Retinoid upregulates the sensitivity of cancer cells to a cytokine by inducing the cytokine receptor

无环类维甲酸，一种合成的类维甲酸类似物，以及干扰素(ifn)-α和-β可诱导肝细胞癌（HCC）细胞凋亡，并在临床上用于预防HCC。在这里，我们发现无环类维a与ifn协同作用，抑制5种人HCC细胞系（JHH7、HuH7、PLC/PRF/5、HLE和HLF）的生长和诱导凋亡（以DNA片段化和染色质凝聚为特征）。这种协同作用仅在细胞用无环类维甲酸预处理时观察到，而天然维甲酸（全反式和9-顺式维甲酸）无效。这种促进可能是由于类视黄醛上调了1型IFN受体（IFNR）的表达。因此，与抗1型IFNR抗体孵育可消除协同作用。IFNR表达增强的同时，IFNR细胞内信号转导分子STAT1的表达和dna结合活性增加，STAT1靶基因2',5'-寡腺苷-5'-三磷酸合成酶的诱导增加。无环类维甲酸对正常人肝细胞（Hc）的生长没有任何影响，可能是由于缺乏IFNR和STAT1的上调。这些结果为使用无环类维甲酸和IFN-β联合生物化学预防HCC提供了理论依据。

Acyclic retinoid, a synthetic retinoid analog, as well as interferons (IFNs)-α and -β induce apoptosis in hepatocellular carcinoma (HCC) cells and are used clinically in the prevention of HCC. Here, we show that acyclic retinoid acts synergistically with IFNs in suppressing the growth and inducing apoptosis (as characterized by DNA fragmentation and chromatin condensation) in 5 human HCC cell lines (JHH7,HuH7,PLC/PRF/5,HLE and HLF). This synergism was only observed when cells were pretreated with the aeyclic retinoid, whereas natural retinoic acids (all-trans and 9-cis retinoic acid) were ineffective. This promotion may be due to up-regulation of type 1 IFN receptor (IFNR) expression by the retinoid. Accordingly, incubation with anti-type 1 IFNR antibody abolished the synergy. Enhanced IFNR expression was accompanied by increased expression and DNA-binding activity of STAT1, an intracellular signal transducing molecule of IFNR, and increased induction of 2',5'-oligoadenyl-5'-triphosphate synthetase, which is a target gene of STAT1. Acyclic retinoid did not have any effects on the growth of normal human hepatocytes (Hc) probably due to lack of IFNR and STAT1 up-regulation. These results provide a rationale for combined biochemoprevention of HCC using acyclic retinoid and IFN-β.