Clinical significance of altered expression of retinoid receptors in oral precancerous and cancerous lesions: Relationship with cell cycle regulators

Alterations in expression of retinoid receptors are implicated in human cancers. We hypothesized that altered expression of retinoic acid receptors (RARα,β,γ) and retinoid X receptor RXRα and their relationship with cell cycle regulators (p53, p16, p21) is associated with development, progression and prognosis of oral cancer. Immunohistochemical analysis of RAR α, β, γ and RXRα proteins was carried out on serial sections from 244 oral squamous cell carcinomas (OSCCs), 102 potentially malignant lesions (65 hyperplasias, 37 dysplasias), 83 matched histologically normal oral tissues and 29 normal mucosa from non‐exposed individuals without oral lesions and correlated with expression of cell cycle regulators p53, p16 and p21 as well as with clinicopathological parameters. Expression of retinoid receptors RARβ, RARγ, RXRα and cell cycle regulators p16 and p21 was decreased in majority of oral SCCs as well as in potentially malignant lesions. Multivariate stepwise logistic regression analysis carried out for comparison of non‐exposed normal oral mucosa with histologically normal oral tissues from patients with oral lesions showed significant loss of RARβ or p53 accumulation (RARβ−/p53+ Odd's ratio, OR = 266.6, p = 0.000); non‐exposed normal mucosa from individuals without oral lesions with potentially malignant lesion was RARβ−/p21−/p53+ (OR = 215.7, p = 0.000); matched normal to potentially malignant stage was RARα+/p21− (OR = 4.414, p = 0.005); hyperplasia to dysplasia was RARα+/p53+ (OR = 4.72, p = 0.005) and potentially malignant to malignant phenotype was RARα+ (OR = 2.061, p = 0.004). The prognostic relevance of these factors was assessed in 115 of these SCC patients who were followed‐up for a maximum period of 94 months (median 21 months). Multivariate analysis using Cox's proportional Hazard's model showed that RARα+/p21− phenotype was associated with shorter disease‐free survival (Hazard's ratio, HR = 1.863, p = 0.0471). To our knowledge, this is the first large study showing alterations in expression of retinoid receptors at the protein level at different stages in development and progression of oral SCC. It also underscored the prognostic significance of retinoid receptors and their interactions with cell cycle regulators in multistep oral tumorigenesis. © 2005 Wiley‐Liss, Inc.