Suppression of SOCS3 increases susceptibility of renal cell carcinoma to interferon-α
Suppression of SOCS3 increases susceptibility of renal cell carcinoma to interferon-α
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DOI：
10.1111/j.1349-7006.2010.01751.x
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发表时间：
2011-01-01
期刊：
影响因子：
5.7
通讯作者：
Yamaguchi, Osamu
中科院分区：
文献类型：
--
作者：
Tomita, Shintaro;Ishibashi, Kei;Yamaguchi, Osamu
干扰素-α是晚期肾癌患者免疫治疗中最常用的药物之一。然而，由于对干扰素-α的耐药性，其好处是有限的。在这项研究中，我们检测了参与干扰素诱导的信号通路的细胞因子信号转导抑制蛋白(SOCS)的抑制是否可以克服肾癌对干扰素的耐药性。采用干扰素耐药株786-O和干扰素敏感株ACHN，观察干扰素-α对ACHN细胞SOCS3表达和细胞增殖的影响。以SOCS3为靶点的siRNA对786-O移植瘤的影响通过SOCS3的表达、形态观察和肿瘤体积来确定。干扰素-α刺激后，786-O细胞SOCS3基因表达水平显著升高，而ACHN细胞SOCS3基因表达水平无明显变化。SOCS3基因在ACHN细胞中的过表达显著抑制了干扰素-α的生长抑制作用。SiRNA抑制786-O细胞SOCS3的表达，通过信号转导和转录激活因子1的磷酸化激活了干扰素信号通路，恢复了对干扰素-α的敏感性。体内研究表明，联合应用SOCS3靶向siRNA可促进干扰素-α诱导的786-O细胞裸鼠移植瘤的细胞死亡和生长抑制。肿瘤的形态观察显示，SOCS3可抑制SOCS3诱导的细胞凋亡、炎症细胞侵袭和纤维化。SOCS3可能是肾细胞癌对干扰素耐药的关键成分。沉默SOCS3基因的表达可能是增强干扰素对人肾癌细胞抗肿瘤作用的有效策略。(《癌症科学》2011；102：57-63)。
Interferon (IFN)-alpha is one of the most commonly used agents in immunotherapy for patients with advanced stage renal cell carcinoma. However, because of the drug resistance to IFN-alpha, its benefits are limited. In this study, we examined whether repression of suppressor of cytokine signaling (SOCS) proteins, which are involved in the IFN-induced signaling pathway, can overcome the IFN resistance of renal cell carcinoma. The effect of IFN-alpha on SOCS3 expression and cell proliferation was examined using IFN-resistant 786-O and IFN-sensitive ACHN cell lines. The effects of SOCS3-targeted siRNA on 786-O xenografts were determined by SOCS3 expression, morphological observation, and tumor volume. The SOCS3 mRNA expression level was significantly increased by IFN-alpha stimulation in 786-O, but not in ACHN cells. The overexpression of SOCS3 by gene transfection in ACHN cells significantly inhibited the growth-inhibitory effect of IFN-alpha. Suppression of SOCS3 expression in 786-O cells by siRNA activated the IFN signaling pathway through signal transducer and activator of transcription 1 phosphorylation and recovered sensitivity to IFN-alpha. An in vivo study indicated that co-administration of SOCS3-targeted siRNA promoted IFN-alpha-induced cell death and growth suppression in 786-O cell xenograft in nude mice. Morphological observation of the tumors revealed the inhibition of SOCS3-induced apoptosis, invasion of inflammatory cells and fibrosis. SOCS3 could be a key component in the resistance to IFN treatment of renal cell carcinoma. Silencing SOCS3 gene expression could be an effective strategy to enhance the antitumor effect of IFN in human renal cell carcinoma cells. (Cancer Sci 2011; 102: 57-63).