Abstract
Retinoids exhibit multiple functions through interaction with nuclear retinoid receptors and have growth-suppressive activity on gastric cancer cells. To better understand the roles of nuclear retinoid receptors during gastric carcinogenesis, we have used in situ hybridization to investigate expression of retinoic acid receptors (RARs) and retinoid x receptors (RXRs) in premalignant and malignant formalin-fixed paraffin-embedded gastric tissues. Histological sections of eight normal, 17 distal normal and nine gastric cancer tissues were hybridized with non-radioactive RNA probes for subtypes of RAR and RXR. Expression of RARα, RARβ, RARγ, RXRα and RXRβ was found in most cell types in gastric mucosa tissues from normal individuals as well as in distal normal tissues from cancer patients. Expression of RARα and RARβ were found in three and seven cancer tissues, respectively, and levels of RXRα mRNA were significantly decreased in poorly differentiated cancer tissues. Among the five investigated nuclear retinoid receptors, only expression of RARα mRNA was significantly decreased in intestinal metaplasia, dysplasia and cancer tissues when compared to adjacent normal tissues. In conclusion, normal gastric mucosa expressed both RARs and RXRs, which supports the physiological role of retinoic acid on normal gastric mucosa. The decrease in RARα expression in premalignant and malignant gastric tissues suggests a significant role of RARα during gastric carcinogenesis.
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16 November 2011
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References
Badley, J. E., Bishop, G. A., St John, T. & Frelinger, J. A. (1988) A simple, rapid method for the purification of poly A+ RNA. Biotechniques 6: 114–116.
Brand, N. J., Petkovich, M., Krust, A., Chambon, P., de The, H., Marchio, A., Tiollais, P. & Dejean, A. (1988) Identification of a second human retinoic acid receptor. Nature (Lond) 332: 850–853.
Castillo, L., Milano, G., Santini, J., Demard, F. & Pierrefite, V. (1997) Analysis of retinoic acid receptor β expression in normal and malignant laryngeal mucosa by a sensitive and routine applicable reverse transcription-polymerase chain reaction enzyme-linked immunosorbent assay method. Clin Cancer Res 3: 2137–2142.
Czerniak, B., Herz, F., Gorczyca, W. & Koss, L. G. (1989) Expression of ras oncogene p21 protein in early gastric carcinoma and adjacent gastric epithelia. Cancer 64: 1467–1473.
Darwiche, N., Celli, G., Tennenbaum, T., Glick, A. B., Yuspa, S. H. & De Luca, L. M. (1995) Mouse skin tumor progression results in differential expression of retinoic acid and retinoid x receptors. Cancer Res 55: 2774–2782.
Darwiche, N., Scita, G., Jones, C., Rutberg, S., Greenwald, E., Tennenbaum, T., Collins, S. J., De Luca, L. M. & Yuspa, S. H. (1996) Loss of retinoic acid receptors in mouse skin and skin tumors is associated with activation of the rasHa oncogene and high risk for premalignant progression. Cancer Res 56: 4942–4949.
Fujii, T. & Yokomori, T. (1991) A clinical study of vitamin A concerning auxiliary chemotherapies after operation of gastric cancer. Gan To Kagaku Ryoho 18: 265–269.
Haenszel, W., Correa, P., Lopez, A., Cuello, C., Zarama, G., Zavala, D. & Fontham, E. (1985) Serum micronutrient levels in relation to gastric pathology. Int J Cancer 36: 43–48.
Hamada, K., Gleason, S. L., Levi, B. Z., Hirschfeld, S., Appella, E. & Ozato, K. (1989) H-2RIIP, a member of the nuclear hormone receptor superfamily that binds to both the regulatory element of major histocompatibility class I genes and the estrogen response element. Proc Natl Acad Sci USA 86: 8289–8293.
Han, J. (1993) Highlights of cancer chemoprevention studies in China. Preventive Med 22: 712–722.
Heyman, R. A., Mangelsdorf, D. J., Dyck, J. A., Stein, R. B., Eichele, G., Evans, R. M. & Thaller, C. (1992) 9-cis-retinoic acid is a high affinity ligand for the retinoid x receptor. Cell 68: 397–406.
Houle, B., Rochette-Egly, C. & Bradley, W. E. (1993) Tumor-suppressive effect of the retinoic acid receptor beta in human epidermoid lung cancer cells. Proc Natl Acad Sci USA 90: 985–989.
Hu, L., Crowe, D. L., Rheinwald, J. G., Chambon, P. & Gudas, L. J. (1991) Abnormal expression of retinoic acid receptors and keratin 19 by human oral and epidermal squamous cell carcinoma cell lines. Cancer Res 51: 3972–3981.
Issing, W. J. & Wustrow, T. P. U. (1996) Expression of retinoic acid receptors in squamous cell carcinomas and their possible implication for chemoprevention. Anticancer Res 16: 2373–2378.
Jiang, S-Y, Shyu, R-Y, Chen, H-Y, Lee, MM-S, Wu, K-L & Yeh, M-Y (1996) In vitro and in vivo growth inhibition of SC-M1 gastric cancer cells by retinoic acid. Oncology 53: 334–340.
Kaiser, A., Herbst, H., Fisher, G., Koenigsmann, M., Berdel, W. E., Riecken, E-O & Rosewicz, S. (1997) Retinoic acid receptor β regulates growth and differentiation in human pancreatic carcinoma cells. Gastroenterology 113: 920–929.
Leblanc, B. P. & Stunnenberg, H. G. (1995) 9-cis retinoic acid signaling: changing partners canses some excitement. Genes Dev 9: 1811–1816.
