Molecular techniques and genetic alterations in head and neck cancer

Ha, Patrick K.; Chang, Steven S.; Glazer, Chad A.; Califano, Joseph A.; Sidransky, David

doi:10.1016/j.oraloncology.2008.05.015

Cited by 75 publications

(62 citation statements)

References 65 publications

(48 reference statements)

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“…This observation is unlikely to be caused by deletions on chromosome 15 as they have not been reported so far to occur within the chromosomal region of NEIL1 in HNSCC. 4,5 No such chromosomal aberrations have been found in 18 out of 20 (90%) of HNSCC cell lines which we used in our experiments. 35 However, it is known that tumors have heterogeneous patterns of somatic genetic and epigenetic alterations.…”

Section: Discussionmentioning

confidence: 72%

“…3 The role of genetic alterations in the development of HNSCC has been extensively studied; however, the role of many affected genes is still unknown. 4,5 Several epigenetically silenced genes have been described in HNSCC including CDKN2A, LHX6, TCF21, CEBPA, SFRP genes, and members of the Fanconi anemia/BRCA pathway. 6 --11 Aberrant DNA methylation of DNA repair genes MGMT, MLH1 or MSH2 has been shown to have a critical role in the development and progression of HNSCC.…”

Section: Introductionmentioning

confidence: 99%

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Epigenetic screen of human DNA repair genes identifies aberrant promoter methylation of NEIL1 in head and neck squamous cell carcinoma

et al. 2012

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Aberrant promoter methylation of different DNA repair genes has a critical role in the development and progression of various cancer types, including head and neck squamous cell carcinomas (HNSCCs). A systematic analysis of known human repair genes for promoter methylation is however missing. We generated quantitative promoter methylation profiles in single CpG units of 160 human DNA repair genes in a set of DNAs isolated from fresh frozen HNSCC and normal tissues using MassARRAY technology. Ninety-eight percent of these genes contained CpG islands (CGIs) in their promoter region; thus, DNA methylation is a potential regulatory mechanism. Methylation data were obtained for 145 genes, from which 15 genes exhibited more than a 20% difference in methylation levels between tumor and normal tissues, manifested either as hypermethylation or as hypomethylation. Analyses of promoter methylation with mRNA expression identified the DNA glycosylase NEIL1 (nei endonuclease VIII-like 1) as the most prominent candidate gene. NEIL1 promoter hypermethylation was confirmed in additional fresh frozen HNSCC samples, normal mucosa, HNSCC cell lines and primary human skin keratinocytes. The investigation of laser-microdissected tissues further substantiated increased methylation levels in tumor versus matched non-tumor cells. Immunohistological analysis revealed significantly less NEIL1 protein expression in tumor tissues. 5-Aza-2 0 -deoxycytidine treatment and DNMT1 knockdown resulted in the re-expression of NEIL1 in HNSCC cell lines, which initially carried hypermethylated promoter regions. In conclusion, our results suggest that DNA methylation contributes to the downregulation of NEIL1 expression and might thus have a role in modulating the response to therapies of HNSCC.

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Section: Discussionmentioning

confidence: 72%

Section: Introductionmentioning

confidence: 99%

Epigenetic screen of human DNA repair genes identifies aberrant promoter methylation of NEIL1 in head and neck squamous cell carcinoma

et al. 2012

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“…Despite recent advances in molecular pathology, little is known regarding the genes or pathways that play key roles in HNSCC (1). To establish a more concise understanding of the biological characteristics of HNSCC, our group has been working on a genome-wide analysis with the aim of identifying the genes that act as the principle drivers of carcinogenesis, invasion and metastasis.…”

