Abstract
Human beta-defensins (hBDs, −1, 2, 3) are a family of epithelial cell derived antimicrobial peptides (AMPs) that protect mucosal membranes from microbial challenges. In addition to their antimicrobial activities, they possess other functions; e.g., cell activation, proliferation, regulation of cytokine/chemokine production, migration, differentiation, angiogenesis, and wound healing processes. It has also become apparent that defensin levels change with the development of neoplasia. However, inconsistent observations published by various laboratories make it difficult to reach a consensus as to the direction of the dysregulation and role the hBDs may play in various cancers. This is particularly evident in studies focusing on oral squamous cell carcinoma (OSCC). By segregating each hBD by cancer type, interrogating methodologies, and scrutinizing the subject cohorts used in the studies, we have endeavored to identify the “take home message” for each one of the three hBDs. We discovered that (1) consensus-driven findings indicate that hBD-1 and−2 are down- while hBD-3 is up-regulated in OSCC; (2) hBD dysregulation is cancer-type specific; (3) the inhibition/activation effect an hBD has on cancer cell lines is related to the direction of the hBD dysregulation (up or down) in the cancer from which the cell lines derive. Therefore, studies addressing hBD dysregulation in various cancers are not generalizable and comparisons should be avoided. Systematic delineation of the fate and role of the hBDs in a specific cancer type may lead to innovative ways to use defensins as prospective biomarkers for diagnostic/prognostic purposes and/or in novel therapeutic modalities.
Highlights
The discovery of human β-defensins in mucosa has led to recognition that they are integral in innate immune protection; shielding mucosal surfaces from microbial challenges
We discovered that disparate published results were often due to: [1] studies using cell lines vs. human tissue samples; [2] results based on human tissue samples varied depending upon whether the comparisons were done with matched or unmatched control samples; [3] conclusions varied when using mRNA-based vs. protein-based studies and; [4] in protein-based studies varying methods to detect defensins [Western, Immunohistochemstry (IHC) or Immunofluorescence microscopy (IFM)] could contribute to disparate findings
Based on the works cited, the production of hBD-1, in the context of cancer, appears to be cancer type and location dependent. This does not appear to be the case with oral cancer, as most of the reported studies showed a decrease in hBD-1 expression levels, while only one reported an increase (Table 1)
Summary
The discovery of human β-defensins (hBDs) in mucosa has led to recognition that they are integral in innate immune protection; shielding mucosal surfaces from microbial challenges. Human β-defensins can be up- or down-regulated depending on the specific cancer type and its anatomical location What does this observation mean for hBD expression in the context of neoplasia? HBDs were reported to behave as tumor suppressors [15, 22, 39] as well as proto-oncogenes [36, 43, 44] While these results may, on-the-surface, appear to be inconsistent, if studies are segregated based on cell lines used, type of cancer being investigated, and the specific hBD studied, a clearer picture unfolds. Based on the works cited, the production of hBD-1, in the context of cancer, appears to be cancer type and location dependent This does not appear to be the case with oral cancer (oral squamous cell carcinoma; OSCC), as most of the reported studies showed a decrease in hBD-1 expression levels, while only one reported an increase (Table 1). Tonsil Esophagus (SCC) Skin (BCC) Skin (SCC) Colon Cervix (SCC) Vulva Lung HBD-3 Oral cavity (OSCC)
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