Abstract
Arecoline, the major alkaloid of areca nut, is known to induce oral carcinogenesis, however, its mechanism is still needed to elucidate. This study investigated the effects of arecoline on cell viability and cell-cycle progression of oral squamous cell carcinoma (OSCC) cells as well as a relevant cellular gene expression. The results showed that a low concentration of arecoline (0.025 μg/ml) increased OSCC cell viability, proportion of cells in G2/M phase and cell proliferation. Simultaneously, it induced IL-6, STAT3 and c-Myc expression. Interestingly, c-myc promoter activity was also induced by arecoline. MiR-22 expression in arecoline-treated OSCC cells was suppressed and comparable to an upregulated c-Myc expression. In arecoline-treated OSCC cells, oncostatin M (OSM) expression was significantly upregulated and inversely correlated with miR-22 expression. Likewise, OSM expression and its post-transcriptional activity were significantly decreased in miR-22-transfected OSCC and 293FT cells. This result demonstrated that miR-22 directly targeted OSM. Interestingly, miR-22 played an important role as a tumor suppresser on suppressing cell proliferation, migration and cell-cycle progression of OSCC cells. This result suggested the effect of arecoline to promote cell proliferation and cell-cycle progression of OSCC cells might be involved in induction of c-Myc expression and reduction of miR-22 resulting in OSM upregulation.
Highlights
Areca nut chewing that is most frequently done in Asia, is a major risk factor for oral squamous cell carcinoma (OSCC) [1]
Arecoline at low concentration increased viability of both ORL-48(T) and ORL136(T) cells (Fig 1C and 1D). These results demonstrated that arecoline at 0.025 μg/ml increased cell viability of OSCC cell lines, this concentration was used in further experiments
This study investigated the effects of various concentrations of arecoline on viability and proliferation of OSCC cells
Summary
Areca nut chewing that is most frequently done in Asia, is a major risk factor for oral squamous cell carcinoma (OSCC) [1]. Arecoline is the main alkaloid in areca nut and is known to have cytotoxic, genotoxic and mutagenic properties, contributing to histologic changes and other biological consequences [2, 3]. It is likely that the effects of arecoline vary depending on cell type, individual idiosyncrasy and dose. Little is known as yet about the various effects of arecoline. Activation of c-Myc is a critical process in cancer development/progression [4]. Various factors can induce c-Myc expression by activation of mitogenic signaling cascades, including IL-6/STAT3 signaling cascade, etc [5]. The few studies about the effect of arecoline on c-Myc induction have been controversial
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