Abstract
Human β-defensin 2 (hBD-2) is a potent antimicrobial peptide that participates in defense against invading bacteria. We recently showed that bacterial components and histamine, through histamine H4 receptor (H4R), are involved in the pathogenesis of the potentially malignant lesion, oral lichen planus (OLP). However, the underlying mechanisms remain unknown. We, therefore, investigated the role of hBD2–histamine crosstalk signaling in promoting OLP pathology. Biopsies from OLP and oral tongue squamous cell carcinoma (OTSCC) patients, and healthy controls were used. Two OTSCC cell lines and normal human oral keratinocytes (HOKs) were used. HBD-2 and other targets were mapped by immunostaining and analyzed by ImageJ2 software. The highly sensitive droplet-digital PCR technology and qRT-PCR were utilized to study the clinically derived and in vitro samples, respectively. H4R was challenged with the specific agonist HST-10 and inverse agonist ST-1007. HBD-2 was highly induced in OLP lesions. In contrast, hBD2 expression was attenuated in OTSCC tissues, while very low levels of hBD-2 messenger RNA (mRNA) were observed in OTSCC cells. Together with tumor necrosis factor-α (TNF-α), histamine upregulated hBD-2 mRNA expression in HOKs. Activation of H4R seems to modulate the expression of epithelial hBD-2. These findings suggest the involvement of hBD-2 in the pathogenesis of OLP and may, thus, be harnessed for therapeutic interventions in OLP.
Highlights
Human β-defensin 2 is a potent antimicrobial peptide produced by epithelial cells, which has a key role in mounting innate immune response against bacteria and other microbial infections [1,2]
Further analysis was performed on oral lichen planus (OLP) specimens, which revealed an induced immunoreactivity of hBD-2 in the subepithelial inflammatory infiltrates (Figure 1C)
The highly sensitive droplet-digitalPCR was utilized to quantify hBD-2 messenger RNA level in clinical samples from OLP patients (n = 14) and normal controls (n = 14). Both normal and OLP tissues expressed hBD-2 mRNA; hBD-2 was more strongly induced in OLP specimens compared to controls, with an average of ~8000 copies/μL of patient sample (p = 0.01; Figure 2A)
Summary
Human β-defensin 2 (hBD-2) is a potent antimicrobial peptide produced by epithelial cells, which has a key role in mounting innate immune response against bacteria and other microbial infections [1,2]. In spite of its role in combating pathogens, altered regulation of hBD-2 is associated with various disorders including cancer [3]. Oral cancer is one of the most common cancers in the world, affecting, inter alia, the oral mucosa and tongue [4]. Oral tongue squamous cell carcinoma (OTSCC) accounts for more than 50% of all malignant tumors in the oral cavity [5]. Inflammatory processes can facilitate cancer development by enhancing immune cell infiltration and stromal remodeling [12]. Oral potentially malignant disorders (OPMDs), including some chronic inflammatory lesions such as oral lichen planus (OLP), predispose patients to develop OTSCC [13,14,15]. A better understanding of the molecular mechanisms involved in such tumorigenic process will pave the way for developing novel and more effective drugs for OTSCC
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