IL-23 promotes growth and proliferation in human squamous cell carcinoma of the oral cavity
IL-23 promotes growth and proliferation in human squamous cell carcinoma of the oral cavity
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DOI：
10.3892/ijo_00000620
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发表时间：
2010-06-01
影响因子：
5.2
通讯作者：
Sakashita, Hideaki
中科院分区：
文献类型：
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作者：
Fukuda, Masakatsu;Ehara, Masahiro;Sakashita, Hideaki
白介素23(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亚基组成，最近的研究发现它是一种与肿瘤相关的细胞因子。像IL-12一样，IL-23主要由激活的树突状细胞和吞噬细胞表达。这些细胞因子拮抗地调节肿瘤微环境中的局部炎症反应和上皮内淋巴细胞的浸润。我们已经证实了IL-23及其受体在人类口腔鳞状细胞癌(HOSCC)细胞系和组织中的表达。因此，本研究通过检测IL-23在体外和体内的表达动力学和核因子-kappaB的活性，探讨IL-23在口腔癌细胞的生长和增殖中是否起作用。IL-23在口腔癌中呈结构性表达，在肿瘤坏死因子-α和IL-23的共同作用下，IL-23表达增强。IL-23促进口腔癌细胞增殖，促进HSC-3细胞核因子-kappaB(NF-kappa B p65，relA)向细胞核的转运。此外，荧光素酶报告实验显示，IL-23强烈诱导RelA活性，并通过RNA干扰下调IL-23证实了这一发现。用来中和IL-23活性的抗人IL-23p19多克隆抗体可下调RELA活性，但不能诱导细胞凋亡。免疫组织化学结果显示，40例口腔鳞状细胞癌中有14例(35%)炎性细胞胞浆和癌细胞呈弱阳性反应。40例鳞癌组织中有30例(75%)呈强阳性反应，尤其与IL-23阳性细胞一致。这些数据表明，IL-23通过促进RELA的核反式激活而上调口腔癌的生长和细胞增殖。
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 intra-epithelial 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-kappa B 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-kappa B (NF-kappa B 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.