Role and mechanism of Glut-1 and H+/K+-ATPase expression in pepsin-induced development of vocal cord leukoplakia

Ao, Yin-Jie; Wu, Tingting; Cao, Zijian; Zhou, Shui‐Hong; Bao, Yang‐Yang; Shen, Lianfang

doi:10.1007/s00405-021-07172-y

Cited by 10 publications

(19 citation statements)

References 32 publications

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“…The inhibition of GLUT1 expression has been reported to block glycolysis and improve radiosensitivity, and also inhibit cell proliferation and glucose uptake in case of laryngeal cancer [19-21, 40, 41]. Acidified pepsin can increase GLUT1 protein expression in VFL epithelial cells [7]; our findings further validated this observation. GLUT1 upregulation in VFL epithelial cells promoted glucose uptake, lactate secretion, cell activity, S phase ratio, and migration capability, which could be partially blocked by 2-DG.…”

Section: Discussionsupporting

confidence: 86%

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Pepsin enhances glycolysis to promote malignant transformation of vocal fold leukoplakia epithelial cells with dysplasia

Zhang

Zhou

et al. 2022

Eur Arch Otorhinolaryngol

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Purpose The mechanism underlying malignant transformation of vocal fold leukoplakia (VFL) and the precise role of the expression of pepsin in VFL remain unclear. This study aimed to investigate the effects of acidified pepsin on VFL epithelial cell growth and migration, and also identify pertinent molecular mechanisms. Methods Immunochemistry and Western blotting were performed to measure glucose transporter type 1 (GLUT1), monocarboxylate transporters 4 (MCT4), and Hexokinase-II (HK-II) expressions. Cell viability, cell cycle, apoptosis, and migration were investigated by CCK-8 assay, flow cytometry and Transwell chamber assay, respectively. Glycolysis-related contents were determined using the corresponding kits. Mitochondrial HK-II was photographed under a confocal microscope using Mito-Tracker Red. Results It was found: the expression of pepsin and proportion of pepsin+ cells in VFL increased with the increased dysplasia grade; acidified pepsin enhanced cell growth and migration capabilities of VFL epithelial cells, reduced mitochondrial respiratory chain complex I activity and oxidative phosphorylation, and enhanced aerobic glycolysis and GLUT1 expression in VFL epithelial cells; along with the transfection of GLUT1 overexpression plasmid, 18FFDG uptake, lactate secretion and growth and migration capabilities of VFL epithelial cell were increased; this effect was partially blocked by the glycolysis inhibitor 2-deoxy-glucose; acidified pepsin increased the expression of HK-II and enhanced its distribution in mitochondria of VFL epithelial cells. Conclusion It was concluded that acidified pepsin enhances VFL epithelial cell growth and migration abilities by reducing mitochondrial respiratory complex I activity and promoting metabolic reprogramming from oxidative phosphorylation to aerobic glycolysis.

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Section: Discussionsupporting

confidence: 86%

“…Laryngopharyngeal reflux (LPR) evidently plays a key role in VFL development and malignant transformation [ 7 , 8 ]. LPR contents include gastric acid as well as non-acid components.…”

Section: Introductionmentioning

confidence: 99%

Pepsin enhances glycolysis to promote malignant transformation of vocal fold leukoplakia epithelial cells with dysplasia

Zhang

Zhou

et al. 2022

Eur Arch Otorhinolaryngol

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“…We earlier reported high pepsin levels in vocal cord polyps and patients with vocal cord leukoplakia [5]; the latter expression level increased significantly as the dysplasia grade rose [5]. We also found that high Glut-1 expression may improve the development of vocal cord leukoplakia by upregulating laryngeal H + /K + -ATPase expression to reactivate absorbed pepsin resulting in laryngeal mucosa injury in vitro [6]. There is the same mechanism of pepsin-mediated tissue damage in vivo is unclear.…”

Section: Introductionmentioning

confidence: 76%

“…Esophageal mucosal epithelial injury is caused principally by gastric acid secreted by the proton pump H + /K + -ATPase [3]; pepsin damages the laryngopharyngeal epithelium [4,5]. Pepsin is abnormally expressed in patients with voice disorders, vocal cord polyps, laryngeal stenosis, vocal cord leukoplakia, and malignant lesions [5,6]. We earlier reported high pepsin levels in vocal cord polyps and patients with vocal cord leukoplakia [5]; the latter expression level increased significantly as the dysplasia grade rose [5].…”

Section: Introductionmentioning

confidence: 99%

The role of Glut-1 and H+/K+-ATPase expression in hyperplasia of mice laryngeal epithelium induced by pepsin

