the implementation of MSP-based diagnostic tests. We quantitatively analyzed the methylation status of the entire MGMT promoter region and applied this information for prognostic prediction using sequencing technology.
METHODS: Between 1998 and 2012, the genomic DNA of 85 tumor samples from newly diagnosed glioblastoma patients was subjected to bisulfite treatment and subdivided into a training set, consisting of fifty-three samples, and a test set, consisting of thirty-two samples. The training set was analyzed by deep Sanger sequencing with a sequencing coverage of up to 96 clones per sample. This analysis quantitatively revealed the degree of methylation of each cytidine phosphate guanosine (CpG) site. Based on these data, we constructed a prognostic prediction system for glioblastoma patients using a supervised learning method. We then validated this prediction system by deep sequencing with a next-generation sequencer using a test set of 32 samples.
RESULTS: The methylation status of the MGMT promoter was correlated with progression-free survival (PFS) in our patient population in the training set. The degree of correlation differed among the CpG sites. Using the data from the top twenty CpG sites, we constructed a prediction system for overall survival (OS) and PFS. The system successfully classified patients into good and poor prognosis groups in both the training set (OS, p = 0.0381; PFS, p = 0.00122) and the test set (OS, p = 0.0476; PFS, p = 0.0376). Conventional MSP could not predict the prognosis in either of our sets. (training set: OS; p = 0.993 PFS; p = 0.113, test set: OS; p = 0.326 PFS; p = 0.342).
CONCLUSIONS: The prognostic ability of our prediction system using sequencing data was better than that of methylation-specific PCR (MSP). Advances in sequencing technologies will make this approach a plausible option for diagnoses based on MGMT promotor methylation.

de Groot JS, Pan X, Meeldijk J, et al.
Validation of DNA promoter hypermethylation biomarkers in breast cancer--a short report.
Cell Oncol (Dordr). 2014; 37(4):297-303 [PubMed] Related Publications
PURPOSE: DNA promoter hypermethylation of tumor suppressor genes is known to occur early in cancer development, including breast cancer. To improve early breast cancer detection, we aimed to investigate whether the identification of DNA promoter hypermethylation might be of added value.
METHODS: The methylation status of a panel of 19 candidate genes (AKR1B1, ALX1, ARHGEF7, FZD10, GHSR, GPX7, GREM1, GSTP1, HOXD1, KL, LHX2, MAL, MGMT, NDRG2, RASGRF2, SFRP1, SFRP2, TM6SF1 and TMEFF2) was determined in formalin-fixed paraffin-embedded normal breast and breast cancer tissue samples using gel-based methylation-specific PCR (MSP).
RESULTS: The promoters of the AKR1B1, ALX1, GHSR, GREM1, RASGRF2, SFRP2, TM6SF1 and TMEFF2 genes were found to be significantly differentially methylated in normal versus malignant breast tissues. Based on sensitivity, specificity and logistic regression analyses the best performing genes for detecting breast cancer were identified. Through multivariate analyses, we found that AKR1B1 and TM6SF1 could detect breast cancer with an area under the curve (AUC) of 0.986 in a receiver operating characteristic (ROC) assessment.
CONCLUSIONS: Based on our data, we conclude that AKR1B1 and TM6SF1 may serve as candidate methylation biomarkers for early breast cancer detection. Further studies are underway to evaluate the methylation status of these genes in body fluids, including nipple aspirates and blood.

