Human papillomavirus oncogenic E6 protein regulates human β-defensin 3 (hBD3) expression via the tumor suppressor protein p53

Abstract

Human β-defensin-3 (hBD3) is an epithelial cell-derived innate immune regulatory molecule overexpressed in oral dysplastic lesions and fosters a tumor-promoting microenvironment. Expression of hBD3 is induced by the epidermal growth factor receptor signaling pathway. Here we describe a novel pathway through which the high-risk human papillomavirus type-16 (HPV-16) oncoprotein E6 induces hBD3 expression in mucosal keratinocytes. Ablation of E6 by siRNA induces the tumor suppressor p53 and diminishes hBD3 in HPV-16 positive CaSki cervical cancer cells and UM-SCC-104 head and neck cancer cells. Malignant cells in HPV-16-associated oropharyngeal cancer overexpress hBD3. HPV-16 E6 induces hBD3 mRNA expression, peptide production and gene promoter activity in mucosal keratinocytes. Reduction of cellular levels of p53 stimulates hBD3 expression, while activation of p53 by doxorubicin inhibits its expression in primary oral keratinocytes and CaSki cells, suggesting that p53 represses hBD3 expression. A p53 binding site in the hBD3 gene promoter has been identified by using electrophoretic mobility shift assays and chromatin immunoprecipitation (ChIP). In addition, the p63 protein isoform ΔNp63α, but not TAp63, stimulated transactivation of the hBD3 gene and was co-expressed with hBD3 in head and neck cancer specimens. Therefore, high-risk HPV E6 oncoproteins may stimulate hBD3 expression in tumor cells to facilitate tumorigenesis of HPV-associated head and neck cancer.

Human beta-defensin 3 contributes to the carcinogenesis of cervical cancer via activation of NF-κB signaling

“…A recent study showed that hBD3 expression was regulated by the high-risk human papillomavirus E6 protein via p53 in oral squamous cell cancers [21]. This intriguing finding prompts the question whether hBD3 is expressed in another HPV-inducing cancer, cervical cancer and if so, whether hBD3 plays a role in the progression of the disease.…”

Alarmins and immunity

“…However, it has gradually been shown that a number of human cancers of squamous keratinocytes (e.g. cervical, esophageal, salivary gland, head and neck carcinoma, colon, etc) show elevated expression of β‐defensin 2 and/or 3 . Both β‐defensin 2 and 3 promotes tumor cell proliferation and/or invasion .…”

“…[194][195][196][197][198][199] Both β-defensin 2 and 3 promotes tumor cell proliferation and/or invasion. 194,197,198 β-defensin 3 upregulation can be triggered by either epidermal growth factor or human papillomavirus 199 and its promotion of tumor cell proliferation involves the activation of NF-κB. 198 In contrast, human β-defensin 1 has been shown to inhibit the proliferation of several types of cancer cells.…”

Impact of HPV infection on oral squamous cell carcinoma

“…TNM and UICC stages are generally still used to describe the size of the tumour and its invasion into the lymphatic system from a topographic point of view, although recently, these systems were shown to be poor at accurately predicting an outcome [4, 5]. The latter classifications of OSCC are used for outcome prediction and decision-making concerning additional radiotherapy in cases of positive nodal metastasis [6]. Therefore, the need to detect reliable predictive biomarkers, genetic alterations or epigenetic modifications in OSCC to estimate recurrence for therapy stratification and planning is significant, and it is also important to identify significant molecular pathways to precisely select patients who are suitable for additional therapy [7–9].…”