Objective: Identify proteins that are differentially expressed between head and neck squamous cell cancer (HNSCC) and patient-matched normal adjacent tissue, and validate findings in a separate patient cohort. Study Design: Cross-sectional study of surgical specimens. Setting: Tertiary care academic medical center. Subjects and Methods: Laser capture microdissection and two-dimensional difference gel electrophoresis were used previously to establish proteomic profiles for tumor and normal adjacent tissue from 14 patients. Here, significance analysis of microarray was used to rank candidate biomarkers. Spots meeting statistical and biological criteria of significance were analyzed by liquid chromatography and tandem mass spectrometry to obtain protein identifications. The expression pattern of the highest-ranked candidate biomarker (cornulin) was validated in a larger, independent patient cohort (n = 68) by immunohistochemical staining of a tissue microarray. Results: Of 732 spots, 117 (15.9%) met criteria for significance. Identities were obtained for 39 spots, representing 17 different proteins. Four proteins were novel in the context of HNSCC: glutathione synthetase, which was upregulated; and cornulin (squamous epithelial heat shock protein 53), guanylate binding protein 6, and heat shock 70 kDa protein 5 (glucose-regulated protein, 78 kDa), which were downregulated. Cornulin functions in the stress response in normal squamous epithelium, and reduced expression has been proposed as a marker of susceptibility to laryngopharyngeal reflux and other stressors. Loss of cornulin expression was confirmed in an independent HNSCC patient cohort (P < 0.001). Conclusions: Downregulation of cornulin is a prominent feature of the molecular signature of HNSCC identified by comparative proteomics. Cornulin may represent a link between HNSCC and other pathologies arising in stratified squamous epithelium.
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