Wang L, Xie PG, Lin YL, et al.
Aberrant methylation of PCDH10 predicts worse biochemical recurrence-free survival in patients with prostate cancer after radical prostatectomy.
Med Sci Monit. 2014; 20:1363-8 [PubMed] Article available free on PMC after 07/11/2015 Related Publications
BACKGROUND: Prostate cancer is a common malignancy in men, and inevitably some patients experience biochemical recurrence after radical prostatectomy. To date, there are no reliable predictors for prostate cancer recurrence, and novel predictors are urgently needed. PCDH10 (protocadherin-10) is a novel tumor suppressor gene, which is down-regulated by promoter methylation in prostate cancer. The aim of this study was to evaluate the feasibility of using PCDH10 methylation to predict the biochemical recurrence (BCR) of prostate cancer after radical prostatectomy.
MATERIAL/METHODS: Fresh tissue samples were obtained from 151 patients with primary prostate cancer, and from 34 patients with benign prostatic hyperplasia (BPH) as control. The methylation status of PCDH10 in prostate cancer tissues and controls were examined using methylation-specific PCR (MSP), and then associated with clinicopathological features and BCR-free survival of patients with prostate cancer.
RESULTS: We found that PCDH10 methylation was detected in 79 (52.3%) patients with prostate cancer, but no methylation was found in controls (P<0.0001). Moreover, PCDH10 methylation was significantly associated with higher preoperative prostate-specific antigen (PSA) level (P <0.0001), higher Gleason Score (P<0.0001), advanced clinical stage (P=0.0002), lymph node metastasis (P=0.0389), angiolymphatic invasion (P=0.0303), and biochemical recurrence (P=0.0068). Moreover, PCDH10 methylation was associated with poor BCR-free survival (P<0.0001), and may be used as an independent predictor of BCR-free survival (P=0.0046).
CONCLUSIONS: Our results indicate that PCDH10 methylation in prostate cancer tissue is an independent prognostic biomarker of worse BCR-free survival of patients with prostate cancer after radical prostatectomy.

Wang F, Yang Y, Fu Z, et al.
Differential DNA methylation status between breast carcinomatous and normal tissues.
Biomed Pharmacother. 2014; 68(6):699-707 [PubMed] Related Publications
Breast cancer has been considered to be a multifactorial disease with a wide array of well-characterized gene mutations and chromosomal abnormalities. However, it is becoming evident that the onset or development of breast cancer also depends on epigenetic factors, although the mechanisms have not been fully elucidated. We performed a genome-wide analysis of DNA methylation of breast carcinomatous tissues and paired normal tissues to examine the differences in methylation between them. Methylation-specific polymerase chain reaction (MSP) was used to validate the hypermethylated genes screened out by DNA methylation microarray. We found that hypomethylation and hypermethylation occurred in 2753 and 1795 genes, respectively, in breast carcinomatous tissues. Meanwhile, gene ontology analysis and ingenuity pathway analysis revealed the function and pathway of several genes whose methylation status was altered in breast carcinomatous tissues. In addition, we investigated the promoter methylation status of four genes in breast carcinomatous tissue and paired normal tissues (n=30) by MSP. Promoter hypermethylation of CRABP1, HOXB13, IFNGR2, and PIK3C3 was found in 37% (11/30), 23% (7/30), 17% (5/30), and 2% (2/30) of the carcinomas, respectively. Mutation of these four important genes was critical to many types of cancer. Our results suggest that DNA methylation mechanisms may be involved in regulating the occurrence and development of breast cancer.

Millares L, Rosell A, Setó L, et al.
Variability in the measurement of the methylation status of lung cancer-related genes in bronchial secretions.
Oncol Rep. 2014; 32(4):1435-40 [PubMed] Related Publications
Assessment of the methylation status of genes related to the development of lung cancer (LC) in bronchial secretions has been proposed as a biomarker for early detection. Several techniques are available to detect gene methylation, and the method chosen may have an effect on the results. A cross-sectional study was conducted in which the methylation status of DAPK, CDKN2A (p16) and RASSF1A genes in sputum and bronchial washing (BW) from subjects at risk for LC was analyzed. The methylation results of both samples were compared, considering BW as the reference. Results obtained by methylation-sensitive PCR (MSP) were validated by methylation-sensitive high-resolution melting (MS-HRM). The methylation results obtained in sputum and BW samples did not show statistically significant differences for any of the three genes analyzed in 65 subjects (McNemar test>0.05). Concordant results between sputum and BW were found in 40 patients for DAPK (61%), in 52 patients for p16 (80%) and in 63 patients for RASSF1 (97%). More methylated samples were found in BW, however, and sputum sensitivities and specificities for the identification of methylation status were 44 and 72% for DAPK gene, 21 and 94% for p16 and 100 and 98% for RASSF1A, respectively. When MSP results were validated by MS-HRM, DAPK and p16 gene samples methylated by MSP appeared to be unmethylated by MS-HRM. One sample showing methylation of RASSF1A gene also showed methylation when tested following MS-HRM procedure. Sputum and BW samples may be considered equally valid for the identification of methylated genes in bronchial secretions. The low sensitivity of sputum for the assessment of the methylation status of DAPK and p16 genes, however, suggests that the analysis of two or more sputum samples, or of a BW obtained semi-invasively, would be needed to attain higher reliability, together with the use of confirmatory techniques for positive results.

