Higuchi Eisaku, Chandraratna Roshantha A S, Hong Waun K, Lotan Reuben
Department of Thoracic/Head and Neck Medical Oncology, The University of Texas, MD Anderson Cancer Center, Houston, TX 77030, USA.
Oncogene. 2003 Jul 24;22(30):4627-35. doi: 10.1038/sj.onc.1206235.
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 beta (RARbeta), 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 RARbeta-expressing cells had either low or undetectable TIG3 levels and vice versa. ATRA (1 microM; 48 h) increased TIG3 mRNA in 4/5 HNSCCs and 3/5 NSCLCs and RARbeta 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 RARalpha 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, RARbeta 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.
维甲酸可以调节各种肿瘤细胞的增殖和分化。人们认为核维甲酸受体通过调节基因转录来介导这些效应。特定维甲酸靶基因的身份才刚刚开始被揭示。介导维甲酸诱导的生长抑制的一个候选基因是新型II类肿瘤抑制基因他扎罗汀诱导基因3（TIG3）。我们检测了5种头颈部鳞状细胞癌（HNSCC）和5种非小细胞肺癌（NSCLC）细胞系中TIG3 mRNA的组成性表达和全反式维甲酸（ATRA）诱导性表达，以确定其是否与它们对ATRA的反应性相关。还检测了另一个假定的维甲酸诱导性肿瘤抑制基因维甲酸受体β（RARβ）的表达模式。在1种HNSCC细胞系和2种NSCLC细胞系中，TIG3的组成性表达较高，而在其他细胞中则为中度至非常低。一些表达RARβ的细胞TIG3水平较低或检测不到，反之亦然。ATRA（1μM；48小时）使4/5的HNSCC和3/5的NSCLC中的TIG3 mRNA增加，并且在一些相同的细胞系中使RARβ mRNA增加，但在未显示TIG3诱导的细胞中也有增加。在大多数反应性细胞中，ATRA在6至12小时内诱导TIG3 mRNA。诱导TIG3所需的ATRA浓度根据细胞系的不同在1至500 nM之间。泛RAR拮抗剂AGN193109和RARα拮抗剂Ro 41 - 5253阻断了ATRA对TIG3的诱导。在大多数组成性或诱导性TIG3表达水平高或中等的细胞中，ATRA抑制了非锚定依赖性集落形成。相比之下，RARβ mRNA表达模式与对ATRA的敏感性无关。这些结果表明，在某些气消化道癌细胞中，TIG3受ATRA通过维甲酸受体调节，并且其被ATRA诱导与非锚定依赖性生长的抑制相关。
