Expression of integrin alphavbeta6 [alphavbeta6] in oral submucous fibrosis: a potentially malignant condition of oral cavity

ABSTRACT

Oral submucous fibrosis [OSF] is a chronic progressive fibrosing disorder of the oral cavity. A common finding in tissue fibrosis is that stromal fibroblasts become 'activated' myofibroblasts and express a-smooth muscle actin [SMA]. TGF-beta1 is considered to have a central role in inducing this myofibroblastic phenotype, and its expression is increased in numerous fibrotic conditions. The epithelial-specific integrin alphavbeta 6 is not detectable on normal oral keratinocytes but is upregulated during tissue remodelling. alphavbeta 6 is a key activator of TGF-b1 through its interaction with the latency-associated peptide [LAP] of the cytokine. The objective of the study was to investigate the role of alphavbeta 6 integrin in the pathogenesis of OSF. We used immunochemistry to examine expressionn of alphavbeta 6 in 41 cases of OSF compared with 14 cases of fibroepithelial hyperplasia, and found significantly higher expression in OSF [p=0.009]. We carried out a TGF- b1 bioassay using a keratinocyte cell line genetically modified to express high levels of alphavbeta 6 [VB6], and found that inhibition of alphavbeta 6 significantly reduced TGF-b1 activation [p<0.0001]. Co-culture of HFFF2 fibroblasts with VB6 cells induced myofibroblast transdifferentiation, producing a marked increase in SMA expression. This was inhibited using anti- alphavbeta 6 antibodies, confirming that myofbroblast generation was alphavbeta 6-dependent. In conclusion, these data show that alphavbeta 6-dependent TGF-b1 activation promotes myofibroblast transdifferentiation, and may be responsible, in part, for the chronic fibrosis seen in OSF