Alice Y Chuang

University of Chicago, Chicago, Illinois, United States

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Publications (32)176.65 Total impact

  • Cancer Research 10/2014; 74(19 Supplement):1384-1384. DOI:10.1158/1538-7445.AM2014-1384 · 9.28 Impact Factor
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    ABSTRACT: Multiple genetic studies have implicated the autophagy-related gene, ATG16L1, in the pathogenesis of Crohn disease (CD). While CD-related research on ATG16L1 has focused on the functional significance of ATG16L1 genetic variations, the mechanisms underlying the regulation of ATG16L1 expression are unclear. Our laboratory has described that microRNAs (miRNAs), key regulators of gene expression, are dysregulated in CD. Here, we report miRNA-mediated regulation of ATG16L1 in colonic epithelial cells as well as Jurkat T cells. Dual luciferase reporter assays following the transfection of vectors containing the ATG16L1 3'-untranslated region (3'UTR) or truncated 3'UTR fragments suggest that the first half of ATG16L1 3'UTR in the 5' end is more functional for miRNA targeting. Of 5 tested miRNAs with putative binding sites within the region, MIR142-3p, upon transient overexpression in the cells, resulted in decreased ATG16L1 mRNA and protein levels. Further observation demonstrated that the luciferase reporter vector with a mutant MIR142-3p binding sequence in the 3'UTR was unresponsive to the inhibitory effect of MIR142-3p, suggesting ATG16L1 is a gene target of MIR142-3p. Moreover, the regulation of ATG16L1 expression by a MIR142-3p mimic blunted starvation- and L18-MDP-induced autophagic activity in HCT116 cells. Additionally, we found that a MIR142-3p inhibitor enhanced starvation-induced autophagy in Jurkat T cells. Our study reveals MIR142-3p as a new autophagy-regulating small molecule by targeting ATG16L1, implying a role of this miRNA in intestinal inflammation and CD.
    Autophagy 01/2014; 10(3). DOI:10.4161/auto.27553 · 11.42 Impact Factor
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    ABSTRACT: Although the cure rate for cutaneous squamous cell carcinoma is high, the diverse spectrum of squamous cell carcinoma has made it difficult for early diagnosis, particularly the aggressive tumors that are highly associated with mortality. Therefore, molecular markers are needed as an adjunct to current staging methods for diagnosing high-risk lesions, and stratifying those patients with aggressive tumors. To identify such biomarkers, we have examined a comprehensive set of 200 histologically defined squamous cell carcinoma and normal skin samples by using a combination of microarray, QRT-PCR and immunohistochemistry analyses. A characteristic and distinguishable profile including matrix metalloproteinase (MMP) as well as other degradome components was differentially expressed in squamous cell carcinoma compared with normal skin samples. The expression levels of some of these genes including matrix metallopeptidase 1 (MMP1), matrix metallopeptidase 10 (MMP10), parathyroid hormone-like hormone (PTHLH), cyclin-dependent kinase inhibitor 2A (CDKN2A), A disintegrin and metalloproteinase with thrombospondin motifs 1 (ADAMTS1), FBJ osteosarcoma oncogene (FOS), interleukin 6 (IL6) and reversion-inducing-cysteine-rich protein with kazal motifs (RECK) were significantly differentially expressed (P≤0.02) in squamous cell carcinoma compared with normal skin. Furthermore, based on receiver operating characteristic analyses, the mRNA and protein levels of MMP1 are significantly higher in aggressive tumors compared with non-aggressive tumors. Given that MMPs represent the most prominent family of proteinases associated with tumorigenesis, we believe that they may have an important role in modulating the tumor microenvironment of squamous cell carcinoma.Modern Pathology advance online publication, 20 December 2013; doi:10.1038/modpathol.2013.217.
