Division of Pathology and Cell Therapy, Chiba Cancer Center Research Institute, 666-2 Nitona, Chuo-ku, Chiba 260-8717, Japan.
Eur J Cancer. 2010 Jan;46(1):180-90. doi: 10.1016/j.ejca.2009.10.002.
Signal pathways of novel type III interferons (IFN-lambdas) are similar to those of type I IFNs (IFN-alpha/beta) but their distinct functions have not been well characterised. We examined the growth suppressive activity of IFN-lambda1 with nine human oesophageal carcinoma cell lines expressing the IFN-lambda receptor complexes. Among them, three lines but not others showed IFN-lambda1-mediated growth suppression by inducing G1 phase arrest or apoptosis. The G1 phase arrest was accompanied by the up-regulation of p21 and dephosphorylation of retinoblastoma (Rb), and the apoptosis was evidenced by cleavage of caspase-3 and poly (ADP-ribose) polymerase (PARP). Similar but not identical susceptibility was found in IFN-alpha-treated oesophageal carcinoma cells. Despite the differential suppressive responses among the cells, all the cells increased the expression of the myxovirus resistance A (MxA) and 2',5'-oligoadenylate synthetase (2',5'-OAS) genes and class I antigens of the major histocompatibility complexes (MHC) with IFN-lambda1 treatment. Fibroblasts and mesenchymal stem cells, positive for IFN-alpha receptor (IFNAR), lacked one of the IFN-lambda receptor complexes and Het-1A, immortalised oesophageal epithelium cells, were insensible to the IFN-lambda1-induced growth suppression. IFN-lambda1 produced combinatory anti-tumour effects with chemotherapeutic agents, cisplatin (CDDP) and 5-fluorouracil (5-FU), in IFN-lambda1-sensitive oesophageal carcinoma cells but not in normal or Het-1A cells, while IFN-alpha achieved the combinatory suppressive effects to normal cells. These data collectively show that IFN-lambda1 responsiveness is tissue-specific due to the restricted receptors expression and is diversified even among cells of the same lineage, and suggest that IFN-lambda1 is a potential therapeutic agent for oesophageal carcinoma without damaging surrounding tissues.
新型 III 型干扰素（IFN-lambdas）的信号通路与 I 型 IFN（IFN-α/β）相似，但它们的独特功能尚未得到很好的描述。我们检查了 IFN-lambda1 在表达 IFN-lambda 受体复合物的九种人食管癌细胞系中的生长抑制活性。其中，三种细胞系而非其他细胞系表现出 IFN-lambda1 通过诱导 G1 期阻滞或凋亡来介导生长抑制。G1 期阻滞伴随着 p21 的上调和视网膜母细胞瘤（Rb）的去磷酸化，凋亡则通过 caspase-3 和多聚（ADP-核糖）聚合酶（PARP）的裂解来证明。在 IFN-α处理的食管癌细胞中发现了类似但不完全相同的易感性。尽管细胞之间的抑制反应存在差异，但所有细胞在 IFN-lambda1 处理后均增加了粘病毒抗性 A（MxA）和 2'，5'-寡腺苷酸合成酶（2'，5'-OAS）基因以及主要组织相容性复合物（MHC）I 类抗原的表达。成纤维细胞和间充质干细胞对 IFN-α受体（IFNAR）呈阳性，但缺乏 IFN-lambda 受体复合物之一，而永生化食管上皮细胞 Het-1A 对 IFN-lambda1 诱导的生长抑制无反应。IFN-lambda1 与化疗药物顺铂（CDDP）和 5-氟尿嘧啶（5-FU）在 IFN-lambda1 敏感的食管癌细胞中产生协同抗肿瘤作用，但在正常细胞或 Het-1A 细胞中则没有，而 IFN-α则对正常细胞产生协同抑制作用。这些数据共同表明，IFN-lambda1 的反应性是组织特异性的，这是由于受体表达受限，即使在同一谱系的细胞中也存在多样性，并且表明 IFN-lambda1 是一种潜在的治疗食管癌细胞的药物，而不会损伤周围组织。
