Humanised antihuman IL-6R antibody with interferon inhibits renal cell carcinoma cell growth in vitro and in vivo through suppressed SOCS3 expression
Humanised antihuman IL-6R antibody with interferon inhibits renal cell carcinoma cell growth in vitro and in vivo through suppressed SOCS3 expression
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DOI：
10.1016/j.ejca.2012.11.038
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发表时间：
2013-05-01
影响因子：
8.4
通讯作者：
Kojima, Yoshiyuki
中科院分区：
文献类型：
--
作者：
Oguro, Toshiki;Ishibashi, Kei;Kojima, Yoshiyuki
白细胞介素6(IL-6)是一种促炎症细胞因子，被认为是肾癌患者预后不良的因素之一。细胞因子信号转导抑制因子3(SOCS3)被IL-6和细胞因子信号负调控因子迅速上调。SOCS3不仅抑制细胞因子介导的JAK/STAT信号转导，而且支持MAPK通路。在我们的研究中，在肾癌细胞系中，786-O细胞中IL-6mRNA的表达水平最高，这也表明在干扰素刺激的条件下，SOCS3mRNA的表达水平最高。相反，在相同条件下，ACHN细胞中IL-6和SOCS3mRNA的表达水平最低。我们的研究旨在评估人源化抗人IL-6受体(IL-6R)抗体在肾癌细胞增殖中的作用及其对信号通路的影响。IL-6R抗体tocilizumab可显著抑制干扰素刺激的786-O细胞的增殖。Western印迹分析显示，tocilizumab增强了干扰素诱导的STAT1的磷酸化，抑制了SOCS3的表达和STAT3和ERK的磷酸化。相反，IL-6抑制ACHN细胞中STAT1的磷酸化，增强STAT3的磷酸化，促进细胞的增殖。托西珠单抗和干扰素联合治疗的体内效果显示，在异种移植模型中，786-O肿瘤生长受到显著抑制。肿瘤形态观察显示肿瘤细胞凋亡、炎性细胞侵袭、纤维化。这些发现表明，使用抗人IL-6R抗体和干扰素联合治疗可能是治疗肾癌的一种新的治疗方法。(C)2012爱思唯尔有限公司。保留所有权利。
Interleukin-6 (IL-6), one of the proinflammatory cytokines, is considered to be one of the factors associated with poor prognosis of patients with renal cell carcinoma (RCC). Suppressor of cytokine signalling-3 (SOCS3) is rapidly up-regulated by IL-6 and a negative regulator of cytokine signalling. SOCS3 not only suppresses cytokine-mediated JAK/STAT signalling, but also sustains MAPK pathways. In our study, among the RCC cell lines, IL-6 mRNA expression was the highest in the 786-O cells, which also showed the highest level of SOCS3 mRNA expression under the condition of interferon stimulation. In contrast, ACHN cells had the lowest expression of both IL-6 and SOCS3 mRNA under the same condition. Our study is undertaken to evaluate the effect of humanised antihuman IL-6 receptor (IL-6R) antibody, which completely neutralises IL-6 activity, in RCC cell proliferation and its effect on signalling pathways. IL-6R antibody, tocilizumab, significantly suppressed cell proliferation in 786-O cells with interferon stimulation. Western blot analysis revealed that the tocilizumab enhanced the interferon-induced phosphorylation of STAT1 and inhibited SOCS3 expression and the phosphorylation of both STAT3 and ERK. In contrast, the IL-6 inhibited STAT1 phosphorylation, enhanced STAT3 phosphorylation and accelerated cell proliferation in ACHN cells. The in vivo effects of combination therapy with tocilizumab and interferon showed significant suppression of 786-O tumour growth in a xenograft model. Morphological observation of the tumours revealed the apoptosis, invasion of inflammatory cells and fibrosis. These findings suggest that combination therapy using an antihuman IL-6R antibody with interferon may represent a novel therapeutic approach for the treatment of RCC. (C) 2012 Elsevier Ltd. All rights reserved.