Expression of retinoic acid receptor gamma correlates with retinoic acid sensitivity and metabolism in head and neck squamous cell carcinoma cell lines

Abstract

Retinoids, analogues of vitamin A, can reverse premalignant lesions and prevent second primary tumors in patients with head and neck squamous cell carcinoma (HNSCC). The effects of retinoids are mediated by retinoic acid receptors (RARs) and retinoid X receptors (RXRs), which act as ligand‐activated transcription factors. The regulation of cell growth, differentiation and retinoid metabolism in normal, premalignant and malignant cells by retinoids is thought to be a result of their effects on gene expression. We investigated mRNA expression of RARs (α, β, and γ) and RXR‐β by means of RNase protection and related this to retinoic acid (RA)‐induced growth inhibition and RA turnover in four HNSCC cell lines (UM‐SCC‐14C, UM‐SCC‐22A, UM‐SCC‐35 and VU‐SCC‐OE). An RA‐resistant subline of UM‐SCC‐35 was generated by exposure to increasing concentrations of RA for 8 months (designated UM‐SCC‐35R). RA turnover was determined on the basis of decreasing RA levels in the cells and culture medium after exposure to 1 μM RA. We found that RAR‐γ mRNA expression was strongly correlated with RA‐induced growth inhibition (p = 0.016, R = 0.92) and RA turnover (p = 0.041, R = 0.86). RAR‐β transcript levels were reduced in three of five cell lines compared with normal mucosa, and these did not correlate with RA‐induced growth inhibition and RA turnover. Expression of RAR‐α and RXR‐β was not substantially altered in any of the cell lines. These findings suggest that in HNSCC cell lines RAR‐γ is the most important retinoid receptor for regulation of RA turnover rate and RA‐induced growth inhibition. © 2001 Wiley‐Liss, Inc.

Expression of retinoid-related genes in serum-free cultures of normal, immortalized and malignant human oral keratinocytes

“…SqCC/Y1 transfected with RARÁ show increased sensitivity to growth inhibition by RA while antisense-transfection causes the opposite effect (10). Furthermore, the expression level of RARÁ correlates to RA sensitivity of head and neck squamous carcinoma cell lines (45). In this regard, the low RARÁ expression levels of SVpgC2a and SqCC/Y1 as detected by micro-array indicate that both lines may be relatively insensitive to retinoid actions.…”

RARγ acts as a tumor suppressor in mouse keratinocytes

“…However, RARb is not expressed in epidermal keratinocytes, and our prior work suggests that RARg plays a pivotal role in retinoid-induced growth arrest in this cell type (Goyette et al, 2000). RARg has also been shown to mediate RA response of cell lines derived from head and neck SCCs and oral SCCs, where RARb expression has been silenced (Oridate et al, 1996;Le et al, 2000;Klaassen et al, 2001).…”

Retinoic acid receptors and tissue-transglutaminase mediate short-term effect of retinoic acid on migration and invasion of neuroblastoma SH-SY5Y cells

“…Though RA can bind only to the RARs, activated RAR heterodimerizes with RXR and RAR/RXR heterodimers bind to RA response element (RARE), resulting in transcriptional activation. Alteration in RAR expression or function has been observed in a variety of cancers; loss of RARb, a probable tumor suppressor gene, is associated with different tumors including lung and squamous cell carcinoma, breast, stomach and prostrate cancers (Xu et al, 1994(Xu et al, , 1997aQui et al, 1999;Lotan et al, 2000;Klaassen et al, 2001;Soprano and Soprano, 2002;Emionite et al, 2003;Niles, 2004).…”