MIIP haploinsufficiency induces chromosomal instability and promotes tumour progression in colorectal cancer.
MIIP haploinsufficiency induces chromosomal instability and promotes tumour progression in colorectal cancer.
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MIIP 单倍体不足诱导染色体不稳定并促进结直肠癌肿瘤进展
DOI：
10.1002/path.4823
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发表时间：
2017-01
期刊：
影响因子：
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通讯作者：
Zhang W
中科院分区：
文献类型：
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作者：
Sun Y;Ji P;Chen T;Zhou X;Yang D;Guo Y;Liu Y;Hu L;Xia D;Liu Y;Multani AS;Shmulevich I;Kucherlapati R;Kopetz S;Sood AK;Hamilton SR;Sun B;Zhang W
迁移和侵袭抑制蛋白（migration and invasion inhibitor protein，MIIP）基因位于1p36.22，是胶质瘤中潜在的抑癌基因。本研究旨在探讨MIIP在结直肠癌（CRC）中的作用及其机制。在526例结直肠组织中，MIIP蛋白表达沿着结直肠腺瘤-癌序列逐渐降低，并与淋巴结转移和远处转移呈负相关（均为p < 0.05）。癌症基因组图谱（TCGA）数据分析显示，MIIP表达降低与MIIP半合子缺失显著相关（p = 0.0005），在27.7%（52/188）的CRC病例中检测到MIIP半合子缺失，并与淋巴结和远处转移相关（两者均p < 0.05）。我们使用锌指核酸酶技术在HCT 116 CRC细胞中缺失了一个拷贝的MIIP基因，并证明MIIP单倍不足导致集落形成以及细胞迁移和侵袭增加，这与两种CRC细胞系中siRNA介导的MIIP敲低的结果一致（所有p < 0.05）。此外，MIIP单倍不足促进体内CRC进展（p < 0.05）。基因组不稳定性和光谱核型分析表明，MIIP单倍不足诱导染色体不稳定性（CIN）。除了调节APC/CCdc 20、securin和cyclin B1的下游蛋白外，MIIP单倍不足还抑制拓扑异构酶II（Topo II）活性并诱导染色体错误分离。因此，我们报告MIIP是一个新的潜在的肿瘤抑制基因在大肠癌。此外，我们的特点是MIIP基因作为一个新的CIN抑制基因，通过改变有丝分裂检查点蛋白的稳定性和干扰拓扑异构酶II活性。版权所有© 2016大不列颠及爱尔兰病理学会。由John Wiley & Sons有限公司出版
The gene encoding migration and invasion inhibitory protein (MIIP), located on 1p36.22, is a potential tumour suppressor gene in glioma. In this study, we aimed to explore the role and mechanism of action of MIIP in colorectal cancer (CRC). MIIP protein expression gradually decreased along the colorectal adenoma–carcinoma sequence and was negatively correlated with lymph node and distant metastasis in 526 colorectal tissue samples (p < 0.05 for all). Analysis of The Cancer Genome Atlas (TCGA) data showed that decreased MIIP expression was significantly associated with MIIP hemizygous deletion (p = 0.0005), which was detected in 27.7% (52/188) of CRC cases, and associated with lymph node and distant metastasis (p < 0.05 for both). We deleted one copy of the MIIP gene in HCT116 CRC cells using zinc finger nuclease technology and demonstrated that MIIP haploinsufficiency resulted in increased colony formation and cell migration and invasion, which was consistent with the results from siRNA‐mediated MIIP knockdown in two CRC cell lines (p < 0.05 for all). Moreover, MIIP haploinsufficiency promoted CRC progression in vivo (p < 0.05). Genomic instability and spectral karyotyping assays demonstrated that MIIP haploinsufficiency induced chromosomal instability (CIN). Besides modulating the downstream proteins of APC/CCdc20, securin and cyclin B1, MIIP haploinsufficiency inhibited topoisomerase II (Topo II) activity and induced chromosomal missegregation. Therefore, we report that MIIP is a novel potential tumour suppressor gene in CRC. Moreover, we characterized the MIIP gene as a novel CIN suppressor gene, through altering the stability of mitotic checkpoint proteins and disturbing Topo II activity. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.