Picard E, Seguin C, Monhoven N, Rochette-Egly C, Siat J, Borrelly J, Martinet Y, Martinet N, Vignaud J M
Laboratoire d'Anatomie Pathologique, Centre Hospitalier Universitaire de Nancy, France.
J Natl Cancer Inst. 1999 Jun 16;91(12):1059-66. doi: 10.1093/jnci/91.12.1059.
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.
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.
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.
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.
维甲酸可抑制高危非肿瘤性支气管病变中的致癌作用，并可降低第二原发性非小细胞肺癌（NSCLC）的风险。维甲酸的作用由核受体介导，即维甲酸受体（RARα、RARβ和RARγ）和维甲酸X受体（RXRα、RXRβ和RXRγ）。我们研究了在NSCLC中是否观察到维甲酸受体体内表达异常。
使用抗维甲酸受体抗体（抗RXRγ抗体除外）和免疫组织化学研究了76例NSCLC患者肺脏正常组织和癌组织配对标本中维甲酸受体的表达。通过原位杂交和逆转录聚合酶链反应（RT-PCR）分析RAR信使核糖核酸。还对样本进行了3号染色体p24区域杂合性缺失（LOH）研究。所有P值均为双侧。
所有研究的受体均在正常肺细胞和高危非肿瘤性病变中表达。在肿瘤细胞中，经常观察到RXRα和RARα的过表达。相反，18%的肿瘤标本中RXRβ表达降低。此外，63%的肿瘤中RARβ表达明显降低（P<0.0001）。通过RT-PCR在41%的肿瘤中观察到RARγ表达降低（P<0.0001）。在41%的有信息患者的肿瘤标本和20%的非肿瘤性病变中观察到3p24区域的LOH。
NSCLC中RARα和RXRα的表达正常或升高。相反，很大比例的肿瘤显示RARβ、RARγ和RXRβ表达明显降低，以及3p24区域高频率的LOH，在非肿瘤性病变中也观察到这种情况。这些数据表明维甲酸受体表达改变可能在肺癌发生中起作用。
