Abstract
We compared the changes in global gene expression between an early stage (the termination of the carcinogen treatment and prior to the appearance of frank tumors) and a late stage (frank squamous cell carcinoma (SCC)) of tongue carcinogenesis induced by the carcinogen 4-nitroquinoline 1-oxide (4-NQO) in a mouse model of human oral cavity and esophageal squamous cell carcinoma. Gene ontology and pathway analyses show that increases in "cell cycle progression" and "degradation of basement membrane and ECM pathways" are early events during SCC carcinogenesis and that changes in these pathways are even greater in the actual tumors. Myc, NFκB complex (NFKB1/RELA), and FOS transcription networks are the major transcriptional networks induced in early stage tongue carcinogenesis. Decreases in metabolism pathways, such as in "tricarboxylic acid cycle" and "oxidative phosphorylation", occurred only in the squamous cell carcinomas and not in the early stages of carcinogenesis. We detected increases in ALDH1A3, PTGS2, and KRT1 transcripts in both the early and late stages of carcinogenesis. The identification of the transcripts and pathways that change at an early stage of carcinogenesis provides potentially useful information for early diagnosis and for prevention strategies for human tongue squamous cell carcinomas.
Highlights
Oral cavity squamous cell carcinomas (OCSCCs), including tongue cancers, account for approximately one half of all head and neck squamous cell carcinomas (HNSCCs) [1]
We focused on gene regulation in this study, and analysis of transcripts significantly increased in the 4-nitroquinoline 1-oxide (4-NQO)(E) group revealed that several transcription network modules were induced, including the Myc transcription network that is associated with activation of the transcription of Ccnb1, the NFκB complex (NFKB1/RELA) transcription network, www.impactjournals.com/oncotarget www.impactjournals.com/oncotarget the FOS transcription network that is associated with increases in the MMP13 transcript level, and the SIRT1 transcription network that is associated with activation of prostaglandin-endoperoxide synthase 2 (PTGS2) gene transcription (Figure 2A)
Our comparison by RNA-seq of genome wide gene expression profiles between an early stage of oral cavity carcinogenesis and a later stage in which frank squamous cell carcinomas are present shows that the pathways of “cell cycle progression” and “disruption of extracellular matrix (ECM) and basement membrane” are activated at an early stage of tongue carcinogenesis (Figure 1 and Table S2), and that even greater changes in these pathways occur at late stages
Summary
Oral cavity squamous cell carcinomas (OCSCCs), including tongue cancers, account for approximately one half of all head and neck squamous cell carcinomas (HNSCCs) [1]. About 60-70% of oral cavity carcinoma cases are diagnosed only after the tumors have become locally advanced [4]. Because of the high morbidity and mortality of advanced stage OCSCC, it is important to identify biomarkers that could be used in addition to histopathological assessment for predicting malignancy. These biomarkers could be very useful in human populations with a high risk for oral cancer, such as people who smoke and drink heavily
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