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首页> 外文期刊>Clinical and diagnostic laboratory immunology >Suppression of Growth by All-trans Retinoic Acid Requires Prolonged Induction of Interferon Regulatory Factor 1 in Cervical Squamous Carcinoma (SiHa) Cells
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Suppression of Growth by All-trans Retinoic Acid Requires Prolonged Induction of Interferon Regulatory Factor 1 in Cervical Squamous Carcinoma (SiHa) Cells

机译：全反式维甲酸抑制生长需要宫颈鳞状细胞癌（SiHa）细胞中干扰素调节因子1的诱导。

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All-trans retinoic acid (ATRA) suppresses growth of cervical dysplasias in vivo, although the sensitivity to retinoids is frequently lost during cervical carcinogenesis. It has been suggested that prolonged treatment or use of higher doses of retinoids might offer favorable response rates. We found SiHa cervical squamous carcinoma cells that were virtually resistant to ATRA-induced growth-inhibitory effects at physiological doses (10?7 to 10?6 M) to be more responsive at pharmacological doses (10?5 to 10?4 M). The growth inhibition by high-dose (10?4 M) ATRA was associated with a sustained activation of interferon regulatory factor 1 (IRF-1), while a low dose (10?6 M) of ATRA activated IRF-1 only transiently. Antisense IRF-1 inhibited the high-dose (10?4 M), ATRA-mediated growth arrest; forced expression of IRF-1 caused a significant reduction in cell growth. High-dose (10?4 M) ATRA increased binding of NF-κB and STAT1 proteins to sequences that originated from the IRF-1 promoter region, while low-dose (10?6 M) ATRA induced only NF-κB binding. A delayed tyrosine phosphorylation of the signal transducer and activator of transcription-1 (STAT1) was observed after high-dose (10?4 M) but not low-dose (10?6 M) ATRA treatment. In agreement with this, induction of IRF-1 mRNA by ATRA was only modest and transient in a STAT1 knockout cell line, suggesting the importance of STAT1 in sustained IRF-1 expression. Our data showed that ATRA is capable of inducing dose-dependent cellular changes, which might be appropriate to overcome resistance to retinoids that frequently develops during cervical carcinogenesis.
机译：全反式维甲酸（ATRA）在体内可抑制子宫颈异型增生，尽管在子宫颈癌变过程中对类维生素A的敏感性经常丧失。已经提出，长期治疗或使用更高剂量的类维生素A可能会提供有利的缓解率。我们发现在生理剂量（10 ？7至？10 ？6 M）下实际上对ATRA诱导的生长抑制作用具有抗性的SiHa宫颈鳞状细胞更具反应性以药理剂量（10 ？5至 10 ？4 M）服用。大剂量（10 ？4 M）ATRA对生长的抑制作用与干扰素调节因子1（IRF-1）的持续激活有关，而小剂量（10 ？4 ？6 < / sup> M）的ATRA仅短暂激活IRF-1。反义IRF-1抑制高剂量（10 ？4 M）ATRA介导的生长停滞。 IRF-1的强制表达导致细胞生长显着减少。大剂量（10 ？4 M）ATRA增强NF-κB和STAT1蛋白与源自IRF-1启动子区域的序列的结合，而小剂量（10 ？4 /）M）ATRA仅诱导NF-κB结合。高剂量（10 ？4 M）后观察到信号转导和转录激活因子1（STAT1）的酪氨酸磷酸化延迟，而小剂量（10 ？6）未观察到酪氨酸磷酸化延迟。 sup> M）ATRA治疗。与此相符的是，在STAT1敲除细胞系中，ATRA对IRF-1 mRNA的诱导只是适度和短暂的，这表明STAT1在持续IRF-1表达中的重要性。我们的数据表明，ATRA能够诱导剂量依赖性细胞变化，这可能适合克服对子宫颈癌变过程中经常形成的类维生素A的耐药性。

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