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Shao C.,The Johns Hopkins Medical Institutions | Tan M.,The Johns Hopkins Medical Institutions | Bishop J.A.,The Johns Hopkins Medical Institutions | Liu J.,University of Pittsburgh | And 13 more authors.
PLoS ONE | Year: 2012

Background: Salivary gland adenoid cystic carcinoma (ACC) is a rare cancer, accounting for only 1% of all head and neck malignancies. ACC is well known for perineural invasion and distant metastasis, but its underlying molecular mechanisms of carcinogenesis are still unclear. Principal Findings: Here, we show that a novel oncogenic candidate, suprabasin (SBSN), plays important roles in maintaining the anchorage-independent and anchorage-dependent cell proliferation in ACC by using SBSN shRNA stably transfected ACC cell line clones. SBSN is also important in maintaining the invasive/metastatic capability in ACC by Matrigel invasion assay. More interestingly, SBSN transcription is significantly upregulated by DNA demethylation induced by 5-aza-2′-deoxycytidine plus trichostatin A treatment and the DNA methylation levels of the SBSN CpG island located in the second intron were validated to be significantly hypomethylated in primary ACC samples versus normal salivary gland tissues. Conclusions/Significance: Taken together, these results support SBSN as novel oncogene candidate in ACC, and the methylation changes could be a promising biomarker for ACC. © 2012 Shao et al. Source


Sobel R.H.,Johns Hopkins University | Califano J.A.,Johns Hopkins Medical Institutions | Califano J.A.,Milton nce Jr Head And Neck Center At The Greater Baltimore Medical Center
Operative Techniques in Otolaryngology - Head and Neck Surgery | Year: 2014

The pterygopalatine fossa is a well-protected region of the skull base, and surgical access for resection of tumors growing in this region can be challenging. Historically, the approach to this anatomical space has been an open transmaxillary technique. This results in disruption of the anterior and posterior walls of the maxillary sinus and numerous postoperative morbidities. More recently, improvements in endoscopic sinus surgery instrumentation and techniques have led to the advent of minimally invasive surgical approaches to the skull base. The use of endoscopes allows for improved visualization and surgical manipulation, as well as reduced postoperative comorbidities. We discuss a graduated, minimally invasive approach to the pterygopalatine fossa. © 2014 Elsevier Inc. Source


Wang Z.,Liaoning Medical University | Brait M.,Milton nce Jr Head And Neck Center At The Greater Baltimore Medical Center | Fertig E.J.,Johns Hopkins University | Considine M.,Johns Hopkins University | And 2 more authors.
International Journal of Oncology | Year: 2016

Salivary gland adenoid cystic carcinoma (ACC) is a rare head and neck malignancy without molecular biomarkers that can be used to predict the chemotherapeutic response or prognosis of ACC. The regulation of gene expression of oncogenes and tumor suppressor genes (TSGs) through DNA promoter methylation may play a role in the carcinogenesis of ACC. To identify differentially methylated genes in ACC, a global demethylating agent, 5-aza-2'-deoxycytidine (5-AZA) was utilized to unmask putative TSG silencing in ACC xenograft models in mice. Fresh xenografts were passaged, implanted in triplicate in mice that were treated with 5-AZA daily for 28 days. These xenografts were then evaluated for genome-wide DNA methylation patterns using the Illumina Infinium HumanMethylation27 BeadChip array. Validation of the 32 candidate genes was performed by bisulfite sequencing (BS-seq) in a separate cohort of 6 ACC primary tumors and 6 normal control salivary gland tissues. Hypermethylation was identified in the HCN2 gene promoter in all 6 control tissues, but hypomethylation was found in all 6 ACC tumor tissues. Quantitative validation of HCN2 promoter methylation level in the region detected by BS-seq was performed in a larger cohort of primary tumors (n=32) confirming significant HCN2 hypomethylation in ACCs compared with normal samples (n=10; p=0.04). HCN2 immunohistochemical staining was performed on an ACC tissue microarray. HCN2 staining intensity and H-score, but not percentage of the positively stained cells, were significantly stronger in normal tissues than those of ACC tissues. With our novel screening and sequencing methods, we identified several gene candidates that were methylated. The most significant of these genes, HCN2, was actually hypomethylated in tumors. However, promoter methylation status does not appear to be a major determinant of HCN2 expression in normal and ACC tissues. HCN2 hypomethylation is a biomarker of ACC and may play an important role in the carcinogenesis of ACC. Source


Wang Z.,Liaoning Medical University | Wang Z.,Johns Hopkins University | Ling S.,Johns Hopkins University | Rettig E.,Johns Hopkins University | And 10 more authors.
Oral Oncology | Year: 2015

Objectives The role of promoter methylation in the development of mucoepidermoid carcinoma (MEC) has not been fully explored. In this study, we investigated the epigenetic landscape of MEC. Methods The Illumina HumanMethylation27 BeadChip array and differential methylation analysis were utilized to screen for epigenetic alterations in 14 primary MEC tumors and 14 matched normal samples. Bisulfite sequencing was used to validate these results, with subsequent quantitative Methylation-Specific PCR (qMSP) to validate chloride intracellular channel protein 3 (CLIC3) in a separate cohort. Furthermore, CLIC3 immunohistochemical (IHC) staining was performed in another separate cohort of MEC. Finally, clinical and pathological characteristics were statistically analyzed for correlation with methylation status of CLIC3 and CLIC3 IHC H-scores by Wilcoxon rank sum, Kruskall-Wallis, and X2 test tests. Results We obtained 6 significantly differentially methylated gene candidates demonstrating significant promoter hyper- or hypo-methylation from the array data. Using bisulfite sequencing, we found one gene, CLIC3, which showed differential methylation between MEC tumor and normal samples in a small validation cohort. qMSP analysis of the CLIC3 promoter in a separate validation set showed significantly lower methylation level in tumor than in normal. The level of CLIC3 methylation in MECs was not statistically correlated with clinical or pathological characteristics. However, IHC staining intensity and distribution of CLIC3 were significantly increased in MECs, compared with those of normal salivary gland tissues. Conclusions Hypomethylation of CLIC3 promoter and its overexpression are significant events in MEC. Its functional role and potential therapeutic utility in MEC are worthy of further exploration. © 2015 Elsevier Ltd. All rights reserved. Source

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