Oral submucous fibrosis (OSF) is considered as a pre-cancerous condition of the oral mucosa and is highly associated with habitual areca quid chewing. Arecoline is the major alkaloid in areca quid and is thought to be involved in the pathogenesis of OSF. Our previous studies have demonstrated that arecoline could induce epithelial–mesenchymal transition (EMT)-related factors in primary human buccal mucosal fibroblasts (BMFs). Therefore, we investigated the expression of zinc finger E-box binding homeobox 1 (ZEB1), which is a well-known transcriptional factor in EMT, in OSF tissues and its role in arecoline-induced myofibroblast transdifferentiation from BMFs. The expression of ZEB1, as well as the myofibroblast marker α-smooth muscle actin (α-SMA), was significantly increased in OSF tissues, respectively. With immunofluorescence analysis, arecoline induced the formation of α-SMA-positive stress fibres in BMFs expressing nuclear ZEB1. Arecoline also induced collagen contraction of BMFs in vitro. By chromatin immunoprecipitation, the binding of ZEB1 to the α-SMA promoter in BMFs was increased by arecoline. The promoter activity of α-SMA in BMFs was also induced by arecoline, while knockdown of ZEB1 abolished arecoline-induced α-SMA promoter activity and collagen contraction of BMFs. Long-term exposure of BMFs to arecoline induced the expression of fibrogenic genes and ZEB1. Silencing of ZEB1 in fibrotic BMFs from an OSF patient also suppressed the expression of α-SMA and myofibroblast activity. Inhibition of insulin-like growth factor receptor-1 could suppress arecoline-induced ZEB1 activation in BMFs. Our data suggest that ZEB1 may participate in the pathogenesis of areca quid–associated OSF by activating the α-SMA promoter and inducing myofibroblast transdifferentiation from BMFs.

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Mountain building and the rock cycle often involve large vertical crustal motions, but their rates and timescales in unmetamorphosed rocks remain poorly understood. We utilize high-resolution magneto-biostratigraphy and backstripping analysis of marine deposits in an active arc-continent suture zone of eastern Taiwan to document short cycles of vertical crustal oscillations. A basal unconformity formed on Miocene volcanic arc crust in an uplifting forebulge starting ~6 Ma, followed by rapid foredeep subsidence at 2.3–3.2 mm yr−1 (~3.4–0.5 Ma) in response to oceanward-migrating flexural wave. Since ~0.8–0.5 Ma, arc crust has undergone extremely rapid (~9.0–14.4 mm yr−1) uplift to form the modern Coastal Range during transpressional strain. The northern sector may have recently entered another phase of subsidence related to a subduction polarity reversal. These transient vertical crustal motions are under-detected by thermochronologic methods, but are likely characteristic of continental growth by arc accretion over geologic timescales.