Expression of retinoid receptor genes and proteins in non-small-cell lung cancer.
BACKGROUND
Retinoids can suppress carcinogenesis in high-risk non-neoplastic bronchial lesions and can reduce the risk of second primary non-small-cell lung cancer (NSCLC). The effects of retinoids are mediated by nuclear receptors, i.e., the retinoic acid receptors (RARalpha, RARbeta, and RARgamma) and the retinoid X receptors (RXRalpha, RXRbeta, and RXRgamma). We investigated whether abnormalities in the in vivo expression of retinoid receptors are observed in NSCLC.


METHODS
Expression of retinoid receptors in paired specimens of normal and cancerous tissues from the lungs of 76 patients with NSCLC was studied by use of antiretinoid receptor antibodies (except those against RXRgamma) and immunohistochemistry. RAR messenger RNAs were analyzed by use of in situ hybridization and by reverse transcription-polymerase chain reaction (RT-PCR). Samples were also studied for loss of heterozygosity (LOH) at chromosome 3p24. All P values are two-sided.


RESULTS
All studied receptors were expressed in normal lung cells and in high- risk non-neoplastic lesions. In tumor cells, overexpression of RXRalpha and RARalpha was frequently observed. In contrast, RXRbeta expression decreased in 18% of the tumor specimens. Furthermore, there was a marked decrease in the expression of RARbeta in 63% of the tumors (P<.0001). Decreased expression of RARgamma was observed by RT-PCR in 41% of the tumors (P<.0001). LOH at 3p24 was observed in 41% of the tumor specimens from informative patients and in 20% of the non-neoplastic lesions.


CONCLUSIONS
Expression of RARalpha and RXRalpha is either normal or elevated in NSCLC. In contrast, a large percentage of tumors show a marked decrease in the expression of RARbeta, RARgamma, and RXRbeta as well as a high frequency of LOH at 3p24, which was also observed in non-neoplastic lesions. These data suggest that altered retinoid receptor expression may play a role in lung carcinogenesis.
Picard
E
E
Laboratoire d'Anatomie Pathologique, Centre Hospitalier Universitaire de Nancy, France.
Seguin
C
C
Monhoven
N
N
Rochette-Egly
C
C
Siat
J
J
Borrelly
J
J
Martinet
Y
Y
Martinet
N
N
Vignaud
J M
JM
D000368:Aged; D002289:Carcinoma, Non-Small-Cell Lung / Q000737:chemistry*; D002893:Chromosomes, Human, Pair 3 / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000032:analysis; D015536:Down-Regulation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D017403:In Situ Hybridization; D019656:Loss of Heterozygosity; D008175:Lung Neoplasms / Q000737:chemistry*; D008297:Male; D008875:Middle Aged; D009687:Nuclear Proteins / Q000032:analysis; D018168:Receptors, Retinoic Acid / Q000032:analysis* / Q000235:genetics; D047488:Retinoid X Receptors; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000032:analysis* / Q000235:genetics; D015854:Up-Regulation
D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D014157:Transcription Factors