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

ABSTRACT: 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-? driven disease. OSF is caused by prolonged chewing of areca nut. Our previous studies reported a pivotal role for TGF-? activation and its effects contributing to OSF. However, the mechanism for activation of TGF-? signaling in OSF is still unknown. In this study we demonstrate activation of TGF-? 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 Ca2+/CAMKII as well as ROS. JNK dependent phosphorylation of ATF2/c-Jun transcription factors resulted in TGF-? transcription and its signaling. pATF2/p-c-Jun were enriched on TGF-? 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-? signaling induced by etiological agent areca nut in the manifestation of fibrosis which can lead to new therapeutic modalities for OSF.

SUBMITTER: Pant I 

PROVIDER: S-EPMC5052620 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature