Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bangalore- 560012, India.
Department of Oral and Maxillofacial Surgery D.A Pandu Memorial- R.V Dental College and Hospital, Bangalore-560078, India.
Sci Rep. 2016 Oct 6;6:34314. doi: 10.1038/srep34314.
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/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.
口腔黏膜下纤维性变（OSF）具有潜在的癌前性，伴随着进行性和不可逆转的细胞外基质沉积，同时伴有上皮萎缩。与其他纤维性疾病一样，OSF 主要是由 TGF-β 驱动的疾病。OSF 是由长期咀嚼槟榔引起的。我们之前的研究报告称，TGF-β 的激活及其对 OSF 的影响起着关键作用。然而，OSF 中 TGF-β 信号激活的机制尚不清楚。在这项研究中，我们在口腔上皮细胞中证实了槟榔的亚细胞毒性剂量对 TGF-β 信号的激活，并发现了 pJNK 在这个过程中的关键作用。与预期结果一致，pJNK 在 OSF 组织中检测到，但在正常组织中未检测到。此外，JNK 的激活被发现依赖于毒蕈碱型乙酰胆碱受体诱导的 Ca/CAMKII 以及 ROS。JNK 依赖性的 ATF2/c-Jun 转录因子磷酸化导致 TGF-β 的转录及其信号转导。pATF2/p-c-Jun 被募集到 TGF-β 启动子上，并在上皮细胞受到槟榔处理时共定位于细胞核内。作为佐证，OSF 组织切片也有核内的 pATF2 和 p-c-Jun。我们的研究结果为槟榔这一致病因子诱导的 TGF-β 信号转导在纤维化表现中的机制提供了全面的细节，这可能为 OSF 带来新的治疗方法。
