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

无环类维生素A（一种合成的类维生素A类似物）以及干扰素（IFN）-α和-β诱导肝细胞癌（HCC）细胞凋亡，并在临床上用于预防HCC。在这里，我们表明，无环类维生素A协同作用，在抑制生长和诱导细胞凋亡（其特征在于DNA片段化和染色质凝聚）在5个人肝癌细胞系（JHH 7，HuH 7，PLC/PRF/5，HLE和HLF）的干扰素。这种协同作用只观察到细胞预处理的aeyloop类维生素A，而天然视黄酸（全反式和9-顺式视黄酸）是无效的。这种促进作用可能是由于类维生素A上调1型IFN受体（IFNR）的表达。因此，与抗1型IFNR抗体孵育消除了协同作用。增强的IFNR表达伴随着增加的STAT 1（IFNR的细胞内信号转导分子）的表达和DNA结合活性，以及增加的2 '，5'-寡腺苷酸-5 '-三磷酸合成酶（其是STAT 1的靶基因）的诱导。无环类维生素A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STAT 1的上调。这些结果为使用无环类维生素A和IFN-β联合生物化学预防HCC提供了理论基础。

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.