Second Division of Oral and Maxillofacial Surgery, Department of Diagnostic and Therapeutic Sciences, Meikai University School of Dentistry, Sakado, Saitama 350-0283, Japan.
Int J Oncol. 2010 Jun;36(6):1355-65. doi: 10.3892/ijo_00000620.
Interleukin (IL)-23 is a heterodimeric cytokine, comprising IL-12p40 and the cloned IL-23-specific p19 subunit, was identified as a cancer-associated cytokine in a recent study. Like IL-12, IL-23 is expressed predominantly by activated dendritic cells and phagocytic cells. These cytokines antagonistically regulate local inflammatory responses in the tumor microenvironment and infiltration by intraepithelial lymphocytes. We have previously demonstrated the expression of IL-23 and its receptors in human oral squamous cell carcinoma (HOSCC) cell lines and tissue. Hence, this study investigated whether IL-23 has a role in the growth and proliferation of oral cancer cells by examining the expression kinetics of IL-23 and NF-kappaB activity, in vitro and in vivo. IL-23, which constitutively expressed in oral cancer, was enhanced by TNF-alpha and IL-23. IL-23 promotes cell proliferation in oral cancer and enhances the transport of nuclear factor-kappaB (NF-kappaB p65, RelA) to the nucleus in HSC-3 cells. Furthermore, luciferase reporter assay showed that IL-23 strongly induces RelA activity, and confirmed this finding by knockdown of IL-23 using RNA interference. Although RelA activity was down-regulated by anti-human IL-23p19 polyclonal antibody, used to neutralize the activity of IL-23, apoptosis was not induced. Immunohistochemistry revealed a weak IL-23 immunoreactivity in the cytoplasm of inflammatory infiltrating cells and in the cancer cells derived from 14 of 40 cases (35%) of oral SCC. In contrast, strong RelA immunoreactivity was observed in 30 of 40 cases of SCC (75%), especially consistent with IL-23 positive cells in SCC tissues. These data suggest that IL-23 up-regulates the growth and cell proliferation of oral cancer by promoting the nuclear transactivation of RelA.
白细胞介素 (IL)-23 是一种异二聚体细胞因子，由 IL-12p40 和克隆的 IL-23 特异性 p19 亚单位组成，在最近的一项研究中被确定为与癌症相关的细胞因子。像 IL-12 一样，IL-23 主要由活化的树突状细胞和吞噬细胞表达。这些细胞因子在肿瘤微环境中拮抗地调节局部炎症反应和上皮内淋巴细胞的浸润。我们之前已经证明了 IL-23 及其受体在人口腔鳞状细胞癌 (HOSCC) 细胞系和组织中的表达。因此，本研究通过检查 IL-23 和 NF-κB 活性的表达动力学，在体外和体内研究了 IL-23 是否在口腔癌细胞的生长和增殖中发挥作用。IL-23 在口腔癌中持续表达，可被 TNF-α 和 IL-23 增强。IL-23 促进口腔癌细胞的增殖，并增强 HSC-3 细胞中核因子-κB (NF-κB p65、RelA)向核内的转运。此外，荧光素酶报告基因分析显示 IL-23 可强烈诱导 RelA 活性，并通过 RNA 干扰敲低 IL-23 证实了这一发现。尽管用抗人 IL-23p19 多克隆抗体下调 RelA 活性可下调 RelA 活性，但并未诱导细胞凋亡。免疫组织化学显示，在 40 例口腔 SCC 中的 14 例（35%）炎性浸润细胞和癌细胞的细胞质中存在较弱的 IL-23 免疫反应性。相比之下，在 40 例 SCC 中观察到强烈的 RelA 免疫反应性（75%），尤其是在 SCC 组织中与 IL-23 阳性细胞一致。这些数据表明，IL-23 通过促进 RelA 的核转激活而上调口腔癌细胞的生长和增殖。