Li W, Deng J, Tang JX
Combined effects methylation of FHIT, RASSF1A and RARβ genes on non-small cell lung cancer in the Chinese population.
Asian Pac J Cancer Prev. 2014; 15(13):5233-7 [PubMed] Related Publications
Epigenetic modifications of tumour suppressor genes are involved in all kinds of human cancer. Aberrant promoter methylation is also considered to play an essential role in development of lung cancer, but the pathogenesis remains unclear.We collected the data of 112 subjects, including 56 diagnosed patients with lung cancer and 56 controls without cancer. Methylation of the FHIT, RASSF1A and RAR-β genes in DNA from all samples and the corresponding gene methylation status were assessed using the methylation-specific polymerase chain reaction (PCR, MSP). The results showed that the total frequency of separate gene methylation was significantly higher in lung cancer compared with controls (33.9-85.7 vs 0 %) (p<0.01).Similar outcomes were obtained from the aberrant methylation of combinations of any two or three genes (p<0.01). There was a tendency that the frequency of combinations of any two or three genes was higher in stage I+II than that in stage III+IV with lung cancer. However, no significant difference was found across various clinical stages and clinic pathological gradings of lung cancer (p>0.05).These observations suggest that there is a significant association of promoter methylation of individual genes with lung cancer risk, and that aberrant methylation of combination of any two or three genes may be associated with clinical stage in lung cancer patients and involved in the initiation of lung cancer tumorigenesis. Methylation of FHIT, RASSF1A and RARβ genes may be related to progression of lung oncogenesis.

Oliver JA, Ortiz R, Melguizo C, et al.
Prognostic impact of MGMT promoter methylation and MGMT and CD133 expression in colorectal adenocarcinoma.
BMC Cancer. 2014; 14:511 [PubMed] Article available free on PMC after 07/11/2015 Related Publications
BACKGROUND: New biomarkers are needed for the prognosis of advanced colorectal cancer, which remains incurable by conventional treatments. O6-methylguanine DNA methyltransferase (MGMT) methylation and protein expression have been related to colorectal cancer treatment failure and tumor progression. Moreover, the presence in these tumors of cancer stem cells, which are characterized by CD133 expression, has been associated with chemoresistance, radioresistance, metastasis, and local recurrence. The objective of this study was to determine the prognostic value of CD133 and MGMT and their possible interaction in colorectal cancer patients.
METHODS: MGMT and CD133 expression was analyzed by immunohistochemistry in 123 paraffin-embedded colorectal adenocarcinoma samples, obtaining the percentage staining and intensity. MGMT promoter methylation status was obtained by using bisulfite modification and methylation-specific PCR (MSP). These values were correlated with clinical data, including overall survival (OS), disease-free survival (DFS), tumor stage, and differentiation grade.
RESULTS: Low MGMT expression intensity was significantly correlated with shorter OS and was a prognostic factor independently of treatment and histopathological variables. High percentage of CD133 expression was significantly correlated with shorter DFS but was not an independent factor. Patients with low-intensity MGMT expression and ≥50% CD133 expression had the poorest DFS and OS outcomes.
CONCLUSIONS: Our results support the hypothesis that MGMT expression may be an OS biomarker as useful as tumor stage or differentiation grade and that CD133 expression may be a predictive biomarker of DFS. Thus, MGMT and CD133 may both be useful for determining the prognosis of colorectal cancer patients and to identify those requiring more aggressive adjuvant therapies. Future studies will be necessary to determine its clinical utility.

