RARβ2 suppression in head and neck squamous cell carcinoma correlates with site, histology and age

Retinoids as important growth and differentiation regulating agents have a potential role in the chemoprevention of head and neck squamous cell carcinoma (HNSCC). Despite the promising preclinical and early clinical findings, limitations of application are raised by intrinsic resistance acquired during carcinogenesis. Retinoic acid receptor β2 (RARβ2) is one of the proximate mediators of retinoid signalling and its expression is often diminished in early stages of head and neck carcinogenesis. One form of retinoid resistance has been associated with the methylation-induced silencing of the RARβ gene. We studied primary HNSCC samples of different anatomical sites in respect of methylation, expression and allelic loss of RARβ gene. A strong correlation (p<0.01) was found between hyper-methylation and reduced expression of RARβ2, however the allelic loss at 3p24, the locus of RARβ, did not considerably influence its mRNA level. Hypopharynx tumors showed significantly lower hypermethylation (p<0.05) and higher mRNA expression levels of RARβ2 compared to the tumors located at other sites of the head and neck. We could also provide evidence that poorly differentiated grade 3 tumors had significantly higher RARβ2 expression and lower methylation levels (p<0.05) than better differentiated grade 1 and grade 2 tumors. In addition, we found a good correlation between the methylation degree of the RARβ2 promoter and the ages of patients. Collectively, our results suggest that evaluation of several factors such as tumor location, age, histology and methylation state of the RARβ gene might contribute to the selection of patients for retinoid-based chemoprevention.