Section: Introductionmentioning

confidence: 99%

Absence of Dickkopf (Dkk)-3 protein expression is correlated with longer disease-free survival and lower incidence of metastasis in head and neck squamous cell carcinoma

et al. 2011

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Abstract. Head and neck squamous cell carcinoma (HNSCC) is one of the most frequently occurring types of cancer worldwide. We focused on the fact that the aberrant function of Wnt/β-catenin signaling is a frequent event in malignancies. Dickkopf (Dkk)-3 is a major negative regulator of Wnt/β-catenin signaling, which is a known tumor suppressor and is down-regulated in various types of cancer. However, the expression profile of the Dkk-3 protein in HNSCC has not yet been reported. The present study was conducted to investigate Dkk-3 protein expression in 90 cases of HNSCC tissue samples and HNSCC-derived cell lines. In contrast to findings available on other types of cancer, the Western blot analysis revealed that HNSCC cell lines expressed the Dkk-3 protein. In immunohistochemistry, 76 cases (84.4%) out of 90 tissue samples were Dkk-3-positive, whereas only 14 cases (15.6%) were negative. Notably, survival analysis showed that the Dkk-3 (-) group exhibited significantly longer disease-free survival (p=0.038), metastasis-free survival (p=0.013) and longer overall survival (p=0.155). The results showed that the Dkk-3 protein was dominantly expressed and may be involved in carcinogenesis and metastasis in HNSCC. Moreover, the findings suggest that the function of Dkk-3 differs depending on the tissue of origin, and that it may exert an oncogenic function in HNSCC.

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“…Despite advances in treatment, facial disfigurement, and functional disturbances including mastication, swallowing, and speech remain distressingly common (2). It is critical to understand key molecular mechanisms in the transformation and spread of OSCC, with a view to designing targeted-or individualisedtherapies (3,4).…”

Section: Introductionmentioning

confidence: 99%

Epithelial-mesenchymal transition in oral squamous cell carcinoma triggered by transforming growth factor-β1 is Snail family-dependent and correlates with matrix metalloproteinase-2 and -9 expressions

Qiao

Johnson²,

Gao³

2010

Int J Oncol

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Abstract. Snail and Slug play important roles in cancer progression by promoting epithelial-mesenchymal transition (EMT). Although Snail is well studied, its role in oral squamous cell carcinoma (OSCC) and its regulatory relationship with Slug remain unclear. We aimed to determine whether Snail and Slug interplay occurs in transforming growth factor-ß1 (TGF-ß1)-initiated EMT of OSCC cells, and to assess the expression of matrix metalloproteinases (MMPs) in this process. Three OSCC cell lines, SCC9, SCC15 and SCC25 were treated with recombinant TGF-ß1 for 0-6 days. Activities of the EMT regulators, Snail and Slug, and of extracellular hallmarks, MMP2 and 9, were detected using real-time PCR and Western blots. An in vitro wound healing assay then assessed short-term EMT, whilst phenotypic changes associated with the above gene expressions were evaluated by immunocytochemistry. Results showed that Slug and MMP9 were up-regulated at both mRNA and protein levels, while Snail expression rose and fell, in concert with expression of MMP2. In the wound healing assay, Snail was seen alone at the invasive front in SCC9 and SCC15 cultures, while both Snail and Slug appeared at wound margins in SCC25. Both MMP2 and MMP9 were detected at wound edges in all cell lines, with MMP2 localised in cell nuclei, MMP9 was restricted to the cytoplasm. The study suggests that both Snail and Slug act as regulators of TGF-ß1-trigged EMT in OSCC cells. Snail may up-regulate MMP2 or MMP9 initiating EMT, while Slug may share a role with Snail in maintaining longer-term EMT, by stimulating MMP9 expression.

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Molecular techniques and genetic alterations in head and neck cancer

Cited by 75 publications

References 65 publications

Epigenetic screen of human DNA repair genes identifies aberrant promoter methylation of NEIL1 in head and neck squamous cell carcinoma

Epigenetic screen of human DNA repair genes identifies aberrant promoter methylation of NEIL1 in head and neck squamous cell carcinoma

Absence of Dickkopf (Dkk)-3 protein expression is correlated with longer disease-free survival and lower incidence of metastasis in head and neck squamous cell carcinoma

Epithelial-mesenchymal transition in oral squamous cell carcinoma triggered by transforming growth factor-β1 is Snail family-dependent and correlates with matrix metalloproteinase-2 and -9 expressions

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