Differential expression of retinoic acid receptors in normal and malignant esophageal tissues

The chemopreventive and chemotherapeutic activities of retinoids may be attributed to their ability to modulate growth, differentiation and apoptosis of epithelial cells, suppress or reverse epithelial carcinogenesis. Many of these effects of retinoids result from modulation of genes by two distinct classes of retinoid receptors: RARs and RXRs, alterations in their expression may lead to tumorigenesis. To determine whether alterations in expression of retinoid receptors are related to the development of esophageal squamous cell carcinomas (ESCCs), the expression of RARalpha, beta, gamma and RXRalpha was studied in 50 untreated primary esophageal carcinomas and 19 distant normal tissues by immunohistochemistry. RARbeta expression was observed in 18/50 (36%) ESCCs, while 16/19 (84%) of matched histologically normal esophageal tissues displayed RARbeta immunopositivity (p=0.001, 0R=3.405). Significant increase in RARalpha immunopositivity was observed in ESCCs (40/50; 80 %) as compared to normal tissues (9/19 cases; 47%) (p=0.008; 0R=2.77). RARgamma expression was observed in ESCCs (37/50cases; 74%) as compared to normal tissues (16/19; 84%); without significant difference. However, poorly differentiated esophageal cancer showed marked decrease in RARy immunopositivity (p=0.017; OR=6.0). Interestingly, increased expression of RXRalpha was observed in 43/50 (86%) ESCCs in comparison with (10/19; 53%) normal tissues (p=0.003; 0R=3.09). Logistic regression analysis revealed RARgamma-/RXRalpha+ phenotype as most significantly associated with dedifferentiation of the tumor (p=0.014; OR=11.0). The hallmark of the study was the significant increase in expression of RARalpha and RXRalpha proteins and loss of expression of RARbeta protein in ESCCs in comparison with the distant normal epithelia.