The Thr300Ala variant in ATG16L1 is associated with improved survival in human colorectal cancer and enhanced production of type I interferon.
The Thr300Ala variant in ATG16L1 is associated with improved survival in human colorectal cancer and enhanced production of type I interferon.
复制标题
ATG16L1中的THR300ALA变体与人类结直肠癌的生存率提高和I型干扰素的产生增强有关。
DOI：
10.1136/gutjnl-2014-308735
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发表时间：
2016-03
期刊：
影响因子：
24.5
通讯作者：
Boone DL
中科院分区：
文献类型：
--
作者：
Grimm WA;Messer JS;Murphy SF;Nero T;Lodolce JP;Weber CR;Logsdon MF;Bartulis S;Sylvester BE;Springer A;Dougherty U;Niewold TB;Kupfer SS;Ellis N;Huo D;Bissonnette M;Boone DL
ATG16L1是一种自噬基因，已知控制宿主对病毒和细菌的免疫反应。最近，ATG16L1(Thr300Ala)的非同义单核苷酸多态，以前被认为是克罗恩病(CD)的危险因素，与甲状腺癌更有利的临床结果相关。这一观察结果背后的机制尚未提出，也不清楚Thr300Ala与临床结果之间是否会在其他癌症中观察到关联。我们假设Thr300Ala影响人类结直肠癌(CRC)的临床结果，并控制结肠癌细胞中的天然抗病毒途径。我们对460例结直肠癌患者进行了基因分型，并评估了ATG16L1Thr300Ala基因与总生存期和临床分期的关系。通过同源重组来检测ATG16L1缺失或Thr300Ala变异体引入对人结直肠癌细胞株的功能影响。我们发现ATG16L1Ala/Ala基因型与较长的总生存期、较少的转移有关。ATG16L1ALA/ALA患者的肿瘤切片表达I型干扰素(干扰素-I)诱导的MXA升高，这表明细胞因子产生的差异可能影响疾病的进展。当Thr300Ala变异体通过同源重组导入人结直肠癌细胞时，不影响批量自噬，但增加了I型干扰素的基础产量。Thr300Ala的引入通过线粒体抗病毒信号传递(MAV)依赖的途径增加了对dsRNA模拟Poly(I：C)的敏感性。ATG16L1中的CD风险等位基因Thr300Ala与人类结直肠癌总存活率的提高有关，这为在结直肠癌患者中对ATG16L1Thr300Ala进行分型提供了理论基础。我们发现Thr300A改变了结直肠癌细胞中MAVS依赖的I型干扰素的产生，提供了一种可能影响临床结果的机制。
ATG16L1 is an autophagy gene known to control host immune responses to viruses and bacteria. Recently, a non-synonymous single-nucleotide polymorphism in ATG16L1 (Thr300Ala), previously identified as a risk factor in Crohn's disease (CD), was associated with more favourable clinical outcomes in thyroid cancer. Mechanisms underlying this observation have not been proposed, nor is it clear whether an association between Thr300Ala and clinical outcomes will be observed in other cancers. We hypothesised that Thr300Ala influences clinical outcome in human colorectal cancer (CRC) and controls innate antiviral pathways in colon cancer cells. We genotyped 460 patients with CRC and assessed for an association between ATG16L1 Thr300Ala and overall survival and clinical stage. Human CRC cell lines were targeted by homologous recombination to examine the functional consequence of loss of ATG16L1, or introduction of the Thr300Ala variant. We found an association between longer overall survival, reduced metastasis and the ATG16L1 Ala/Ala genotype. Tumour sections from ATG16L1 Ala/Ala patients expressed elevated type I interferons (IFN-I)-inducible, MxA, suggesting that differences in cytokine production may influence disease progression. When introduced into human CRC cells by homologous recombination, the Thr300Ala variant did not affect bulk autophagy, but increased basal production of type I IFN. Introduction of Thr300Ala resulted in increased sensitivity to the dsRNA mimic poly(I:C) through a mitochondrial antiviral signalling (MAVS)-dependent pathway. The CD-risk allele, Thr300Ala, in ATG16L1 is associated with improved overall survival in human CRC, generating a rationale to genotype ATG16L1 Thr300Ala in patients with CRC. We found that Thr300A alters production of MAVS-dependent type I IFN in CRC cells, providing a mechanism that may influence clinical outcomes.