title: Comprehensive evaluation of caspase-14 in vulvar neoplasia: an opportunity for treatment with black raspberry extract.
abstract: OBJECTIVE
  The aim of this study is to determine the expression of caspase-14, a key protein in maturation of squamous epithelia, in archival malignant and premalignant vulvar squamous lesions and examine in-vitro effects of a black raspberry extract (BRB-E) on a vulvar squamous cell carcinoma (VSCC) cell line.
  
  
  METHODS
  VSCC cell cultures were exposed to different BRB-E concentrations and used to create cell blocks. Immunohistochemistry for caspase-14 was performed on cell block sections, whole tissue sections, and a tissue microarray consisting of normal vulvar skin, lichen sclerosus (LS), classic and differentiated vulvar intraepithelial neoplasia (cVIN and dVIN respectively), and VSCC.
  
  
  RESULTS
  LS demonstrated abnormal full thickness (5/11) or absent (1/11) caspase-14 staining. dVIN often showed markedly reduced expression (4/7), and cVIN occasionally demonstrated either absent or reduced caspase-14 (6/22). VSCC predominantly had absent or markedly reduced caspase-14 (26/28). VSCC cell cultures demonstrated a significant increase in caspase-14 (p=0.013) after BRB-E treatment: 7.3% (±2.0%) of untreated cells showed caspase-14 positivity, while 21.3% (±8.9%), 21.7% (±4.8%), and 22.6% (±5.3%) of cells were positive for caspase-14 after treatment with 200, 400, and 800 μg/mL BRB-E, respectively. Pair-wise comparisons between the treatment groups and the control demonstrated significant differences between no treatment with BRB-E and each of these treatment concentrations (Dunnett's adjusted p-values: 0.024, 0.021, and 0.014, respectively).
  
  
  CONCLUSIONS
  Caspase-14 is frequently decreased in premalignant and malignant vulvar squamous lesions, and is upregulated in VSCC cell culture by BRB-E. BRB-E should be further explored and may ultimately be incorporated in topical preparations.
authors.affiliation: Department of Pathology, The Ohio State University Wexner Medical Center, 410 W 10th Ave, Columbus, OH 43210, USA.
authors.forename: Amy S
authors.initials: AS
authors.lastname: Joehlin-Price
authors.affiliation: Department of Pathology, The Ohio State University Wexner Medical Center, 410 W 10th Ave, Columbus, OH 43210, USA.
authors.forename: Camille T
authors.initials: CT
authors.lastname: Elkins
authors.affiliation: Center for Biostatistics, The Ohio State University, 2012 Kenny Rd, Columbus, OH 43221, USA.
authors.forename: Julie A
authors.initials: JA
authors.lastname: Stephens
authors.affiliation: Department of Obstetrics and Gynecology, The Ohio State University Wexner Medical Center, 370 W 9th Ave, Columbus, OH 43210, USA.
authors.forename: David E
authors.initials: DE
authors.lastname: Cohn
authors.affiliation: Division of Environmental Health Sciences, College of Public Health, The Ohio State University, 1841 Neil Ave, Columbus, OH 43210, USA; The Ohio State University Comprehensive Cancer Center, 300 W 10th Ave, Columbus, OH 43210, USA.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Knobloch
authors.affiliation: Division of Environmental Health Sciences, College of Public Health, The Ohio State University, 1841 Neil Ave, Columbus, OH 43210, USA; The Ohio State University Comprehensive Cancer Center, 300 W 10th Ave, Columbus, OH 43210, USA.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Weghorst
authors.affiliation: Department of Pathology, The Ohio State University Wexner Medical Center, 410 W 10th Ave, Columbus, OH 43210, USA. Electronic address: adrian.suarez@osumc.edu.
authors.forename: Adrian A
authors.initials: AA
authors.lastname: Suarez
mesh_terms: D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D053456:Caspase 14 / Q000096:biosynthesis*; D045744:Cell Line, Tumor; D005260:Female; D005638:Fruit / Q000737:chemistry; D006801:Humans; D007150:Immunohistochemistry; D010936:Plant Extracts / Q000627:therapeutic use*; D065856:Rubus / Q000737:chemistry*; D014846:Vulvar Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology
chemical_list: D010936:Plant Extracts; D053456:Caspase 14
keywords: Black raspberry extract; Caspase-14; Lichen sclerosus; Squamous cell carcinoma; Vulvar intraepithelial neoplasia; Vulvar squamous cell carcinoma