    Modern Pathology 12/2013; DOI:10.1038/modpathol.2013.217 · 6.36 Impact Factor
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    ABSTRACT: Methylation of CpG islands in the promoter region of genes acts as a significant mechanism of epigenetic gene silencing in head and neck cancer. In the present study, we assessed the association of epigenetic alterations of a panel of 12 genes [nucleolar protein 4 (NOL4), iroquois homeobox 1 (IRX1), SLC5A8, LRRC3B, FUSSEL18, EBF3, GBX2, HMX2, SEPT9, ALX3, SOCS3 and LHX6] with head and neck squamous cell carcinoma (HNSCC) via a candidate gene approach. After the initial screening of methylated CpG islands on the promoter regions by bisulfite sequencing using salivary rinse samples, only two genes had methylated CpG dinucleotides on their promoter regions in tumor samples and absence of methylated CpGs were found in normal salivary rinse samples after bisulfite modification and bisulfite sequencing. We then performed real-time quantitative methylation-specific PCR (QMSP) on 16 salivary rinse and 14 normal mucosal samples from healthy subjects and 33 HNSCC tumor samples for the two genes selected. After validation with QMSP, one gene, NOL4, was highly methylated (91%) in tumor samples and unmethylated in normal salivary rinses and minimally methylated in normal mucosal samples demonstrating cancer-specific methylation in HNSCC tissues. Although the IRX1 gene was observed as methylated in normal mucosal and salivary rinse samples, the methylation values of these normal samples were very low (<10%). In conclusion, we identified NOL4 as a highly specific promoter methylated gene associated with HNSCC. IRX1 may have potential as a biomarker for HNSCC and should be assessed in a larger cohort.
    Oncology Reports 12/2013; 31(2). DOI:10.3892/or.2013.2927 · 2.19 Impact Factor
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    ABSTRACT: Crohn's disease (CD) is associated with defective sensing of pathogens in genetically susceptible individuals. Nucleotide-binding oligomerization domain containing 2 (NOD2) mutations in coding regions are strongly linked to CD pathogenesis. Our laboratory has reported that microRNAs (miRNAs) are differentially expressed in CD. However, miRNA regulation of NOD2 remains unknown. This study was designed to determine whether miRNAs regulate NOD2 expression as well as downstream nuclear factor kappaB activation and inflammatory responses in colonic epithelial HCT116 cells. NOD2 and miRNA expression in stimulated HCT116 cells were assessed by quantitative reverse transcription-polymerase chain reaction. Regulation of NOD2 expression by miRNAs was determined by luciferase reporter construct assays and transfection of specific miRNA mimics. Regulation of NOD2 signaling and immune response by miRNAs was assessed by transfection of mimics followed by muramyl dipeptide stimulation. Muramyl dipeptide-induced increases in NOD2, interleukin-8, and CXCL3 expression were inversely associated with miRNA expression. Overexpression of miR-192, miR-495, miR-512, and miR-671 suppressed NOD2 expression, muramyl dipeptide-mediated NF-κB activation, and messenger RNA expressions of interleukin-8 and CXCL3 in HCT116 cells. A single-nucleotide polymorphism (rs3135500) located in the NOD2 3'-untranslated region significantly reduced miR-192 effects on NOD2 gene expression. To our knowledge, this is the first report demonstrating that miRNAs regulate NOD2 and its signaling pathway. Four miRNAs downregulate NOD2 expression, suppress NF-κB activity, and inhibit interleukin-8 and CXCL3 messenger RNA expression. Treatment of CD with miRNAs may represent a potential anti-inflammatory therapeutic strategy in CD patients with and without NOD2 gene mutations.
