Retinoid acid receptor expression is helpful to distinguish between adenoma and well-differentiated carcinoma in the thyroid
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Retinoid receptors (RRs) play a key role in cell proliferation and differentiation. We characterized the expression of RA receptors and retinoid X receptors (RARs and RXRs) in a series of 111 thyroid tumors and investigated the mechanisms responsible for their deregulation: hypermethylation of the RARB2 promoter, loss of heterozygosity (LOH) in the regions of RARB and RXRA, and altered expression of CRBP1 and enzymes involved in RA biosynthesis (RDH10 and RALDH2). Expression of RALDH2 and RDH10 was conserved in 100 % of adenomas and in 90 and 98 %, respectively, of carcinomas, whereas staining for CRBP1 was decreased in 9 % of FAs and 28 % of carcinomas, mainly anaplastic carcinomas (55 %). We found an abnormal expression of RARA, RARB, RXRA, and RXRB in 67, 69, 66, and 73 %, respectively, of thyroid carcinomas (n = 78) and in 9, 9, 9, and 33 % of follicular adenomas (n = 33) (p < 0.001). An abnormal staining pattern of at least two of these markers had 90 % sensitivity and 91 % specificity for a diagnosis of malignancy. Promoter hypermethylation of RARB2 was observed in some anaplastic carcinomas (14 %). LOH was found to be common at the RARB locus (3p24–3p25) and the RXRA locus (9q34), respectively, in 44 and 55 % of carcinomas and in 27 and 43 % of adenomas. In conclusion, immunohistochemical staining for RARs and RXRs may help in the differential diagnosis between well-differentiated carcinoma and follicular adenoma. Further investigation should be carried out to determine whether the characterization of RR expression might identify patients who could benefit from therapy with RA derivatives.
KeywordsRetinoids RAR RXR Promoter methylation Loss of heterozygosity Thyroid cancer
The authors thank Mrs. Caroline Chapusot (Department of Pathology, CHU Dijon), Mrs. Brigitte Léotard, Ms. Aline Saunier (Department of Genetics, CHU Nancy), Ms. Julie Zinszner (Department of Pathology, CHU Nancy) for technical support, Mr. Marc Soudant (Epidemiology and Clinical Evaluation, CHU Nancy) for statistical analysis, and Mrs. Jacqueline Zevnick for reviewing the manuscript.
Conflict of interest
The authors have no conflict of interest to declare.
- 4.Fernandez CA, Puig-Domingo M, Lomena F, Estorch M, Camacho Marti V, Bittini AL, Marazuela M, Santamaria J, Castro J, Martinez de Icaya P, Moraga I, Martin T, Megia A, Porta M, Mauricio D, Halperin I (2009) Effectiveness of retinoic acid treatment for redifferentiation of thyroid cancer in relation to recovery of radioiodine uptake. J Endocrinol Invest 32:228–233. Google Scholar
- 6.Simon D, Korber C, Krausch M, Segering J, Groth P, Gorges R, Grunwald F, Muller-Gartner HW, Schmutzler C, Kohrle J, Roher HD, Reiners C (2002) Clinical impact of retinoids in redifferentiation therapy of advanced thyroid cancer: final results of a pilot study. Eur J Nucl Med Mol Imaging 29:775–782. doi: 10.1007/s00259-001-0737-6 PubMedCrossRefGoogle Scholar
- 9.Haugen BR, Larson LL, Pugazhenthi U, Hays WR, Klopper JP, Kramer CA, Sharma V (2004) Retinoic acid and retinoid X receptors are differentially expressed in thyroid cancer and thyroid carcinoma cell lines and predict response to treatment with retinoids. J Clin Endocrinol Metab 89:272–280PubMedCrossRefGoogle Scholar
