{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T05:36:13Z","timestamp":1778132173832,"version":"3.51.4"},"reference-count":51,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2010,10,25]],"date-time":"2010-10-25T00:00:00Z","timestamp":1287964800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["pathsocjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Pathology"],"published-print":{"date-parts":[[2011,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Oral submucous fibrosis (OSF) is a premalignant, fibrosing disorder of the mouth, pharynx, and oesophagus, with a malignant transformation rate of 7\u201313%. OSF is strongly associated with areca (betel) nut chewing and worldwide, over 5 million people are affected. As \u03b1v\u03b26 integrin is capable of promoting both tissue fibrosis and carcinoma invasion, we examined its expression in fibroepithelial hyperplasia and OSF. \u03b1v\u03b26 was markedly up\u2010regulated in OSF, with high expression detected in 22 of 41 cases (<jats:italic>p<\/jats:italic> &lt; 0.001). We investigated the functional role of \u03b1v\u03b26 using oral keratinocyte\u2010derived cells genetically modified to express high \u03b1v\u03b26 (VB6), and also NTERT\u2010immortalized oral keratinocytes, which express low \u03b1v\u03b26 (OKF6\/TERT\u20101). VB6 cells showed significant \u03b1v\u03b26\u2010dependent activation of TGF\u2010\u03b21, which induced transdifferentiation of oral fibroblasts into myofibroblasts and resulted in up\u2010regulation of genes associated with tissue fibrosis. These experimental <jats:italic>in vitro<\/jats:italic> findings were confirmed using human clinical samples, where we showed that the stroma of OSF contained myofibroblasts and that TGF\u2010\u03b21\u2010dependent Smad signalling was detectable both in keratinocytes and in myofibroblasts. We also found that arecoline, the major alkaloid of areca nuts, up\u2010regulated keratinocyte \u03b1v\u03b26 expression. This was modulated through the M<jats:sub>4<\/jats:sub> muscarinic acetylcholine receptor and was suppressed by the M<jats:sub>4<\/jats:sub> antagonist, tropicamide. Arecoline\u2010dependent \u03b1v\u03b26 up\u2010regulation promoted keratinocyte migration and induced invasion, raising the possibility that this mechanism may support malignant transformation. Over 80% of OSF\u2010related oral cancers examined had moderate\/high \u03b1v\u03b26 expression. These data suggest that the pathogenesis of OSF may be epithelial\u2010driven and involve arecoline\u2010dependent up\u2010regulation of \u03b1v\u03b26 integrin. Copyright \u00a9 2010 Pathological Society of Great Britain and Ireland. Published by John Wiley &amp; Sons, Ltd.<\/jats:p>","DOI":"10.1002\/path.2786","type":"journal-article","created":{"date-parts":[[2010,9,27]],"date-time":"2010-09-27T04:01:23Z","timestamp":1285560083000},"page":"366-377","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":99,"title":["Betel\u2010derived alkaloid up\u2010regulates keratinocyte alphavbeta6 integrin expression and promotes oral submucous fibrosis"],"prefix":"10.1002","volume":"223","author":[{"given":"Karwan 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