    Inflammatory Bowel Diseases 11/2013; DOI:10.1097/01.MIB.0000436954.70596.9b · 5.48 Impact Factor
  • Zili Zhai, Feng Wu, Alice Y Chuang, John H Kwon
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    ABSTRACT: The microRNAs (miRNAs) regulate gene expression at the posttranscriptional level. ATG16L1, an essential component for autophagy and a risk gene for Crohn's disease, contains two binding sites in the 3'UTR for miR-17 family, including miRs-20a, -93, -106a, and -106b. The purpose of this study was to assess the effects of these miRNAs on ATG16L1 expression and autophagic activity in HCT116 cells. The functional binding sites in the ATG16L1 3'UTR were evaluated by transfection of pMIR-GLO vectors bearing the wild type or mutant 3'UTR into cells for luciferase reporter assay. The miRNA regulation of ATG16L1 expression was determined by quantitative real-time polymerase chain reaction and Western blot. The miRNA regulation of autophagic activity was evaluated by examining LC3II formation using Western blot and confocal imaging. Both miR-106a and miR-106b mimics inhibited starvation-induced autophagy. The miR-106b mimic reduced ATG16L1 protein expression. Luciferase reporter assays showed that mutating the binding sequence at the positions 1036 to 1042 abrogated miR-106b regulation of ATG16L1 3'UTR luciferase activity. In addition, miR-106a and miR-106b overexpression inhibited the expression of several other autophagy genes, including ATG12. miR-106b targets ATG16L1 and modulates autophagy, partially through the binding site at the 3' end of ATG16L1 3'UTR. miR-106a regulates autophagy, possibly irrelevant to ATG16L1 regulation. Both miR-106a and miR-106b regulate multiple autophagy genes so that they may play an integral role in fine-tuning autophagy.
    Inflammatory Bowel Diseases 07/2013; DOI:10.1097/MIB.0b013e31829e71cf · 5.48 Impact Factor
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    ABSTRACT: Silencing of tumor suppressor genes plays a vital role in head and neck carcinogenesis. Aberrant hypermethylation in the promoter region of some known or putative tumor suppressor genes occurs frequently during the development of various types of cancer including head and neck squamous cell carcinoma (HNSCC). In this study we used an expanded mRNA expression profiling approach followed by microarray expression analysis to identify epigenetically inactivated genes in HNSCC. Two HNSCC cell lines were treated with 5-aza-2'-deoxycytidine followed by microarray analysis to identify epigenetically silenced genes in HNSCC. We found 1,960, 614 and 427 genes were upregulated in the HNSCC cell lines JHU-012, JHU-011 and the combination of both cell lines, respectively. HNSCC tumor and normal mucosal samples were used for gene profiling by a 47K mRNA gene expression array and we found 7,140 genes were downregulated in HNSCC tumors compared to normal mucosa, as determined by microarray analysis, and were integrated with cell line data. Integrative analysis defined 126 candidate genes, of which only seven genes showed differential methylation in tumors and no methylation in normal mucosa after bisulfite sequencing. Following validation by QMSP, one gene, guanine nucleotide-binding protein γ-7 (GNG7), was confirmed to be highly methylated in tumors and unmethylated in normal mucosal and salivary rinse samples demonstrating cancer-specific methylation in HNSCC tissues. TXNIP and TUSC2 were partially methylated in tumors and normal salivary rinses but unmethylated in normal mucosa. We concluded that GNG7 is a highly specific promoter methylated gene associated with HNSCC. In addition, TXNIP and TUSC2 are also potential biomarkers for HNSCC.
    International Journal of Oncology 04/2013; 42(4):1427-36. DOI:10.3892/ijo.2013.1808 · 2.77 Impact Factor
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    ABSTRACT: Silencing of tumor suppressor genes plays a vital role in head and neck carcinogenesis. In this study we aimed to evaluate aberrant p16(INK4a) gene promoter methylation in patients with head and neck cancer. Methylation of the gene was investigated by bisulfite modification/methylation-specific polymerase chain reaction and gene expression levels were analyzed by quantitative reverse transcription-polymerase chain reaction in tumors and matched normal tissue samples from Turkish patients with head and neck cancer. The promoter region of the p16(INK4a) gene was methylated in 67.5% and 28.6% of the primary tumors and the corresponding normal tissue, respectively. This difference was highly significant. In concordance, p16(INK4a) gene expression was downregulated in 67.5% of the tumor samples. Methylation and the absence of expression in the tumors were observed in 48% of the patients. Our data indicate that methylation of the p16(INK4a) gene is a frequent event in primary head and neck cancer and that it plays a major role in the silencing of p16(INK4a) gene expression during tumor development. © 2011 Wiley Periodicals, Inc. Head Neck, 2011.
