Acquired cholesteatoma epithelial hyperproliferation: Roles of cell proliferation signal pathways

Xie, Shuang; Xiang, Yuyan; Wang, Xiaoli; Ren, Hongmiao; Yin, Tailang; Ren, Jun; Liu, Wei

doi:10.1002/lary.25834

Cited by 30 publications

(25 citation statements)

References 70 publications

(78 reference statements)

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“…Although it is an extra‐label indication, we prescribed oclacitinib to the latter two dogs in an attempt to treat the chronic aural inflammation, which seems to play a fundamental role in multiple aetiopathogenic mechanisms of acquired cholesteatoma . Additionally, it is suggested in humans that the IL‐6/STAT3 signalling pathway is active and may play an important role in the epithelial hyperproliferation of acquired cholesteatoma . During this study, the clinical signs were managed with no relapse in the dogs treated with oclacitinib.…”

Section: Discussionmentioning

confidence: 86%

“…34 Additionally, it is suggested in humans that the IL-6/ STAT3 signalling pathway is active and may play an important role in the epithelial hyperproliferation of acquired cholesteatoma. 35 During this study, the clinical signs were managed with no relapse in the dogs treated with oclacitinib. More study is necessary to elucidate the efficacy and risk of oclacitinib as a component of postprocedural management in canine cholesteatomas.…”

Section: Discussionmentioning

confidence: 89%

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Clinical analysis and nonsurgical management of 11 dogs with aural cholesteatoma

Imai¹,

Kondo

Suganuma³

et al. 2019

Veterinary Dermatology

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Background Aural cholesteatomas, also called tympanokeratomas, are destructive and expansile growths of keratinizing epithelium that develop in the middle ear. They have been reported sporadically in dogs, and surgery is usually the recommended treatment. Objectives To describe the common clinical, radiological and histological findings of cholesteatoma; to report on the outcome of conservative management. Animals Eleven dogs (13 ears) with cholesteatomas. Methods and materials Medical records were reviewed for dogs diagnosed with cholesteatoma between 2012 and 2018. All dogs had computed tomography (CT) and/or magnetic resonance imaging (MRI) followed by trans‐canal endoscopic procedure (TEP) for removal and biopsy of middle ear lesions. Dogs were then treated with in‐clinic flushing initially weekly tapered to monthly, as well as at‐home ear cleaning and application of topical otic steroid medication, initially daily then tapered to once or twice weekly. Results Nine dogs had a history of chronic otitis externa; head tilt or facial paralysis was present in seven and four cases, respectively. Otic examination identified a protruding nodule in seven ears. CT demonstrated soft tissue‐like material in 12 bullae and expansion in seven bullae. MRI revealed minimally contrast‐enhancing bulla contents in 12 ears. Post‐TEP and with maintenance medical treatment, nine ears had no further signs of middle ear disease during a mean follow‐up of 27.9 months. Conclusions and clinical importance The results suggest that otitis externa may not necessarily precede cholesteatoma in all dogs. MRI appears to be more sensitive than CT for identifying cholesteatomas. Conservative treatment of cholesteatomas could be useful before or as an alternative to surgery.

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Section: Discussionmentioning

confidence: 86%

Section: Discussionmentioning

confidence: 89%

Clinical analysis and nonsurgical management of 11 dogs with aural cholesteatoma

Imai¹,

Kondo

Suganuma³

et al. 2019

Veterinary Dermatology

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“…In addition to neoplastic disease, previous studies have demonstrated that miRNA-125b is down-regulated in psoriasis, which is characterised by hyperproliferation of keratinocytes, and that miRNA-125b can regulate the growth of keratinocytes in psoriasis [9][10][11]. Cholesteatoma is mainly composed of keratinocytes and has characteristics of abnormal proliferation [12]. However, reports on miR-125b in cholesteatoma have yet to be published.…”

