Deficiency of Interferon-Gamma or Its Receptor Promotes Colorectal Cancer Development
Deficiency of Interferon-Gamma or Its Receptor Promotes Colorectal Cancer Development
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干扰素-γ或其受体的缺乏促进结直肠癌的发展
DOI：
10.1089/jir.2014.0132
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发表时间：
2015-04-01
影响因子：
2.3
通讯作者：
Qu, Xianjun
中科院分区：
文献类型：
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作者：
Wang, Lu;Wang, Yan;Qu, Xianjun
干扰素-γ及其受体亚基的基因变异与结直肠癌的风险和确诊后的生存密切相关。然而，干扰素-γ或干扰素-γ受体功能缺失在结直肠癌发病机制中的作用尚不清楚。在这里，我们通过培育一种变种的APC(Min/+)小鼠来研究内源性干扰素-γ缺乏在APC(腺瘤性息肉病)介导的肠道肿瘤中的作用。APC(Min/+)干扰素-γ(+/-)小鼠出现腺瘤数量和大小增加，其中41.7%发展为腺癌。对腺瘤的分子分析表明，干扰素-γ杂合性缺失促进了EGFR/ERK1/2和Wnt/β-catenin信号转导。在体外，干扰素-γ可抑制APC突变的HT-29结肠癌细胞的增殖，而对表达野生型APC的HCT-116结肠癌细胞的增殖无影响。此外，我们还用针对其受体亚基之一干扰素-γR1的小干扰RNA攻击了HT-29细胞。我们发现，在HT-29细胞中，下调干扰素-γ-R1基因可以刺激细胞增殖和集落形成，这也与EGFR/ERK1/2和Wnt/β-catenin信号的调控有关。因此，我们的结果有力地支持了这样的观点，即干扰素-γ和干扰素-伽玛素R1在结直肠癌的发展中起到了限速因子的作用，揭示了它们在癌症生物学中的新作用。
Genetic variations in interferon-gamma (IFN-gamma) and its receptor (IFN gamma R) subunits are closely associated with the risk of colorectal cancer (CRC) and survival after diagnosis. However, the role of loss of IFN-gamma or IFN gamma R function in the pathogenesis of CRC remains unclear. Here, we investigated the role of endogenous IFN-gamma deficiency in adenomatous polyposis coli (Apc)-mediated intestinal tumor by developing a variant of Apc(Min/+) mice. The Apc(Min/+)IFN-gamma(+/-) mice presented with increased number and size of adenomas, and 41.7% of these mice developed adenocarcinoma. Molecular analyses of the adenomas suggested that heterozygous deletion of IFN-gamma promoted EGFR/Erk1/2 and Wnt/beta-catenin signaling. In vitro, IFN-gamma administration inhibited Apc-mutated HT-29 colon cancer cell proliferation and had no effect on the proliferation of HCT-116 colon cancer cells that express wild-type Apc. Besides, we challenged HT-29 cells with small interfering RNA targeting one of its receptor subunits IFN gamma R1. We found that knockdown of IFN gamma R1 in HT-29 cells stimulated cell proliferation and colony formation, which was also related to the regulation of EGFR/Erk1/2 and Wnt/beta-catenin signaling. Thus, our results strongly support the notion that IFN-gamma and IFN gamma R1 act as a rate-limiting factor in the development of CRC, uncovering a novel role for them in cancer biology.