    Head & Neck 10/2012; 34(10):1470-5. DOI:10.1002/hed.21949 · 3.01 Impact Factor
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    ABSTRACT: Cancer testis antigens (CTAs) are proteins that are normally expressed only in male germ cells and are aberrantly upregulated in a variety of cancers such as melanomas and lung cancer. MAGEA proteins belong to Class I CTAs and are being utilized as targets for cancer immunotherapy. Despite the discovery of the first CTA (MAGEA1) 20 years ago, the functions of these proteins remain poorly understood and evidence suggests both oncogenic as well as tumor suppressive roles for these proteins. Herein, we investigated the role of MAGEA4 in promoting cell growth. When overexpressed, MAGEA4 promotes growth of spontaneously transformed normal oral keratinocytes (NOK-SI). To understand the mechanism of growth stimulation by MAGEA4, we explored the effect of overexpressing MAGEA4 on cell cycle and apoptosis. MAGEA4 inhibits growth arrest of cells in the G1 phase of the cell cycle. We also found that overexpression of MAGEA4 inhibits G418-induced apoptosis of NOK-SI cells. Interestingly, this inhibition was accompanied by repression of two p53 downstream genes, BAX and CDKN1A. Our results indicate that MAGEA4 promotes growth by preventing cell cycle arrest and by inhibiting apoptosis mediated by the p53 transcriptional targets.
    Oncology Reports 07/2012; 28(4):1498-502. DOI:10.3892/or.2012.1934 · 2.19 Impact Factor
  • Cancer Research 04/2012; 72(8 Supplement):4041-4041. DOI:10.1158/1538-7445.AM2012-4041 · 9.28 Impact Factor
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    ABSTRACT: The cisplatin-induced ATM-dependent phosphorylated (p)-ΔNp63α plays an important role in transcriptional regulation of specific genes encoding mRNAs and microRNAs (miRs) implicated in cell death, cell survival, and chemoresistance. The p-ΔNp63α-induced miR-885-3p functions as a critical regulator of MDM4, ATK1, BCL2, ATG16L2, ULK2, CASP2, and CASP3 mRNAs via pairing with their respective 'recognition' sequences. Cisplatin exposure modulated the levels of target proteins (reduced BCL2, AKT1, ATG16L2, and ULK2, while activated MDM4) in cisplatin-sensitive wild type ΔNp63α cells leading to distinct changes in cell viability. Finally, miR-885-3p modulated the cisplatin-induced TP53-dependent mitochondrial apoptosis by up regulation of MDM4 levels and down regulation of BCL2 levels in mitochondria. Altogether, our results support the notion that miR-885-3p might contribute in regulation of cell viability, apoptosis and/or autophagy in squamous cell carcinoma cells upon cisplatin exposure.
    Cell cycle (Georgetown, Tex.) 11/2011; 10(22):3938-47. DOI:10.4161/cc.10.22.18107 · 5.01 Impact Factor
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    ABSTRACT: Nonmelanoma skin carcinoma (NMSC) is the most frequent cancer in the USA with over 1.3 million new diagnoses a year; however due to an underappreciation of its associated mortality and growing incidence and its ability to be highly aggressive, the molecular mechanism is not well delineated. Whereas the molecular profiles of melanoma have been well characterized, those for cutaneous squamous cell carcinoma (cSCC) have trailed behind. This importance of the new staging paradigm is linked to the ability currently to better clinically cluster similar biologic behavior in order to risk-stratify lesions and patients. In this paper we discuss the trends in NMSC and the etiologies for the subset of NMSC with the most mortality, cutaneous SCC, as well as where the field stands in the discovery of a molecular profile. The molecular markers are highlighted to demonstrate the recent advances in cSCC.
