干扰素-α通过上调头颈部鳞状细胞癌中的 RIG-I 增强 EGFR 靶向治疗的抗肿瘤活性。
Interferon-alpha enhances the antitumour activity of EGFR-targeted therapies by upregulating RIG-I in head and neck squamous cell carcinoma.
机构信息
Department of Oral Maxillofacial-Head and Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Stomatology, Shanghai 200011, China.
Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
出版信息
Br J Cancer. 2018 Feb 20;118(4):509-521. doi: 10.1038/bjc.2017.442. Epub 2018 Jan 18.
BACKGROUND
The epidermal growth factor receptor (EGFR)-targeted therapies have been tested in the clinic as treatments for head and neck squamous cell carcinoma (HNSCC). Owing to intrinsic or acquired resistance, EGFR-targeted therapies often lead to a low response rate and treatment failure. Interferon-alpha (IFNα) is a chemosensitising agent and multi-functional cytokine with a tumour inhibitory effect. However, the synergic effect of IFNα and EGFR-targeted therapies (erlotinib and nimotuzumab) and their mechanisms in HNSCC remain unclear.
METHODS
The interactions between IFNα, erlotinib, and nimotuzumab were evaluated in vitro in HNSCC cells. The synergistic effect of IFNα (20 000 IU per day, s.c.), erlotinib (50 mg kg per day, i.g.) and nimotuzumab (10 mg kg per day, i.p.) was further confirmed in vivo using HNSCC xenografts in nude mice. The upregulation of retinoic-acid inducible gene I (RIG-I) induced by IFNα and EGFR-targeted therapies and its mechanism were detected in vitro and in vivo.
RESULTS
IFNα enhances the antitumour effects of erlotinib and nimotuzumab on HNSCC cells both in vitro and in vivo. Importantly, both IFNα and EGFR-targeted therapies promote the expression of RIG-I by activating signal transducers and activators of transcription 1 (STAT1) in HNSCC cells. RIG-I knockdown reduced the sensitivity of HN4 and HN30 cells to IFNα, erlotinib, and nimotuzumab. Moreover, IFNα transcriptionally induced RIG-I expression in HNSCC cells through STAT1.
CONCLUSIONS
IFNα enhances the effect of EGFR-targeted therapies by upregulating RIG-I, and its expression may represent a predictor of the effectiveness of a combination treatment including IFNα in HNSCC.
背景
表皮生长因子受体（EGFR）靶向治疗已在临床上作为头颈部鳞状细胞癌（HNSCC）的治疗方法进行了测试。由于内在或获得性耐药，EGFR 靶向治疗往往导致低反应率和治疗失败。干扰素-α（IFNα）是一种具有化学增敏作用的多功能细胞因子，具有肿瘤抑制作用。然而，IFNα 与 EGFR 靶向治疗（厄洛替尼和尼莫司汀）的协同作用及其在 HNSCC 中的机制尚不清楚。
方法
在 HNSCC 细胞中评估 IFNα、厄洛替尼和尼莫司汀之间的相互作用。在裸鼠的 HNSCC 异种移植模型中进一步证实 IFNα（每天 20000IU，sc）、厄洛替尼（每天 50mg/kg，ig）和尼莫司汀（每天 10mg/kg，ip）的协同作用。在体外和体内检测 IFNα 和 EGFR 靶向治疗诱导的视黄酸诱导基因 I（RIG-I）的上调及其机制。
结果
IFNα 增强了厄洛替尼和尼莫司汀对 HNSCC 细胞的抗肿瘤作用，无论是在体外还是体内。重要的是，IFNα 和 EGFR 靶向治疗通过激活信号转导子和转录激活子 1（STAT1）促进 RIG-I 在 HNSCC 细胞中的表达。RIG-I 敲低降低了 HN4 和 HN30 细胞对 IFNα、厄洛替尼和尼莫司汀的敏感性。此外，IFNα 通过 STAT1 转录诱导 RIG-I 在 HNSCC 细胞中的表达。
结论
IFNα 通过上调 RIG-I 增强 EGFR 靶向治疗的效果，其表达可能代表包括 IFNα 在内的联合治疗有效性的预测因子。
Zotero 插件