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Increased Retinoic Acid Receptor-ß₄ Correlates In vivo with Reduced Retinoic Acid Receptor-ß₂ in Esophageal Squamous Cell Carcinoma

Departments of ¹ Clinical Cancer Prevention, ² Biostatistics and Applied Mathematics, ³ Pathology, and ⁴ Gastrointestinal Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas

Requests for reprints: Xiao-chun Xu, Department of Clinical Cancer Prevention, Unit 1360, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: 713-745-2940; Fax: 713-563-5747. E-mail: xxu{at}mdanderson.org

Different retinoic acid receptor-ß (RAR-ß) isoforms seem to have contrasting biological effects in human carcinogenesis. Both in vitro and in vivo data indicate that RAR-ß₂ expression is frequently lost or reduced (and transfecting RAR-ß₂ suppresses growth and promotes apoptosis) in various cancer cells and tissues, whereas RAR-ß₄ expression is increased in several cancer cell lines. To clarify the effects of different RAR-ß isoforms in esophageal carcinogenesis, we used real-time quantitative reverse transcription-PCR to assess in vivo RAR-ß mRNA levels in specimens of normal and malignant human esophageal tissue, comparing these levels with each other and the expressions of other genes. RAR-ß₂ mRNA expression was significantly reduced (i.e., lower in cancer than normal tissue) in 67% (18 of 27, P = 0.001) and RAR-ß₄ mRNA was increased in 52% (14 of 27, P = 0.054) of our esophageal cancer cases. The expressions of RAR-ß₁, chicken ovalbumin upstream promoter-transcription factor-I (COUP-TFI), COUP-TFII, and peroxisome proliferator-activated receptor- (PPAR-) mRNA were reduced, whereas epidermal growth factor receptor and cyclin D1 expressions were increased in tumor compared with in normal tissues. Reduced RAR-ß₂ expression correlated with increased RAR-ß₄ expression (P = 0.002) and with the suppression of COUP-TFI and COUP-TFII (P = 0.050 and 0.023, respectively) in tumor samples. These are the first in vivo expression patterns of RAR-ß₂ and RAR-ß₄ reported in humans or animals and support the in vitro data on these isoforms and their contrasting biological effects in human carcinogenesis.

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