    08/2011; 2011:231475. DOI:10.1155/2011/231475
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    ABSTRACT: The incidence of cutaneous squamous cell carcinoma (cSCC) is increasing. Although most patients achieve complete remission with surgical treatment, those with advanced disease have a poor prognosis. The American Joint Committee on Cancer (AJCC) is responsible for the staging criteria for all cancers. For the past 20 years, the AJCC cancer staging manual has grouped all nonmelanoma skin cancers, including cSCC, together for the purposes of staging. However, based on new evidence, the AJCC has determined that cSCC should have a separate staging system in the 7th edition AJCC staging manual. We sought to present the rationale for and characteristics of the new AJCC staging system specific to cSCC tumor characteristics (T). The Nonmelanoma Skin Cancer Task Force of AJCC reviewed relevant data and reached expert consensus in creating the 7th edition AJCC staging system for cSCC. Emphasis was placed on prospectively accumulated data and multivariate analyses. Concordance with head and neck cancer staging system was also achieved. A new AJCC cSCC T classification is presented. The T classification is determined by tumor diameter, invasion into cranial bone, and high-risk features, including anatomic location, tumor thickness and level, differentiation, and perineural invasion. The data available for analysis are still suboptimal, with limited prospective outcomes trials and few multivariate analyses. The new AJCC staging system for cSCC incorporates tumor-specific (T) staging features and will encourage coordinated, consistent collection of data that will be the basis of improved prognostic systems in the future.
    Journal of the American Academy of Dermatology 06/2011; 64(6):1051-9. DOI:10.1016/j.jaad.2010.08.033 · 5.00 Impact Factor
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    ABSTRACT: Aim of this study was to determine whether BORIS (Brother of the Regulator of Imprinted Sites) is a regulator of MAGEA2, MAGEA3, and MAGEA4 genes in lung cancer. Changes in expression of MAGEA genes upon BORIS induction/knockdown were studied. Recruitment of BORIS and changes in histone modifications at their promoters upon BORIS induction were analyzed. Luciferase assays were used to study their activation by BORIS. Changes in methylation at these promoters upon BORIS induction were evaluated. Alteration of BORIS expression by induction/knockdown directly correlated with expression of MAGEA genes. BORIS was enriched at their promoters in H1299 cells, which show high expression of these cancer testis antigens (CTA), compared with normal human bronchial epithelial (NHBE) cells which show low expression of the target CTAs. BORIS induction in A549 cells resulted in increased amounts of BORIS and activating histone modifications at their promoters along with a corresponding increase in their expression. Similarly, BORIS binding at these promoters in H1299 correlates with enrichment of activating modifications, whereas absence of BORIS binding in NHBE is associated with enrichment of repressive marks. BORIS induction of MAGEA3 was associated with promoter demethylation, but no methylation changes were noted with activation of MAGEA2 and MAGEA4. These data suggest that BORIS positively regulates these CTAs by binding and inducing a shift to a more open chromatin conformation with promoter demethylation for MAGEA3 or independent of promoter demethylation in case of MAGEA2 and MAGEA4 and may be a key effector involved in their derepression in lung cancer.
    Clinical Cancer Research 05/2011; 17(13):4267-76. DOI:10.1158/1078-0432.CCR-11-0653 · 8.19 Impact Factor
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    ABSTRACT: Nasopharyngeal carcinoma (NPC) is a rare malignancy with unique genetic, viral and environmental characteristic that distinguishes it from other head and neck carcinomas. The clinical management of NPC remains challenging largely due to the lack of early detection strategies for this tumor. In our study, we have sought to identify novel genes involved in the pathogenesis of NPC that might provide insight into this tumor's biology and could potentially be used as biomarkers. To identify these genes, we studied the epigenetics of NPC by characterizing a panel of methylation markers. Eighteen genes were evaluated by quantitative methylation-specific polymerase chain reaction (PCR) in cell lines as well as in tissue samples including 50 NPC tumors and 28 benign nasopharyngeal biopsies. Significance was evaluated using Fisher's exact test and quantitative values were optimized using cut off values derived from receiver-operator characteristic curves. The methylation status of AIM1, APC, CALCA, deleted in colorectal carcinomas (DCC), DLEC, deleted in liver cancer 1 (DLC1), estrogen receptor alpha (ESR), FHIT, KIF1A and PGP9.5 was significantly associated with NPC compared to controls. The sensitivity of the individual genes ranged from 26 to 66% and the specificity was above 92% for all genes except FHIT. The combination of PGP9.5, KIF1A and DLEC had a sensitivity of 84% and a specificity of 92%. Ectopic expression of DCC and DLC1 lead to decrease in colony formation and invasion properties. Our results indicate that methylation of novel biomarkers in NPC could be used to enhance early detection approaches. Additionally, our functional studies reveal previously unknown tumor suppressor roles in NPC.
