Hinokitiol ablates myofibroblast activation in precancerous oral submucous fibrosis by targeting Snail

Yang, Hui‐Wen; Lu, Michael S.-C.; Chiu, Yu‐Wei; Liao, Yi-Wen; Huang, Yu‐Feng; Chueh, Pin Ju; Hsieh, Pei‐Ling; Yu, Cheng–Chia

doi:10.1002/tox.22531

Cited by 21 publications

(26 citation statements)

References 35 publications

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“…In the last experiment ( Figure 6 C,D), we demonstrated that the knockdown of IL-6 hindered the myofibroblast activities in Snail-overexpressing cells. In addition to the direct binding of Snail to α-SMA [ 24 ], these results indicated that sufficient IL-6 was also required for Snail to induce myofibroblast activities. Along with the findings of Snail-regulated myofibroblast phenotypes, we showed that IL-6 may exert its fibrosis ability and elicit myofibroblast transdifferentiation via the modulation of numerous fibrosis factors and Snail in oral fibroblasts.…”

Section: Discussionmentioning

confidence: 99%

“…It has been shown that Snail is sufficient to repress epithelial genes like E-cadherin by binding to E-box sequences through the zinc-finger domains [ 21 ]. As a matter of fact, the elevated expression of Snail has been found in various types of fibrosis [ 22 , 23 ] and our previous study revealed that Snail was able to bind to the E-box in the α-SMA promoter in buccal mucosal fibroblasts (BMFs) [ 24 ]. Moreover, it has been shown that arecoline increased Snail expression in human oral keratinocytes and the overexpression of Snail was proven to be associated with the clinico-pathologic features of OSCCs [ 25 ].…”

Section: Introductionmentioning

confidence: 99%

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

Peng

Liao

et al. 2020

Cancers

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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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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Peng

Liao

et al. 2020

Cancers

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“…Apart from these results, we demonstrated how butylidenephthalide interfered the arecoline‐induced activation of myofibroblasts. Our previous studies have shown that arecoline upregulated the expression of α‐SMA in BMFs via an increase in the binding of Snail to the α‐SMA promoter . Figure A illustrated the E‐box region in the promoter region of α‐SMA ([sbox]CAAATG[sbox], −498 to −493), and arecoline‐induced binding of Snail in α‐SMA promoter was significantly suppressed by butylidenephthalide treatment using chromatin immunoprecipitation (Figure B).…”

Section: Resultsmentioning

confidence: 99%

“…Given that our recent work has shown that Snail could bind to the E‐box region in the α‐SMA promoter, we examined whether butylidenephthalide impeded the direct binding of Snail on α‐SMA. In agreement with our hypothesis, butylidenephthalide inhibited the direct binding of Snail and ameliorated the activation of myofibroblasts.…”

Section: Discussionmentioning

confidence: 99%

“…Cells were fixed with 1% formaldehyde and lysed with mammalian cell lysis buffer (Pierce, Thermo Fisher Scientific) followed by micrococcal nuclease (Fermentas, Thermo Fisher Scientific) treatment. The fragmented DNA solution was diluted with ChIP dilution buffer and precleared by Protein A Mag Sepharose (GE Healthcare). Anti‐Snail antibody or normal mouse IgG was added to the lysate and incubated overnight.…”

Section: Methodsmentioning

confidence: 99%

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Butylidenephthalide abrogates the myofibroblasts activation and mesenchymal transdifferentiation in oral submucous fibrosis

Liao

Hsieh

et al. 2018

Environmental Toxicology

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Oral submucous fibrosis (OSF) is a premalignant disorder in the oral cavity, and areca nut chewing habit has been implicated in the persistent activation of myofibroblasts and the subsequent fibrosis. Therefore, it is critical to ameliorate the excessive activities of myofibroblasts prior to the malignant transformation of OSF. In the current study, we evaluated the cytotoxicity of butylidenephthalide (BP), a major phthalide ingredient of Angelica sinensis, in fibrotic buccal mucosal fibroblasts (fBMFs) as well as various myofibroblast hallmarks, including the phenotypical characteristics and fibrosis-related markers. Our results demonstrated that myofibroblast activities, including collagen gel contraction, migration, invasion and wound healing abilities were inhibited in response to BP. The expression levels of myofibroblast marker, α-smooth muscle actin (α-SMA), fibronectin and type 1 collagen A1 were decreased after exposure of BP. Moreover, we found that the EMT-related markers, Twist, Snail and ZEB1 were all downregulated after BP treatment. Most importantly, our findings demonstrated that BP impeded the binding of Snail to the E-box region in the α-SMA promoter, which may lead to inhibition of the arecoline-induced myofibroblast activities. Collectively, our data indicated that BP reduced numerous myofibroblast features in fBMFs and hindered the binding of Snail to α-SMA, thereby may function as an effective and natural antifibrosis compound.

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Slug mediates myofibroblastic differentiation to promote fibrogenesis in buccal mucosa

Fang

Hsia

Hsieh

et al. 2018

Journal Cellular Physiology

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Epithelial-mesenchymal transition (EMT) has been implicated in fibrogenesis and carcinogenesis; however, the exact role of EMT-inducer Slug in the progression of precancerous oral submucous fibrosis (OSF) has not been investigated. In the current study, we showed that the expression of Slug was upregulated in OSF tissues and associated with various myofibroblast markers. After silence of Slug in fibrotic buccal mucosal fibroblasts (fBMFs), the elevated myofibroblast activities and fibrosis markers were all downregulated. Our data revealed that arecoline, an areca nut alkaloid, increased the expression of Slug in normal BMFs, and inhibition of Slug successfully prevented the arecoline-induced myofibroblast activation. Additionally, overexpression of Slug in BMFs stimulated the activities of myofibroblasts, indicating that upregulation of Slug by arecoline contributes to the myofibroblast transdifferentiation. Most importantly, Slug was able to bind to the E-box of type I collagen, leading to increased expression of type I collagen. Altogether, this study demonstrated the abnormal elevation of Slug in OSF and its significance in arecoline-induced fibrogenesis. Moreover, downregulation of Slug could be a potential target for OSF remedy via suppression of myofibroblast activities and type I collagen.

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Hinokitiol ablates myofibroblast activation in precancerous oral submucous fibrosis by targeting Snail

Cited by 21 publications

References 35 publications

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

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

Butylidenephthalide abrogates the myofibroblasts activation and mesenchymal transdifferentiation in oral submucous fibrosis

Slug mediates myofibroblastic differentiation to promote fibrogenesis in buccal mucosa

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