Zhai X, Li SJ
Methylation of RASSF1A and CDH13 genes in individualized chemotherapy for patients with non-small cell lung cancer.
Asian Pac J Cancer Prev. 2014; 15(12):4925-8 [PubMed] Related Publications
BACKGROUND: This study aimed to evaluate the methylation of RASSF1A and CDH13 gene promoter regions as a marker for monitoring chemotherapeutic efficacy with personalized medicine for patients with NSCLC, in the hope of providing a new direction for NSCLC individualized chemotherapy.
MATERIALS AND METHODS: 42 NSCLC patients and 40 healthy controls were included. Patient blood samples were collected in the whole process of chemotherapy. Methylation of RASSF1A and CDH13 gene promoter regions was detected by the methylation specific polymerase chain reaction (MSP).
RESULTS: The rate of RASSF1A and CDH13 gene methylation in 42 cases of NSCLC patients was significantly higher than in 40 healthy controls (52.4% to 0.0%, 54.8% to 0.0%, p<0.05). After the chemotherapy, the hyper-methylation of RASSF1A and CDH13 genes in PR group and SD group decreased significantly (p<0.05), and was significantly different from that in PD group (p<0.05), but not as compared with healthy controls (P>0.05). With chemotherapy, RASSF1A and CDH13 promoter region methylation rate in 42 cases of patients showed a declining trend.
CONCLUSIONS: The methylation level of RASSF1A and CDH13 gene promoter region can reflect drug sensitivity of tumors to individualized treatment.

Liang K, Zhou G, Zhang Q, et al.
Expression of hippo pathway in colorectal cancer.
Saudi J Gastroenterol. 2014 May-Jun; 20(3):188-94 [PubMed] Article available free on PMC after 07/11/2015 Related Publications
BACKGROUND/AIMS: Hippo pathway plays a crucial role in cell proliferation, apoptosis, and tumorigenesis. This study aimed to investigate the expression of Hippo pathway components in the progression and metastasis of colorectal cancer (CRC).
MATERIALS AND METHODS: Quantitative real-time polymerase chain reaction (qRT-PCR) was used to examine the mRNA expression levels of MST1, LATS2, YAP, TAZ, TEAD1, CDX2, and OCT4, and western blot (WB) was used to examine the protein expression levels of MST1, YAP, TEAD1, and CDX2 in 30 specimens of human colorectal adenomas, 50 pairs of human CRC tissues, and adjacent nontumorous tissues from CRC patients. Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) was used as the housekeeping gene in qRT-PCR.
RESULTS: The mRNA expression levels of MST1 and LATS2 showed an increasing tendency from CRC to adjacent nontumorous tissues (P < 0.001). Conversely, the mRNA expression levels of YAP, TAZ, TEAD, and OCT4 showed a decreasing tendency from CRC to adjacent nontumorous tissues (P < 0.001). MST1 protein was downregulated and YAP and TEAD1 proteins were upregulated in CRC (all P < 0.001). The mRNA and protein expression levels of CDX2 in CRC were significantly lower than those in colorectal adenomas and adjacent nontumorous tissues (P < 0.001), but there was no significant difference between the latter two groups (qRT-PCR, P = 0.113; WB, P = 0.151). Furthermore, statistical analysis showed that the expression levels of Hippo signal pathway components were associated with tumor differentiation, lymph node metastasis, and TNM stage.
CONCLUSION: Hippo pathway is suppressed in the progression from colorectal adenomas to CRC and is associated with CRC progression and metastasis. This study suggests the components of Hippo pathway might be prognostic indicators for CRC patients.

Tan SX, Hu RC, Liu JJ, et al.
Methylation of PRDM2, PRDM5 and PRDM16 genes in lung cancer cells.
Int J Clin Exp Pathol. 2014; 7(5):2305-11 [PubMed] Article available free on PMC after 07/11/2015 Related Publications
AIMS: To investigate the changes of expression and methylation status of PRDM2, PRDM5, PRDM16 in lung cancer cells after treatment with demethylation agent.
METHODS: A549 (lung adenocarcinoma cell line), HTB-182 (lung squamous cell carcinoma cell line) and HBE (normal bronchial cell line) were treated with 5-aza-2dC. The methylation state of PRDM2, PRDM5, PRDM16 was detected by MSP. The expression of PRDM2, PRDM5, PRDM16 was detected by RT-PCR and Western blot analysis. Cell growth was detected by MTT assay.
RESULTS: 5-aza-2-dC reduced the methylation of PRDM2, PRDM5, PRDM16 gene in A549 and HTB-182 cells but not in HBE cells. Consistently, 5-aza-2dC increased mRNA and protein expression of PRDM2, PRDM5, PRDM16 in A549 and HTB-182 cells but not in HBE cells. Furthermore, 5-aza-2dC inhibited the growth of A549 and HTB-182 cells but not HBE cells.
CONCLUSIONS: PRDM2, PRDM5, PRDM16 promoters are methylated and their expression is suppressed in lung cancer cells. Demethylation drug 5-aza-2dC could upregulate the expression of PRDM2, PRDM5, PRDM16 and suppress lung cancer cell growth. 5-aza-2dC has potential to be used for lung cancer therapy by epigenetic mechanism.

