Positive Feedback Loop of SNAIL-IL-6 Mediates Myofibroblastic Differentiation Activity in Precancerous Oral Submucous Fibrosis

Oral submucosal fibrosis (OSF) is a premalignant disorder of the oral cavity, and areca nut chewing is known to be a major etiological factor that could induce epithelial to mesenchymal transition (EMT) and activate buccal mucosal fibroblasts (BMFs). However, this detailed mechanism is not fully understood. In this study, we showed that the upregulation of Snail in OSF samples and fibrotic BMFs (fBMFs) may result from constant irritation by arecoline, a major alkaloid of the areca nut. The elevation of Snail triggered myofibroblast transdifferentiation and was crucial to the persistent activation of fBMFs. Meanwhile, Snail increased the expression of numerous fibrosis factors (e.g., α-SMA and collagen I) as well as IL-6. Results from bioinformatics software and a luciferase-based reporter assay revealed that IL-6 was a direct target of Snail. Moreover, IL-6 in BMFs was found to further increase the expression of Snail and mediate Snail-induced myofibroblast activation. These findings suggested that there was a positive loop between Snail and IL-6 to regulate the areca nut-associated myofibroblast transdifferentiation, which implied that the blockage of Snail may serve as a favorable therapeutic strategy for OSF treatment.

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LINC00084/miR-204/ZEB1 Axis Mediates Myofibroblastic Differentiation Activity in Fibrotic Buccal Mucosa Fibroblasts: Therapeutic Target for Oral Submucous Fibrosis

Journal of Personalized Medicine ◽

10.3390/jpm11080707 ◽

2021 ◽

Vol 11 (8) ◽

pp. 707

Author(s):

Yu-Hsien Lee ◽

Yi-Wen Liao ◽

Ming-Yi Lu ◽

Pei-Ling Hsieh ◽

Cheng-Chia Yu

Keyword(s):

Epithelial To Mesenchymal Transition ◽

Oral Submucous Fibrosis ◽

Collagen Gel ◽

Luciferase Reporter ◽

Areca Nut ◽

Mesenchymal Transition ◽

Collagen Gel Contraction ◽

Non Coding Rna ◽

Submucous Fibrosis ◽

Long Non Coding Rna

Oral submucosal fibrosis (OSF) is a precancerous condition in the oral cavity and areca nut consumption has been regarded as one of the etiologic factors implicated in the development of OSF via persistent activation of buccal mucosal fibroblasts (BMFs). It has been previously reported that an epithelial to mesenchymal transition (EMT) factor, ZEB1, mediated the areca nut-associated myofibroblast transdifferentiation. In the current study, we aimed to elucidate how areca nut affected non-coding RNAs and the subsequent myofibroblast activation via ZEB1. We found that long non-coding RNA LINC00084 was elicited in the BMFs treated with arecoline, a major alkaloid of areca nut, and silencing LINC00084 prevented the arecoline-induced activities (such as collagen gel contraction, migration, and wound healing capacities). The upregulation of LINC00084 was also observed in the OSF tissues and fibrotic BMFs (fBMFs), and positively correlated with several fibrosis factors. Moreover, we showed knockdown of LINC00084 markedly suppressed the myofibroblast features in fBMFs, including myofibroblast phenotypes and marker expression. The results from the luciferase reporter assay confirmed that LINC00084 acted as a sponge of miR-204 and miR-204 inhibited ZEB1 by directly interacting with it. Altogether, these findings suggested that the constant irritation of arecoline may result in upregulation of LINC00084 in BMFs, which increased the ZEB1 expression by sequestering miR-204 to induce myofibroblast transdifferentiation.

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Egr-1 mediates low dose Arecoline induced human oral mucosa fibroblasts proliferation by transaction the expression of Wnt5a

10.21203/rs.3.rs-33342/v1 ◽

2020 ◽

Author(s):

Qiang Chen ◽

Jiuyang Jiao ◽

Youyuan Wang ◽

Zhihui Mai ◽

Jing Ren ◽

...

Keyword(s):

Oral Mucosa ◽

Collagen Synthesis ◽

Low Dose ◽

Oral Submucous Fibrosis ◽

High Dose ◽

Areca Nut ◽

Therapeutic Drugs ◽

Submucous Fibrosis ◽

Oral Submucosal Fibrosis ◽

Submucosal Fibrosis

Abstract Background Arecoline is the main carcinogens in Areca nut that induce oral submucous fibrosis to develop into cancer. However, many previous studies have showed that Arecoline may inhibit proliferation and prevent collagen synthesis of fibroblasts. Results High dose Arecoline (> 32 µg/ml) could inhibit but low dose Arecoline (< 16 µg/ml) could promote the proliferation of human oral fibroblasts. Wnt5a was both sufficient and necessary for the promotion of fibrobasts proliferation. Egr-1, but not NF-κB, FOXO1, Smad2 or Smad3, mediated the expression of Wnt5a in fibrobasts. The specific siRNAs of Egr-1, Egr inhibitors or Wnt5a antibodies treatment blocked Arecoline induced Wnt5a upregulation and fibroblasts proliferation. Conclusions Egr-1 mediates low dose Arecoline induced human oral mucosa fibroblasts proliferation by transaction the expression of Wnt5a, and Egr inhibitors or Wnt5a antibodies are potential therapeutic drugs of oral submucosal fibrosis and oral cancer.

