Damdinsuren Bazarragchaa, Nagano Hiroaki, Wada Hiroshi, Kondo Motoi, Ota Hideo, Nakamura Masato, Noda Takehiro, Natsag Javzandulam, Yamamoto Hirofumi, Doki Yuichiro, Umeshita Koji, Dono Keizo, Nakamori Shoji, Sakon Masato, Monden Morito
Department of Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan.
Int J Oncol. 2007 Jan;30(1):201-8.
Interferon (IFN) is a promising drug for prevention and treatment of hepatocellular carcinoma (HCC) in combination with chemotherapeutic agents. We previously reported that the spectra of antiproliferative activity and synergistic effect of IFN-beta when combined with anticancer drugs are more potent than those of IFN-alpha in HCC cells. However, the mechanism of the diverse antitumor effects of the IFNs is not understood yet. We studied the expression of IFN alpha receptor 2 (IFNAR2), STATs, and IFN-alpha, IFN-beta's growth-inhibitory effect, signal transduction and binding to IFNAR2 on three HCC cell lines and a tumor xenografted mouse model (12 animals/group). From the results, IFN-beta showed a significantly stronger growth-inhibitory effect than IFN-alpha on the HuH7 cell line (expressing low IFNAR2), however it was similarly high on PLC/PRF/5 and weak on HLE. In the nude mouse tumor xenograft model, IFN-beta injection significantly suppressed tumor volume relative to vehicle injection, while IFN-alpha showed weaker growth-inhibition. IFN signal transduction (phosphorylated-STAT1, 3) induced by IFN-beta was higher than that by IFN-alpha in HuH7 and tumor xenografts. Pretreatment of hepatoma cells with anti-IFNAR2 antibody blocked the IFN signaling, more for IFN-alpha. IFN-alpha's antiproliferative effect was reduced by the antibody in lower concentrations compared to that of IFN-beta. Taken together, the HCC cells that express low IFNAR2 and are resistant to IFN-alpha were sensitive to the growth-inhibitory effect of IFN-beta, which might be mediated by stronger IFN signal transduction and distinct binding to IFNAR compared to IFN-alpha.
干扰素（IFN）是一种与化疗药物联合用于预防和治疗肝细胞癌（HCC）的有前景的药物。我们之前报道过，在肝癌细胞中，IFN-β与抗癌药物联合时的抗增殖活性谱和协同效应比IFN-α更强。然而，IFN不同抗肿瘤作用的机制尚未明确。我们研究了IFNα受体2（IFNAR2）、信号转导和转录激活因子（STATs）以及IFN-α、IFN-β在三种肝癌细胞系和一种肿瘤异种移植小鼠模型（每组12只动物）上的生长抑制作用、信号转导及与IFNAR2的结合情况。结果显示，IFN-β对HuH7细胞系（表达低水平IFNAR2）的生长抑制作用明显强于IFN-α，但对PLC/PRF/5细胞系的作用同样显著，对HLE细胞系的作用较弱。在裸鼠肿瘤异种移植模型中，相对于注射溶媒，注射IFN-β可显著抑制肿瘤体积，而IFN-α的生长抑制作用较弱。在HuH7细胞系和肿瘤异种移植模型中，IFN-β诱导的IFN信号转导（磷酸化STAT1、3）高于IFN-α。用抗IFNAR2抗体预处理肝癌细胞可阻断IFN信号，对IFN-α的阻断作用更强。与IFN-β相比，较低浓度的抗体即可降低IFN-α的抗增殖作用。综上所述，表达低水平IFNAR2且对IFN-α耐药的肝癌细胞对IFN-β的生长抑制作用敏感，这可能是由于与IFN-α相比，IFN-β具有更强的IFN信号转导及与IFNAR的独特结合。