Tao YF, Xu LX, Lu J, et al.
Metallothionein III (MT3) is a putative tumor suppressor gene that is frequently inactivated in pediatric acute myeloid leukemia by promoter hypermethylation.
J Transl Med. 2014; 12:182 [PubMed] Article available free on PMC after 07/11/2015 Related Publications
BACKGROUND: Acute myeloid leukemia (AML) is the second most common form of leukemia in children. Aberrant DNA methylation patterns are a characteristic feature in various tumors, including AML. Metallothionein III (MT3) is a tumor suppresser reported to show promoter hypermethylated in various cancers. However, the expression and molecular function of MT3 in pediatric AML is unclear.
METHODS: Eleven human leukemia cell lines and 41 pediatric AML samples and 20 NBM/ITP (Norma bone marrow/Idiopathic thrombocytopenic purpura) control samples were analyzed. Transcription levels of MT3 were evaluated by semi-quantitative and real-time PCR. MT3 methylation status was determined by methylation specific PCR (MSP) and bisulfite genomic sequencing (BSG). The molecular mechanism of MT3 was investigated by apoptosis assays and PCR array analysis.
RESULTS: The MT3 promoter was hypermethylated in leukemia cell lines. More CpG's methylated of MT3 was observed 39.0% pediatric AML samples compared to 10.0% NBM controls. Transcription of MT3 was also significantly decreased in AML samples compared to NBM/ITP controls (P < 0.001); patients with methylated MT3 exhibited lower levels of MT3 expression compared to those with unmethylated MT3 (P = 0.049). After transfection with MT3 lentivirus, proliferation was significantly inhibited in AML cells in a dose-dependent manner (P < 0.05). Annexin V assay showed that apoptosis was significantly upregulated MT3-overexpressing AML cells compared to controls. Real-time PCR array analysis revealed 34 dysregulated genes that may be implicated in MT3 overexpression and apoptosis in AML, including FOXO1.
CONCLUSION: MT3 may be a putative tumor suppressor gene in pediatric AML. Epigenetic inactivation of MT3 via promoter hypermethylation was observed in both AML cell lines and pediatric AML samples. Overexpression of MT3 may inhibit proliferation and induce apoptosis in AML cells. FOXO1 was dysregulated in MT3-overexpressing cells, offering an insight into the mechanism of MT3-induced apoptosis. However, further research is required to determine the underlying molecular details.

Haroun RA, Zakhary NI, Mohamed MR, et al.
Assessment of the prognostic value of methylation status and expression levels of FHIT, GSTP1 and p16 in non-small cell lung cancer in Egyptian patients.
Asian Pac J Cancer Prev. 2014; 15(10):4281-7 [PubMed] Related Publications
BACKGROUND: Methylation of tumor suppressor genes has been investigated in all kinds of cancer. Tumor specific epigenetic alterations can be used as a molecular markers of malignancy, which can lead to better diagnosis, prognosis and therapy. Therefore, the aim of this study was to evaluate the association between gene hypermethylation and expression of fragile histidine triad (FHIT), glutathione S-transferase P1 (GSTP1) and p16 genes and various clinicopathologic characteristics in primary non-small cell lung carcinomas (NSCLC).
MATERIALS AND METHODS: The study included 28 primary non-small cell lung carcinomas, where an additional 28 tissue samples taken from apparently normal safety margin surrounding the tumors served as controls. Methylation-specific polymerase chain reaction (MSP) was performed to analyze the methylation status of FHIT, GSTP1 and p16 while their mRNA expression levels were measured using a real-time PCR assay with SYBR Green I.
RESULTS: The methylation frequencies of the genes tested in NSCLC specimens were 53.6% for FHIT, 25% for GSTP1, and 0% for p16, and the risk of FHIT hypermethylation increased among patients with NSCLC by 2.88, while the risk of GSTP1 hypermethylation increased by 2.33. Hypermethylation of FHIT gene showed a highly significant correlation with pathologic stage (p<0.01) and a significant correlation with smoking habit and FHIT mRNA expression level (p<0.05). In contrast, no correlation was observed between the methylation of GSTP1 or p16 and smoking habit or any other parameter investigated (p>0.05).
CONCLUSIONS: RESULTS of the present study suggest that methylation of FHIT is a useful biomarker of biologically aggressive disease in patients with NSCLC. FHIT methylation may play a role in lung cancer later metastatic stages while GSTP1 methylation may rather play a role in the early pathogenesis.