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Prevalence of Oral Sub Mucosal Fibrosis in Pre- Anesthesia Clinic in India: A Cross Sectional Observational Study

Journal of Pharmaceutical Research International ◽

10.9734/jpri/2021/v33i38a32077 ◽

2021 ◽

pp. 218-222

Author(s):

Sweety Agrawal ◽

Pratibha Deshmukh ◽

Shweta Takalkar ◽

Parag Sabale ◽

Vivek Chakole

Keyword(s):

Observational Study ◽

Airway Management ◽

Oral Submucous Fibrosis ◽

Mouth Opening ◽

Clinical Feature ◽

Cross Sectional ◽

Submucous Fibrosis ◽

Stage 1 ◽

Oral Submucosal Fibrosis ◽

Submucosal Fibrosis

Introduction: Oral submucous fibrosis (OSMF) is a premalignant lesion of the buccal mucosa usually caused by chewing of betel nut, areca nut and tobacco. OSMF causes difficulty in laryngoscopy and intubation of the trachea. Patient of submucosal fibrosis do come for emergency and elective surgeries requiring general anaesthesia. In such scenario maintaining airway is a big challenge for anaesthesiologist. Knowledge of Prevalence of submucosal fibrosis in local region and degree of OSMF with difficult intubation may help anaesthesiologist to prepare and plan airway management in such conditions. Aims and Objectives: To evaluate the prevalence of oral submucous fibrosis in patients coming in pre-anaesthesia clinic and assessment of airway and prevalence of degree of OSMF by measuring Interincisal mouth opening in patients of oral submucosal fibrosis. Methods: Cross-sectional observational study was conducted in the department of anaesthesiology on 500 patients coming in pre-anaesthesia clinic. Patients were identified and sent to dental department for confirmation of diagnosis OSMF if one or more clinical feature of OSMF were present. A detailed proforma was used to record demographic parameter, the type of tobacco, betelnut and areccanut chewing habits, difficulty in mouth opening, inter incisor distance. OSMF was divided in 4 stages on the basis of inter incisor distance. Results: Prevalence rate of submucosal fibrosis patients coming in our pre-anaesthesia clinic was 8%. Thirty patients were found to be in stage 1 (75%.), nine patients were found to be in stage 2 (22.5%) and only one patient was in stage 3. Conclusion: Being aware of the prevalence of OSMF in the region and stages of OSMF in regard to inter incisor distance in pre-operative clinic helps anaesthesiologists to prepare and plan airway management. And hence surgical exploration can be avoided.

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Egr-1 mediates low-dose arecoline induced human oral mucosa fibroblast proliferation via transactivation of Wnt5a expression

BMC Molecular and Cell Biology ◽

10.1186/s12860-020-00325-7 ◽

2020 ◽

Vol 21 (1) ◽

Author(s):

Qiang Chen ◽

Jiuyang Jiao ◽

Youyuan Wang ◽

Zhihui Mai ◽

Jing Ren ◽

...

Keyword(s):

Oral Mucosa ◽

Low Dose ◽

Oral Submucous Fibrosis ◽

Subsequent Development ◽

Fibroblast Proliferation ◽

Antibody Treatment ◽

Submucous Fibrosis ◽

High Doses ◽

Oral Submucosal Fibrosis ◽

Submucosal Fibrosis

Abstract Background Arecoline is an alkaloid natural product found in the areca nut that can induce oral submucous fibrosis and subsequent development of cancer. However, numerous studies have shown that arecoline may inhibit fibroblast proliferation and prevent collagen synthesis. Results High doses of arecoline (> 32 μg/ml) could inhibit human oral fibroblast proliferation, while low doses of arecoline (< 16 μg/ml) could promote the proliferation of human oral fibroblasts. Wnt5a was found to be both sufficient and necessary for the promotion of fibroblast proliferation. Egr-1 could mediate the expression of Wnt5a in fibroblasts, while NF-κB, FOXO1, Smad2, and Smad3 did not. Treatment with siRNAs specific to Egr-1, Egr inhibitors, or Wnt5a antibody treatment could all inhibit arecoline-induced Wnt5a upregulation and fibroblast proliferation. Conclusions Egr-1 mediates the effect of low dose arecoline treatment on human oral mucosa fibroblast proliferation by transactivating the expression of Wnt5a. Therefore, Egr inhibitors and Wnt5a antibodies are potential therapies for treatment of oral submucosal fibrosis and oral cancer.

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Molecular Pathogenesis of Oral Submucous Fibrosis: A Critical Appraisal

Biomedical & Pharmacology Journal ◽

10.13005/bpj/1835 ◽

2019 ◽

Vol 12 (04) ◽

pp. 2027-2036 ◽

Cited By ~ 2

Author(s):

Arpita Rai ◽

Musarrat Siddiqui ◽

Shama Parveen ◽

Saba Parveen ◽

Abdur Rasheed ◽

...

Keyword(s):

Critical Appraisal ◽

Epithelial Mesenchymal Transition ◽

Oral Submucous Fibrosis ◽

Molecular Pathogenesis ◽

Areca Nut ◽

Mesenchymal Transition ◽

Potentially Malignant ◽

Submucous Fibrosis ◽

Malignant Condition

Oral submucous fibrosis (OSMF) is a chronic, potentially malignant condition of the oral mucosa and the habitual chewing of areca nut is believed to be the most potent etiological factor. The role of reactive oxygen species (ROS), epithelial-mesenchymal transition (EMT) and various cytokines and growth factors has been established in recent studies. The components of areca nut particularly, arecoline, flavonoids and copper have been found to affect fibroblasts, endothelial and epithelial cells through various biological pathways which are either down-regulated or up-regulated during different stages of the disease. However, the underlying molecular pathogenesis of OSMF is still partially understood.

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