Decreased expression of retinoic acid receptors, transforming growth factor beta, involucrin, and cornifin in cervical intraepithelial neoplasia

Cervical intraepithelial neoplasia (CIN) I, II, and III represent a spectru m of premalignant epithelial changes and are ideal targets for application of chemoprevention strategies. Intermediate end point biomarkers are increa singly being used as surrogate end points to monitor clinical chemopreventi on trials. To identify potential biomarkers in cervical epithelium, we anal yzed the expression of nuclear retinoic acid receptor (RAR) mRNA by in situ hybridization, involucrin, cornifin, and transforming growth factors (TGFs ) beta 1 and beta 2 by immunohistochemistry in cervical specimens, which co ntained adjacent normal epithelium and CIN lesions from 52 patients. These biomarkers were expressed in all adjacent normal cervical epithelia, wherea s all CIN lesions including CIN I, CIN II, and CIN III exhibited decreased expression of RAR-alpha by 55.8%, RAR-beta by 64.7%, RAR-gamma by 54.9%, in volucrin by 80.8%, cornifin by 88.5%, TGF-beta 1 by 89.7%, and TGF-beta 2 b y 85.7%. Viewed as a whole, these biomarkers were down-regulated in 100% of the CIN lesions. Because all of these biomarkers can be modulated in vitro by retinoids, they may serve as intermediate biomarkers for retinoid chemo prevention trials in the patients with CIN lesions.