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Oral submucous fibrosis (OSF) is potentially premalignant with progressive and irreversible extracellular matrix deposition accompanied by epithelial atrophy and like other fibrotic disorders, is primarily a TGF-β driven disease. OSF is caused by prolonged chewing of areca nut. Our previous studies reported a pivotal role for TGF-β activation and its effects contributing to OSF. However, the mechanism for activation of TGF-β signaling in OSF is still unknown. In this study we demonstrate activation of TGF-β signaling with sub-cytotoxic dose of areca nut in epithelial cells and discovered a key role for pJNK in this process. In good correlation; pJNK was detected in OSF tissues but not in normal tissues. Moreover, activation of JNK was found to be dependent on muscarinic acid receptor induced Ca 2+ /CAMKII as well as ROS. JNK dependent phosphorylation of ATF2/c-Jun transcription factors resulted in TGF-β transcription and its signaling. pATF2/p-c-Jun were enriched on TGF-β promoter and co-localized in nuclei of epithelial cells upon areca nut treatment. In corroboration, OSF tissue sections also had nuclear pATF2 and p-c-Jun. Our results provide comprehensive mechanistic details of TGF-β signaling induced by etiological agent areca nut in the manifestation of fibrosis which can lead to new therapeutic modalities for OSF.

Role of areca nut induced JNK/ATF2/Jun axis in the activation of TGF-β pathway in precancerous Oral Submucous Fibrosis