Liang, K-Y & Zeger, S. L. (1986) Longitudinal data analysis using generalized linear models. Miometrika 73: 13–22.
Lotan, R., Xu, X. C., Lippman, S. M., Ro, J. Y., Lee, J. S., Lee, J. J. & Hong, W. K. (1995) Suppression of retinoic acid receptor-β in premalignant oral lesions and its up-regulation by isotretinoin. N Engl J Med 332: 1405–1410.
McGregor, F., Wagner, E., Felix, D., Soutar, D., Parkinson, K. & Harrison, P. R. (1997) Inappropriate retinoic acid receptor-β expression in oral dysplasias: correlation with acquisition of the immortal phenotype. Cancer Res 57: 3886–3889.
Miasoedov, D. V., V’iunitskaia, L. V., Chernukhina, L. A. & Donchenko, G. V. (1989) Blood vitamin A contents in patients with stomach cancer. Voprosy Onkologii 35: 945–958.
Mangelsdorf, D. J., Ong, E. S., Dyck, J. A. & Evan, R. M. (1990) Nuclear receptor that identifies a novel retinoic acid response pathway. Nature (Lond) 345: 224–229.
Mangelsdorf, D. J., Umesono, K. & Evan, R. M. (1994). The retinoid receptors. In The Retinoids, Sporn MB, Roberts AB and Goodman DS (eds), pp. 319–349. Raven Press: New York
Petkovich, M., Brand, N. J., Krust, A. & Chambon, P. (1987) A human retinoic acid receptor which belongs to the family of nuclear receptors. Nature (Lond) 330: 444–450.
Shyu, R-Y, Jiang, S-Y, Huang, T-C, Wu, K-L, Roffler, S. R. & Yeh, M-Y (1995) Growth regulation by all-trans-retinoic acid and retinoic acid receptor messenger ribonucleic acids expression in gastric cancer cells. Eur J Cancer 31A: 237–243.
Soman, N. R., Correa, P., Ruiz, B. A. & Wogan, G. N. (1991) The TPR-MET oncogenic rearrangement is present and expressed in human gastric carcinoma and precursor lesions. Proc Natl Acad Sci USA 88: 4892–4896.
Tahara, E. (1993) Molecular mechanism of stomach carcinogenesis. J Cancer Res Clin Oncol 119: 265–272.
Tsuchiya, C., Ohshima, S. & Takahama, M. (1997) Detection of c-Ki-ras oncogene mutation in gastric adenomas with formalin-fixed, paraffin-embedded biopsy materials. J Gastroenterol 32: 28–33.
Watanabe, H., Jass, J. R. & Sabin, L. H. (1989). Histological typing of esophageal and gastric tumors. In World Health Organization International Histological Classification of Tumors, pp. 20–26. Springer-Verlag: Berlin
Widschwendter, M., Berger, J., Daxenbichler, G., Muller-Holzner, E., Widschwendter, A., Mayr, A., Marth, C. & Zeimet, A. G. (1997) Loss of retinoic acid receptor β expression in breast cancer and morphologically normal adjacent tissue but not in the normal breast tissue distant from the cancer. Cancer Res 57: 4158–4161.
Xu, X. C., Ro, J. Y., Lee, J. S., Shin, D. M., Hong, W. K. & Lotan, R. (1994a) Differential expression of nuclear retinoid receptors in normal, premalignant and malignant head and neck tissues. Cancer Res 54: 3580–3587.
Xu, X-C, Clifford, J. L., Hong, W. K. & Lotan, R. (1994b) Detection of nuclear retinoic acid receptor mRNA in histological tissue sections using nonradioactive in situ hybridization histochemistry. Diagnostic Mol Pathol 3: 122–131.
Xu, X. C., Sozzi, G., Lee, J. S., Pastorino, U., Pilotti, S., Jurie, J. M., Hong, W. K. & Lotan, R. (1997a) Suppression of retinoic acid receptor beta in non-small-cell lung cancer in vivo: implication for lung cancer development. J Natl Cancer Inst 89: 624–629.
Xu, X. C., Sneige, N., Liu, X., Nandagiri, R., Lee, J. J., Lukmanji, F., Hortobagyi, G., Lippmann, S. M., Dhingra, K. & Lotan, R. (1997b) Progressive decrease in nuclear retinoic acid receptor β messenger RNA levels during breast carcinogenesis. Cancer Res 57: 4992–4996.
Yoshida, K., Hamatani, K., Koide, H., Ikeda, H., Nakamura, N., Akiyama, M., Tsuchiyama, H., Nakayama, E. & Shiku, H. (1988) Preparation of anti-ras Mr 21 000 protein monoclonal antibodies and immunohistochemical analyses on expression of ras genes in human stomach and thyroid cancers. Cancer Res 48: 5503–5509.
Zelent, A., Krust, A., Petkovich, M., Kastner, P. & Chambon, P. (1989) Cloning of murine α and β retinoic acid receptors and a novel receptor γ predominantly expressed in skin. Nature (Lond) 339: 714–717.
Zhang, X. K., Lehmann, J. M., Hoffmann, B., Dawson, M. I., Cameron, J., Graupner, G., Tran, P. & Pfhal, M. (1992) Homodimer formation of retinoid X receptor induced by 9-cis retinoic acid. Nature (Lond) 358: 587–591.
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Jiang, SY., Shen, SR., Shyu, RY. et al. Expression of nuclear retinoid receptors in normal, premalignant and malignant gastric tissues determined by in situ hybridization. Br J Cancer 80, 206–214 (1999). https://doi.org/10.1038/sj.bjc.6690340
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DOI: https://doi.org/10.1038/sj.bjc.6690340
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