Section: Introductionmentioning

confidence: 99%

Low expression of microRNA-125b enhances the expression of STAT3 and contributes to cholesteatoma growth

et al. 2019

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Introduction: MicroRNA-125b has been found to be down-regulated in many types of malignant tumours and diseases with excessive proliferation of keratinocytes, such as cutaneous squamous cell carcinoma and psoriasis. Cholesteatoma, which is mainly composed of keratinocytes, also has characteristics of abnormal proliferation similar to a malignant tumour. However, the expression and regulatory mechanisms of miR-125b and its downstream genes in cholesteatoma have not been clarified. Material and methods: Real time fluorescence quantitative PCR was applied to detect the expression of miR-125b in the cholesteatoma and corresponding retroauricular skin. Immunohistochemical staining and western blot were used to detect signal transducers and activators of transcription 3 (STAT3) and the downstream gene cyclinD1, survivin, and vascular endothelial growth factor (VEGF) in the cholesteatoma and corresponding retroauricular skin. The targeted regulatory relationship between miR-125b and STAT3 was confirmed by dual luciferase reporter assay. Proliferation and apoptosis of transfected HaCaT cells were detected by MTS, cell cycle, and apoptosis assays. Results: We observed down-regulation of miR-125b and up-regulation of STAT3, cyclinD1, survivin, and VEGF in cholesteatoma tissues. STAT3 was a direct target gene of miR-125b. Inhibition of miR-125b enhanced STAT3 and its downstream genes expression, promoted HaCaT cell proliferation, and inhibited apoptosis. Conclusions: The results of this study demonstrate that miR-125b can influence the growth of cholesteatoma by targeting STAT3 and its downstream genes, including cyclinD1, survivin, and VEGF, thus providing an opportunity to establish new medical therapy strategies and facilitating further study of the pathogenesis of cholesteatoma.

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“…Middle ear cholesteatoma is a well-circumscribed cystic lesion that occurs when a keratinizing squamous epithelium grows abnormally in the temporal bone 1 . Cholesteatoma keratinocytes exhibit proliferation and migration characteristics akin to a tumor 2 , 3 , and numerous researchers have demonstrated upregulation of tumor-related genes and markers of proliferation in cholesteatoma specimens 4 - 7 . Cholesteatoma-associated otitis media is a common disease in otolaryngology, and the pathogenesis of cholesteatoma is a topic of intense research.…”

Section: Introductionmentioning

confidence: 99%

Downregulation of MiR-203a Disinhibits Bmi1 and Promotes Growth and Proliferation of Keratinocytes in Cholesteatoma

Zang¹,

Hui²,

Yang³

et al. 2018

Int. J. Med. Sci.

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Background: Keratinocytes are the predominant cell type in a cholesteatoma, and microRNA (miR)-203a has been shown to be essential for the growth and differentiation of keratinocytes. The regulatory mechanisms of miR-203a and Bmi1—the predicted target of miR-203a that is associated with cholesteatoma—have not been clarified.Methods: Real-time PCR and western blot were carried out for the detection of miRNAs, mRNAs, and proteins, including miR-203a, Bmi1, and phosphorylated (p-)Akt. Immunohistochemical staining was applied to observe the expression and distribution of Bmi1 and of p-Akt in cholesteatoma and in control retroauricular skin. The dual luciferase reporter assay was used to analyze the relationship between miR-203a and Bmi1. Ectopic miR-203a and Bmi1 were transfected into an immortalized line of human keratinocytes (HaCaT cells), and the roles of these molecules in cell proliferation, apoptosis, and migration were explored.Results: Cholesteatoma tissues were characterized by downregulation of miR-203a and concomitant upregulation of Bmi1. Results of the dual-luciferase reporter assay indicated that Bmi1 was a direct target gene of miR-203a. Silencing of miR-203a increased Bmi1 expression; promoted proliferation, colony formation, and migration of HaCaT cells; and inhibited apoptosis. Moreover, p-Akt was significantly increased in cholesteatoma tissues and was positively correlated with Bmi1. Suppression of Bmi1 reduced p-Akt expression in HaCaT cells; subsequent inhibition of miR-203a reversed this phenomenon.Conclusions: Our results reveal that miR-203a may regulate cholesteatoma growth and proliferation by targeting Bmi1. These findings provide insight for the development of novel nonsurgical options for cholesteatoma.

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Acquired cholesteatoma epithelial hyperproliferation: Roles of cell proliferation signal pathways

Abstract: NA Laryngoscope, 126:1923-1930, 2016.

Cited by 30 publications

References 70 publications

Clinical analysis and nonsurgical management of 11 dogs with aural cholesteatoma

Clinical analysis and nonsurgical management of 11 dogs with aural cholesteatoma

Low expression of microRNA-125b enhances the expression of STAT3 and contributes to cholesteatoma growth

Downregulation of MiR-203a Disinhibits Bmi1 and Promotes Growth and Proliferation of Keratinocytes in Cholesteatoma

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