Cao

et al. 2022

Eur Arch Otorhinolaryngol

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Purpose To explore the role played by Glut-1 and H+/K+-ATPase in pepsin-induced, mouse laryngeal epithelial proliferation, growth, and development. Methods We established a mouse model of laryngopharyngeal reflux and measured Glut-1 and H+/K+-ATPase expression levels in mouse laryngeal epithelium treated with artificial gastric juice containing pepsin. Results Artificial pepsin-containing gastric juice induced significant hyperplastic changes in mouse laryngeal epithelium compared to control mice at 15, 30, and 45 days. Inhibition of Glut-1 expression by 2-DG significantly suppressed such hyperplasia compared to mice exposed to artificial gastric juice containing pepsin at 15, 30, and 45 days. After treatment with pepsin-containing artificial gastric juice, RT-PCR and Western blotting showed that the levels of Glut-1 and H+/K+-ATPase α, β increased significantly. Conclusions Pepsin-containing artificial gastric juice promoted mouse laryngeal epithelial hyperplasia associated with abnormal expression of Glut-1 and H+/K+-ATPase α, β.

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“…The underlying etiologies for the development of leukoplakia patches or plaques are long-term smoking and alcohol abuse, inhaled irritant substances, and viral infections such as HPV [ 12 ]. Other possible etiological factors are occupational hazards, nutritional deficiencies, vocal misuse/abuse, chronic infections, hormonal disorders, and laryngopharyngeal reflux disease [ 8 , 13 , 14 ].…”

Section: Introductionmentioning

confidence: 99%

Videolaryngoendoscopic and Stroboscopic Evaluation in Predicting the Malignancy Risk of Vocal Fold Leukoplakia

Leduchowska

Morawska

Pietruszewska

2022

JCM

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Background: Vocal fold leukoplakia (VFL), despite our knowledge of its etiopathogenetic factors, and the development of laryngeal visualization, remains a diagnostic and therapeutic challenge. Objective: This research aimed to explore the efficacy of clinical and morphological feature identification in videolaryngoendoscopy (VLE) using a three-tier classification, and videolaryngostroboscopy (VLS) in predicting the risk of VFL malignant transformation. Material and Methods: We examined 98 patients with VFL by flexible endoscopy under VLE and VLS. Morphological characteristics of 123 lesions including the surface, margin, and texture were assessed; then, VFL was subdivided into three types: I—flat and smooth, II—elevated and smooth, and III—rough. Based on the histopathological findings, 76 (61.79%) lesions were classified as low- and 47 (38.21%) lesions as high-grade dysplasia. Results: The inter-rater agreement between two raters evaluating the VFL in VLE was almost perfect (Cohen’s kappa = 0.826; p < 0.00; 95% CI 0.748–0.904). In ROC curve analysis, the AUC difference between Rater I and Rater II was 0.024 (0.726 vs. 0.702). In multivariate analysis, high-risk VFL was positively related to unilateral plaque localization (p = 0.003), the type III VLE classification (p = 0.013), absence of a mucosal wave (p = 0.034), and a positive history of alcohol consumption (p = 0.047). In ROC analysis, VLE had an AUC of 0.726, with a high sensitivity of 95.7% and low specificity of 40.8%. The NPV was high, at 93.9%; however, the PPV was low, at 50%. The proposed logistic regression model including features significant in multivariate analysis showed lower sensitivity (80.9% vs. 95.7%) and lower NPV (86.2% vs. 93.9%); however, the specificity and PPV were improved (73.7% vs. 40.8% and 65.5% vs. 50.0%, respectively). Conclusions: The combination of clinical history with endoscopic (plaque morphology) and stroboscopic examination (mucosal wave assessment) can fairly estimate the degree of dysplasia in VFL and thus is recommended for use in clinical settings. The findings of this study can be used to guide the decision regarding immediate biopsy or watchful waiting.

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Role and mechanism of Glut-1 and H+/K+-ATPase expression in pepsin-induced development of vocal cord leukoplakia

Cited by 10 publications

References 32 publications

Pepsin enhances glycolysis to promote malignant transformation of vocal fold leukoplakia epithelial cells with dysplasia

Pepsin enhances glycolysis to promote malignant transformation of vocal fold leukoplakia epithelial cells with dysplasia

The role of Glut-1 and H+/K+-ATPase expression in hyperplasia of mice laryngeal epithelium induced by pepsin

Videolaryngoendoscopic and Stroboscopic Evaluation in Predicting the Malignancy Risk of Vocal Fold Leukoplakia

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