    International Journal of Cancer 03/2011; 128(6):1393-403. DOI:10.1002/ijc.25443 · 5.01 Impact Factor
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    ABSTRACT: Human papillomavirus (HPV) type 16 can integrate into the host genome, thereby rendering the viral coding genes susceptible to epigenetic modification. Using bisulfite genomic sequencing, we determined the methylation status of all 110 CpG sites within the viral epigenome in advanced stage III/IV HPV-16-associated head and neck cancers. We found that the viral genome was hypomethylated in the majority of head and neck cancers, in particular within the viral regulatory region, long control region (LCR), which controls transcription of the E6 and E7 oncogenes. The hypomethylation status of LCR correlated with detectable levels of E6 and E7 expression, which suggests that the tumors may still be dependent on these viral oncogenes to maintain the malignant phenotype. In addition to the methylation status of LCR, we report other potential factors which may influence intratumoral E6 and E7 expression including viral copy number and integration site. We were able to detect the viral epigenetic alterations in sampled body fluids, such as serum and saliva, which correlated with the changes observed in the primary tumors. Because viral epigenetic changes occur in the setting of viral integration into the human genome, the detection of methylated HPV genes in the serum and/or saliva may have diagnostic potential for early detection strategies of viral integration and assessment of risk for cancer development in high-risk individuals. Our findings also support continued targeting of the E6 and/or E7 antigens through various vaccine strategies against HPV-associated cancers.
    Cancer Prevention Research 02/2011; 4(2):207-17. DOI:10.1158/1940-6207.CAPR-10-0147 · 5.27 Impact Factor
  • Journal of Surgical Research 02/2011; 165(2):335-335. DOI:10.1016/j.jss.2010.11.192 · 2.12 Impact Factor
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    ABSTRACT: Head and neck squamous cell carcinoma (HNSCC) cells exposed to cisplatin (CIS) displayed a dramatic ATM-dependent phosphorylation of ΔNp63α that leads to the transcriptional regulation of downstream mRNAs. Here, we report that phospho (p)-ΔNp63α transcriptionally deregulates miRNA expression after CIS treatment. Several p-ΔNp63α-dependent microRNA species (miRNAs) were deregulated in HNSCC cells upon CIS exposure, including miR-181a, miR-519a, and miR-374a (downregulated) and miR-630 (upregulated). Deregulation of miRNA expression led to subsequent modulation of mRNA expression of several targets (TP53-S46, HIPK2, ATM, CDKN1A and 1B, CASP3, PARP1 and 2, DDIT1 and 4, BCL2 and BCL2L2, TP73, YES1, and YAP1) that are involved in the apoptotic process. Our data support the notion that miRNAs are critical downstream targets of p-ΔNp63α and mediate key pathways implicated in the response of cancer cells to chemotherapeutic drugs.
