Abstract
Constituents of tobacco that can cause DNA adduct formation and oxidative stress are implicated in the development of head and neck squamous cell carcinoma (HNSCC). However, there are few studies on the mechanism(s) that underlie tobacco-associated HNSCC. Here, we used a model in which tumors were induced in rats using 4-nitroquinoline 1-oxide (4NQO), which mimicked tobacco-related HNSCC, and analyzed the expression profiles of microRNAs and mRNAs. Our results indicated that 57 miRNAs and 474 mRNA/EST transcripts exhibited differential expression profiles between tumor and normal tongue tissues. In tumor tissue, the expression levels of rno-miR-30 family members (rno-miR-30a, rno-miR-30a-3p, rno-miR-30b-5p, rno-miR-30c, rno-miR-30d, rno-miR-30e and rno-miR-30e-3p) were only 8% to 37% of those in the control group. The GO terms enrichment analysis of the differentially expressed miRNAs indicated that oxidation reduction was the most enriched process. Low expression of miR-30 family members in human HNSCC cell lines and tissues was validated by qPCR. The results revealed that the expression of miR-30b-5p and miR-30e-5p was significantly decreased in the TCGA HNSCC dataset and validation datasets, and this decrease in expression further distinguishes HNSCC associated with tobacco use from other subtypes of HNSCC. CCK8, colony formation, transwell migration and HNSCC xenograft tumor assays indicated that miR-30b-5p or miR-30e-5p inhibited proliferation, migration and invasion in vitro, and miR-30b-5p suppressed tumor growth in vivo. Moreover, we uncovered that KRAS might be the potential target gene of miR-30e-5p or miR-30b-5p. Thus, our data clearly showed that decreased expression of miR-30e-5p or miR-30b-5p may play a crucial role in cancer development, especially that of tobacco-induced HNSCC, and may be a novel candidate biomarker and target for this HNSCC subtype.
Highlights
Head and neck squamous cell carcinoma (HNSCC) is one of the most common malignant tumors worldwide, accounting for approximately 3.8% of all malignant cancers [1, 2]
The expression of the miRNAs miR-30c-5p, miR-30d-5p, and miR-30e-3p was verified to be decreased in tongue SCC tissues, which was in agreement with the results of miRNA microarray analysis (Figure S1B)
We used a rat model of 4-nitroquinoline 1-oxide (4NQO)-induced carcinogenesis to identify miRNAs and their targets that are involved in regulating the onset of head and neck squamous cell carcinoma (HNSCC) caused by tobacco and to initially identify the key miRNAs contributing to gene regulation during this developmental period
Summary
Head and neck squamous cell carcinoma (HNSCC) is one of the most common malignant tumors worldwide, accounting for approximately 3.8% of all malignant cancers [1, 2]. The consumption of tobacco is an established major etiological factor in the development of HNSCC [3]. In the Indian subcontinent, HNSCC is the single most common malignancy, and it is mainly caused by the use of chewing tobacco and related products [4]. Over the past few decades, the HNSCC incidence rate has increased among both males and females in several countries in Eastern and Northern Europe and among females in Southern and Western Europe, which largely reflects the ongoing tobacco epidemic [6, 7]. In many other more developed countries, as tobacco use has decreased, the HNSCC incidence rate has begun to decline in both males and females [7]
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