Abstract
Retinoids can regulate the proliferation and differentiation of various tumor cells. It is thought that nuclear retinoid receptors mediate these effects by regulating gene transcription. The identity of specific retinoid target genes is only beginning to be unraveled. One candidate for mediating retinoid-induced growth suppression is the novel class II tumor suppressor gene tazarotene-induced gene 3 (TIG3). We examined the constitutive and all-trans retinoic acid (ATRA)-inducible expression of TIG3 mRNA in five head and neck squamous cell carcinoma (HNSCC) and five nonsmall cell lung carcinoma (NSCLC) cell lines to determine whether it is associated with their responsiveness to ATRA. The expression patterns of retinoic acid receptor β (RARβ), another putative retinoid-inducible tumor suppressor gene, were also examined. The constitutive TIG3 expression was high in one HNSCC cell line and two NSCLC cell lines, and moderate to very low in the other cells. Some RARβ-expressing cells had either low or undetectable TIG3 levels and vice versa. ATRA (1 μ M; 48 h) increased TIG3 mRNA in 4/5 HNSCCs and 3/5 NSCLCs and RARβ mRNA in some of the same cell lines, but also in cells that did not show TIG3 induction. TIG3 mRNA was induced by ATRA between 6 and 12 h in most of the responsive cells. ATRA concentrations required for TIG3 induction ranged from 1 to 500 nM depending on the cell line. The pan-RAR antagonists AGN193109 and the RARα antagonist Ro 41-5253 blocked TIG3 induction by ATRA. ATRA suppressed anchorage-independent colony formation in most cells that had a high or moderate constitutive or induced TIG3 expression level. In contrast, RARβ mRNA expression pattern was not correlated with sensitivity to ATRA. These results suggest that TIG3 is regulated by ATRA via retinoid receptors in certain aerodigestive tract cancer cells, and its induction by ATRA is associated with the suppression of anchorage-independent growth.
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Acknowledgements
We thank Dafna Lotan for her excellent technical assistance. We also thank Dr Sarah Wardlaw for critically reading this manuscript. This study was supported in part by P50 DE11906 grant from the National Institute of Dental and Craniofacial Research and by PO1 CA52051, U19 CA68437, and CCSG CA16672 (DNA Sequencing Core) grants from the National Cancer Institute.
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Higuchi, E., Chandraratna, R., Hong, W. et al. Induction of TIG3, a putative class II tumor suppressor gene, by retinoic acid in head and neck and lung carcinoma cells and its association with suppression of the transformed phenotype. Oncogene 22, 4627–4635 (2003). https://doi.org/10.1038/sj.onc.1206235
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DOI: https://doi.org/10.1038/sj.onc.1206235
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