    Cell death and differentiation 01/2011; 18(7):1220-30. DOI:10.1038/cdd.2010.188 · 8.39 Impact Factor
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    ABSTRACT: Silencing of tumor suppressor genes plays a vital role in head and neck carcinogenesis. In this study, we aimed to evaluate to the utility of aberrant promoter hypermethylation for detection in a panel of 10 genes (KIF1A, EDNRB, CDH4, TERT, CD44, NISCH, PAK3, VGF, MAL and FKBP4) in head and neck squamous cell carcinoma (HNSCC) via a candidate gene approach. We investigated methylation of the gene promoters by bisulfite modification and quantitative methylation-specific PCR (Q-MSP) in a preliminary study of a limited cohort of salivary rinses from healthy subjects (n = 61) and patients with HNSCC (n = 33). The methylation status of 2 selected genes (EDNRB and KIF1A) were then analyzed in 15 normal mucosa samples from a healthy population, 101 HNSCC tumors and the corresponding salivary rinses from 71 out of the 101 HNSCC patients were collected before treatment. The promoter regions of CDH4, TERT, VGF, MAL, FKBP4, NISCH and PAK3 were methylated in normal salivary rinses while no methylation of CD44 was observed in either normal salivary rinses or tumor samples. However, KIF1A and EDNRB were methylated in 98 and 97% of primary HNSCC tissues respectively and were only methylated in 2 and 6.6% of normal salivary rinses. In addition, KIF1A and EDNRB were methylated in 38 and 67.6% of salivary rinses from HNSCC patients, respectively. Promoter hypermethylation of KIF1A and EDNRB is a frequent event in primary HNSCC, and these genes are preferentially methylated in salivary rinses from HNSCC patients. KIF1A and EDNRB are potential biomarkers for HNSCC detection.
    International Journal of Cancer 11/2010; 127(10):2351-9. DOI:10.1002/ijc.25248 · 5.01 Impact Factor
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    ABSTRACT: Methylation profiling of tumor suppressor gene (TSGs) promoters is quickly becoming a powerful diagnostic tool for the early detection, prognosis, and even prediction of clinical response to treatment. Few studies address this in salivary gland tumors (SGTs); hence the promoter methylation profile of various TSGs was quantitatively assessed in primary SGT tissue to determine if tumor-specific alterations could be detected. DNA isolated from 78 tumor and 17 normal parotid gland specimens was assayed for promoter methylation status of 19 TSGs by fluorescence-based, quantitative methylation-specific PCR (qMSP). The data were utilized in a binary fashion as well as quantitatively (using a methylation quotient) allowing for better profiling and interpretation of results. The average number of methylation events across the studied genes was highest in salivary duct carcinoma (SDC), with a methylation value of 9.6, compared to the normal 4.5 (p<0.0003). There was a variable frequency and individual methylation quotient detected, depending on the TSG and the tumor type. When comparing normal, benign, and malignant SGTs, there was a statistically significant trend for increasing methylation in APC, Mint 1, PGP9.5, RAR-beta, and Timp3. Screening promoter methylation profiles in SGTs showed considerable heterogeneity. The methylation status of certain markers was surprisingly high in even normal salivary tissue, confirming the need for such controls. Several TSGs were found to be associated with malignant SGTs, especially SDC. Further study is needed to evaluate the potential use of these associations in the detection, prognosis, and therapeutic outcome of these rare tumors.
    PLoS ONE 05/2010; 5(5):e10828. DOI:10.1371/journal.pone.0010828 · 3.53 Impact Factor

Publication Stats

733 Citations
176.65 Total Impact Points

Institutions

  • 2011–2014
    • University of Chicago
      • Department of Medicine
      Chicago, Illinois, United States
    • Greater Baltimore Medical Center
      Baltimore, Maryland, United States
  • 2007–2013
    • Johns Hopkins University
      • • Department of Dermatology
      • • Department of Otolaryngology - Head and Neck Surgery
      Baltimore, Maryland, United States
    • The Australian Society of Otolaryngology Head & Neck Surgery
      Evans Head, New South Wales, Australia
  • 2006–2013
    • Johns Hopkins Medicine
      • • Department of Dermatology
      • • Department of Otolaryngology - Head and Neck Surgery
      Baltimore, Maryland, United States
  • 2005
    • University of Manitoba
      • Manitoba Institute of Cell Biology
      Winnipeg, Manitoba, Canada