Expression and up-regulation of retinoic acid receptor-beta is associated with retinoid sensitivity and colony formation in esophageal cancer cell lines.

Retinoids exhibit chemotherapeutic and chemopreventive activities, possibly due to their ability to modulate cell growth, differentiation, and apoptosis. These effects are thought to be mediated by nuclear retinoic acid (RA) receptors (RARs) and retinoid X receptors, each of which includes three subtypes (alpha, beta, and gamma) that act as transcription factors. To determine whether RARs play a role in mediating the effects of RA on human esophageal cancer (HEC) cells, we analyzed the effects of RA on: (a) the growth, differentiation, and apoptosis in seven HEC cell lines; (b) receptor expression; (c) receptor modulation by RA; and (d) expression of receptors in 20 surgical HEC specimens. RA inhibited the growth of five of seven cell lines and also the constitutive expression of the squamous differentiation markers cytokeratin 1 and transglutaminase I in all cell lines. The growth inhibition by RA was due to the induction of apoptosis in the five cell lines. All seven cell lines expressed RAR-alpha and RAR-gamma, and four cell lines showed some changes by RA, but not associated with apoptosis. In contrast, RAR-beta was expressed in five of seven cell lines and up-regulated by RA in these five cell lines, which were associated with apoptosis. Two cell lines that failed to express RAR-beta showed no growth inhibition or apoptosis and no RAR-beta inducibility. Interestingly, only these two cell lines were able to form colonies in soft agar. RAR-alpha, RAR-beta, and RAR-gamma mRNAs were expressed in all 20 adjacent normal esophageal tissues. The expression of RAR-alpha and RAR-gamma remains positive in HEC specimens, but RAR-beta expression was detected in only 6 of 20 HEC specimens. These data suggest that the expression of RAR-beta is associated with response of HEC cells to RA and that the loss of RAR-beta expression may be associated with HEC development.