Dataset Information

Identification of Ethanol and 4-Nitroquinoline-1-Oxide Induced Epigenetic and Oxidative Stress Markers During Oral Cavity Carcinogenesis.

ABSTRACT: Head and neck squamous cell carcinoma (HNSCC) is a cancer that is characterized by its high morbidity and mortality rates. While tobacco use and alcohol consumption are 2 major contributing factors for HNSCC carcinogenesis, how the combination of tobacco and alcohol increases HNSCC risk is not understood.We combined the 4-nitroquinoline-1-oxide (4-NQO) oral carcinogenesis and Meadows-Cook alcohol mouse models to elucidate the molecular events and to identify the novel biomarkers associated with oral cancer development.By genome-wide RNA-seq of tongue samples (3 mice per group), we identified changes in transcripts that mediate alcohol metabolism and oxidative stress (Aldh2, Aldh1a3, Adh1, Adh7, and Cyp2a5) in mice treated with 4-NQO followed by ethanol (4-NQO/EtOH) as compared to the vehicle control/untreated (V.C./Untr.) samples. We measured major, global increases in specific histone acetylation and methylation epigenetic marks (H3K27ac, H3K9/14ac, H3K27me3, and H3K9me3) in the oral cavities of V.C./EtOH, 4-NQO/Untr., and 4-NQO/EtOH treatment groups compared to the V.C./Untr. group. We detected changes in histone epigenetic marks near regulatory regions of genes involved in ethanol metabolism by chromatin immunoprecipitation. For instance, the Aldh2 promoter showed increased H3K27me3 marks, and Aldh2 mRNA levels were reduced by 10-fold in 4NQO/EtOH versus V.C./Untr. tongue samples. 4-NQO/EtOH treatment also caused increases in markers of oxidative stress, including 4-HNE, MCT4/SLC16a3, and TOM20, as measured by immunohistochemistry.We delineate a mechanism by which 4-NQO and ethanol can regulate gene expression during the development of HNSCC and suggest that histone epigenetic marks and oxidative stress markers could be the novel biomarkers and targets for the prevention of HNSCC.

SUBMITTER: Urvalek AM

PROVIDER: S-EPMC4597780 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

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Publications

Identification of Ethanol and 4-Nitroquinoline-1-Oxide Induced Epigenetic and Oxidative Stress Markers During Oral Cavity Carcinogenesis.

Urvalek Alison M AM Osei-Sarfo Kwame K Tang Xiao-Han XH Zhang Tuo T Scognamiglio Theresa T Gudas Lorraine J LJ

Alcoholism, clinical and experimental research 20150801 8

<h4>Background</h4>Head and neck squamous cell carcinoma (HNSCC) is a cancer that is characterized by its high morbidity and mortality rates. While tobacco use and alcohol consumption are 2 major contributing factors for HNSCC carcinogenesis, how the combination of tobacco and alcohol increases HNSCC risk is not understood.<h4>Methods</h4>We combined the 4-nitroquinoline-1-oxide (4-NQO) oral carcinogenesis and Meadows-Cook alcohol mouse models to elucidate the molecular events and to identify th ...[more]

PMID: 26207766

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Project description:BACKGROUND:Oral squamous cell carcinoma (OSCC) is the sixth largest group of malignancies globally and the single largest group of malignancies in the Indian subcontinent. Despite the advances in treatment and therapeutic modalities the five year survival rate of OSCC has not changed in the last few decades, and remains less than 40%. Several studies have focused on defining molecular markers that can either detect cancer at an early stage or can predict patient's outcome. However, such markers are still undefined. Keratins (K) are epithelia predominant intermediate filament proteins which are expressed in a differentiation dependent and site specific manner. Keratins are being used as biomarkers in different epithelial disorders including cancer. They are associated with desmoplakin and ?6?4 integrin which are components of desmosomes and hemidesmosomes respectively. MATERIALS AND METHODS:4-Nitroquinoline 1-Oxide (4NQO) was used as a carcinogen for the development of various stages of oral carcinogenesis in rat lingual mucosa. Two-Dimentional gel electrophoresis was performed for the separation of Keratins followed by western blotting for their specific identification. Western blotting and RT PCR was carried out for desmoplakin and ?6?4 integrin respectively to understand their levels. Immunohistochemical analysis was carried out to further study the localization of desmoplakin and ?6 integrin. RESULTS:In this study we have analysed the alterations in Keratins and associated proteins during sequential stages of 4NQO induced rat oral carcinogenesis. Our results showed that the alterations primarily begin after the dysplastic changes in the lingual epithelium like the elevation of Keratins 5/6a, ectopic expression of Keratin 8, increase in suprabasal expression of ?6 integrin and increase in desmoplakin levels. Most of these alterations persisted till the development of SCC except desmoplakin, the levels of which were downregulated in papillomatous lesions and SCC. Many of these alterations have also been documented in human oral carcinogensis. CONCLUSION:Thus, 4NQO model of rat lingual carcinogenesis reproduces majority of the changes that are seen in human oral carcinogenesis and it can be exploited for the development of biomarkers.

Dataset Information

Identification of Ethanol and 4-Nitroquinoline-1-Oxide Induced Epigenetic and Oxidative Stress Markers During Oral Cavity Carcinogenesis.

Publications

Identification of Ethanol and 4-Nitroquinoline-1-Oxide Induced Epigenetic and Oxidative Stress Markers During Oral Cavity Carcinogenesis.

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