Bhagat R, Kumar SS, Vaderhobli S, et al.
Epigenetic alteration of p16 and retinoic acid receptor beta genes in the development of epithelial ovarian carcinoma.
Tumour Biol. 2014; 35(9):9069-78 [PubMed] Related Publications
Silencing of tumor suppressor and tumor-related genes by promoter hypermethylation is one of the major events in ovarian carcinogenesis. In this study, we analyzed aberrant promoter methylation of p16 and RAR-β genes in 134 epithelial ovarian carcinomas (EOCs), 23 low malignant potential (LMP) tumors, 26 benign cystadenomas, and 15 normal ovarian tissues. Methylation was investigated by methylation-specific PCR (MSP), and the results were confirmed by bisulfite DNA sequencing. Relative gene expression of p16 and RAR-β was done using quantitative reverse transcriptase PCR (qRT-PCR) on 51 EOC cases, 9 LMP tumors, and 7 benign cystadenomas with 5 normal ovarian tissues. Aberrant methylation for p16 and RAR-β was present in 43 % (58/134) and 31 % (41/134) in carcinoma cases, 22 % (05/23) and 52 % (12/23) in LMP tumors, and 42 % (11/26) and 69 % (18/26) in benign cystadenomas. No methylation was observed in any of the normal ovarian tissues. The mRNA expression level of p16 and RAR-β was significantly downregulated in EOC and LMP tumors than the corresponding normal tissues whereas the expression level was normal in benign cystadenomas for p16 and slightly reduced for RAR-β. A significant correlation of p16 promoter methylation was observed with reduced gene expression in EOC. For RAR-β, no significant correlation was observed between promoter methylation and gene expression. Our results suggest that epigenetic alterations of p16 and RAR-β have an important role in ovarian carcinogenesis and that mechanism along with methylation plays a significant role in downregulation of RAR-β gene in ovarian cancer.

Sabir M, Baig RM, Ali K, et al.
Retinoblastoma (RB1) pocket domain mutations and promoter hyper-methylation in head and neck cancer.
Cell Oncol (Dordr). 2014; 37(3):203-13 [PubMed] Related Publications
BACKGROUND: The RB1 gene plays a pivotal role in cell cycle regulation. In this case-control study we searched for alterations in the RB1 pocket domain and its promoter region in head and neck cancer (HNC) patients in the Pakistani population.
METHODS: For germline mutation analyses, 380 blood samples from HNC patients and 350 blood samples from control individuals were included. Polymerase chain reaction (PCR) and single strand conformational polymorphism (SSCP) assays, followed by sequence analyses, were used for the RB1 pocket domain mutation screens. For the RB1 promoter methylation screens, 72 HNC tumor samples along with adjacent uninvolved tissues were tested using a methylation-specific polymerase chain reaction (MSP) assay.
RESULTS: RB1 (pocket domain and spacer region) sequence analysis revealed one frameshift and seven non-synonymous missense mutations. The frequency of missense mutations in exon 14, i.e., g76474C > T, g76475G > C and g76476A > G, resulting in Arg455Ser, was found to be highest (0.10). Missense mutations g76467G > C (exon14), g76468T > C (exon14), g77041A > T and g77043A > T (exon 16), when analyzed via Alamut biosoftware version 2.0, were found to be present in highly conserved amino acids with Align GVGD scores C15 (GV: 0.00-GD: 21.82), C65 (GV: 0.00-GD: 83.33) and C65 (GV: 0.00-GD: 98.69), respectively. These missense mutations were found to be deleterious by SIFT score: 0.00 (median 3.64). RB1 promoter methylation analysis revealed that 16% of its cytosines (3% in CpG) were methylated in the HNC tumor samples.
CONCLUSION: Our findings indicate that both genetic and epigenetic RB1 changes may contribute to the pathogenesis of HNC in the Pakistani population.

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