Downregulation of RIG-I mediated by ITGB3/c-SRC/STAT3 signaling confers resistance to interferon-α-induced apoptosis in tumor-repopulating cells of melanoma

作者：Yong Li, Yingqiu Song, Pindong Li, Mingxing Li, Haizhou Wang, Tao Xu, Xiongjie Yu, Yuandong Yu, Yunyan Tai, Ping Chen, Xiaojun Cai, Xianhe Wang, Longchao Xiang, Rui Deng, Xiufang Zhang, Liping Gao, Xuanbin Wang, Jing Liu, Fengjun Cao · 发表于：Journal for ImmunoTherapy of Cancer · 年份：2020 · DOI：10.1136/jitc-2019-000111 · 被引用次数：39 · 研究领域：interferon and immune responses、Retinoids in leukemia and cellular processes、Cytokine Signaling Pathways and Interactions

BACKGROUND: Interferon-α (IFN-α) plays a pivotal role in host antitumor immunity, and the evasion of IFN-α signaling pathway can lead to IFN-α resistance during the treatment of cancer. Although the interplay between IFN-α and tumor cells has been extensively investigated in differentiated tumor cells, much less attention has been directed to tumor-repopulating cells (TRCs). METHODS: Three-dimentional soft fibrin matrix was used to select and grow highly malignant and tumorigenic melanoma TRCs. The regulation of integrin β3 (ITGB3)-c-SRC-STAT signaling pathway in melanoma TRCs was investigated both in vitro and in vivo. The relevant mRNA and protein expression levels were analyzed by qRT-PCR and western blot analysis. Immunoprecipitation and chromatin immunoprecipitation (ChIP) followed by qPCR (ChIP-qPCR) assays were performed to detect protein-protein and protein-DNA interactions. The clinical impacts of retinoic acid inducible gene-I (RIG-I) were assessed in melanoma datasets obtained from The Cancer Genome Atlas and Gene Expression Omnibus profiles. RESULTS: IFN-α-induced apoptosis was decreased in melanoma TRCs. Compared with conventional flask-cultured cells, IFN-α-mediated STAT1 activation was diminished in melanoma TRCs. Decreased expression of RIG-I in melanoma TRCs led to diminished activation of STAT1 via enhancing the interaction between Src homology region 2 domain-containing phosphatase-1 and STAT1. In addition, low expression levels of RIG-I correlated with poo...