- 11.Elisei R, Vivaldi A, Agate L, Ciampi R, Molinaro E, Piampiani P, Romei C, Faviana P, Basolo F, Miccoli P, Capodanno A, Collecchi P, Pacini F, Pinchera A (2005) All-trans-retinoic acid treatment inhibits the growth of retinoic acid receptor beta messenger ribonucleic acid expressing thyroid cancer cell lines but does not reinduce the expression of thyroid-specific genes. J Clin Endocrinol Metab 90:2403–2411PubMedCrossRefGoogle Scholar
- 12.Martinet N, Alla F, Farre G, Labib T, Drouot H, Vidili R, Picard E, Gaube MP, Le Faou D, Siat J, Borelly J, Vermylen P, Bazarbachi T, Vignaud JM, Martinet Y (2000) Retinoic acid receptor and retinoid X receptor alterations in lung cancer precursor lesions. Cancer Res 60:2869–2875PubMedGoogle Scholar
- 21.Lee ES, Issa JP, Roberts DB, Williams MD, Weber RS, Kies MS, El-Naggar AK (2008) Quantitative promoter hypermethylation analysis of cancer-related genes in salivary gland carcinomas: comparison with methylation-specific PCR technique and clinical significance. Clin Cancer Res 14:2664–2672. doi: 10.1158/1078-0432.CCR-07-1232 PubMedCrossRefGoogle Scholar
- 22.Li R, Saito T, Tanaka R, Satohisa S, Adachi K, Horie M, Akashi Y, Kudo R (2005) Hypermethylation in promoter region of retinoic acid receptor-beta gene and immunohistochemical findings on retinoic acid receptors in carcinogenesis of endometrium. Cancer Lett 219:33–40. doi: 10.1016/j.canlet.2004.06.044 PubMedCrossRefGoogle Scholar
- 23.Hu S, Liu D, Tufano RP, Carson KA, Rosenbaum E, Cohen Y, Holt EH, Kiseljak-Vassiliades K, Rhoden KJ, Tolaney S, Condouris S, Tallini G, Westra WH, Umbricht CB, Zeiger MA, Califano JA, Vasko V, Xing M (2006) Association of aberrant methylation of tumor suppressor genes with tumor aggressiveness and BRAF mutation in papillary thyroid cancer. Int J Cancer 119:2322–2329PubMedCrossRefGoogle Scholar
- 24.Mohammadi-Asl J, Larijani B, Khorgami Z, Tavangar SM, Haghpanah V, Kheirollahi M, Mehdipour P (2011) Qualitative and quantitative promoter hypermethylation patterns of the P16, TSHR, RASSF1A and RARbeta2 genes in papillary thyroid carcinoma. Med Oncol 28:1123–1128. doi: 10.1007/s12032-010-9587-z PubMedCrossRefGoogle Scholar
- 27.Miller WH Jr (1998) The emerging role of retinoids and retinoic acid metabolism blocking agents in the treatment of cancer. Cancer 83:1471–1482. doi: 10.1002/(SICI)1097-0142(19981015)83:8<1471::AID-CNCR1>3.0.CO;2–6 PubMedCrossRefGoogle Scholar
- 29.Sigstad E, Paus E, Bjoro T, Berner A, Groholt KK, Jorgensen LH, Sobrinho-Simoes M, Holm R, Warren DJ (2012) The new molecular markers DDIT3, STT3A, ARG2 and FAM129A are not useful in diagnosing thyroid follicular tumors. Mod Pathol 25:537–547. doi: 10.1038/modpathol.2011.188 PubMedCrossRefGoogle Scholar
- 31.Zhou H, Liu W, Su Y, Wei Z, Liu J, Kolluri SK, Wu H, Cao Y, Chen J, Wu Y, Yan T, Cao X, Gao W, Molotkov A, Jiang F, Li WG, Lin B, Zhang HP, Yu J, Luo SP, Zeng JZ, Duester G, Huang PQ, Zhang XK (2010) NSAID sulindac and its analog bind RXRalpha and inhibit RXRalpha-dependent AKT signaling. Cancer Cell 17:560–573. doi: 10.1016/j.ccr.2010.04.023 PubMedCrossRefGoogle Scholar
- 34.Yang Q, Yoshimura G, Nakamura M, Nakamura Y, Shan L, Suzuma T, Tamaki T, Umemura T, Mori I, Kakudo K (2001) Allelic loss of chromosome 3p24 correlates with tumor progression rather than with retinoic acid receptor beta2 expression in breast carcinoma. Breast Cancer Res Treat 70:39–45PubMedCrossRefGoogle Scholar