KMT2C Mutations in Diffuse-Type Gastric Adenocarcinoma Promote Epithelial-to-Mesenchymal Transition.
KMT2C Mutations in Diffuse-Type Gastric Adenocarcinoma Promote Epithelial-to-Mesenchymal Transition.
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DOI：
10.1158/1078-0432.ccr-17-1679
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发表时间：
2018-12-15
期刊：
影响因子：
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通讯作者：
Yoon SS
中科院分区：
文献类型：
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作者：
Cho SJ;Yoon C;Lee JH;Chang KK;Lin JX;Kim YH;Kook MC;Aksoy BA;Park DJ;Ashktorab H;Smoot DT;Schultz N;Yoon SS
劳伦弥漫型胃腺癌（DGA）是基因组稳定。我们确定赖氨酸（K）特异性甲基转移酶2C（KMT2C）作为一个经常突变的基因，并检查其在DGA进展中的作用。对27例接受胃切除术的DGA患者的肿瘤样本进行全外显子组测序，并在27例肿瘤中的11例（41%）中鉴定出赖氨酸（K）特异性甲基转移酶2C（KMT2C）突变。DGA中KMT2C突变的这种高频率在先前的研究中尚未发现。135例接受胃切除术的DGA患者肿瘤中通过免疫组织化学检测的KMT2C表达与更晚期的肿瘤分期（p = 0.023）和更差的总生存期（p = 0.017）呈负相关。HFE-145胃上皮细胞中KMT2C shRNA敲低促进上皮向间质转化（EMT），如EMT相关蛋白N-cadherin和Slug表达增加所证明。KMT2C敲低后胃上皮细胞的迁移和侵袭增加了47 - 88倍。在已经失去KMT2C表达的DGA细胞系MKN-45和SNU-668中，KMT2C再表达降低了EMT相关蛋白的表达，使细胞迁移降低了52 - 60%，并且使细胞侵袭降低了50 - 74%。与野生型类器官相比，源自表达KMT2C的DGA类器官的侧翼异种移植物生长更慢，并且失去了它们的浸润前沿。EMT可导致获得癌症干细胞（CSC）表型。DGA细胞系中KMT2C的再表达减少了77 - 78%的球体形成，并通过促进DNA损伤和凋亡逆转了CSC对化疗的抗性。KMT2C在某些DGA人群中经常发生突变。KMT2C缺失与总体生存率降低相关，并促进EMT。
Lauren diffuse type gastric adenocarcinoma (DGA) is genomically stable. We identified lysine (K)-specific methyltransferase 2C (KMT2C) as a frequently mutated gene and examined its role in DGA progression. Whole exome sequencing on tumor samples of 27 patients with DGA who underwent gastrectomy and identified lysine (K)-specific methyltransferase 2C (KMT2C) as mutated in 11 of 27 tumors (41%). This high frequency of KMT2C mutations in DGA has not been found in prior studies. KMT2C expression by immunohistochemistry in tumors from 135 DGA patients undergoing gastrectomy inversely correlated with more advanced tumor stage (p=0.023) and worse overall survival (p = 0.017). KMT2C shRNA knockdown in HFE-145 gastric epithelial cells promoted epithelial-to-mesenchymal transition (EMT) as demonstrated by increased expression of EMT-related proteins N-cadherin and Slug. Migration and invasion in gastric epithelial cells following KMT2C knockdown increased by 47–88 fold. In the DGA cell lines MKN-45 and SNU-668, which have lost KMT2C expression, KMT2C re-expression decreased expression of EMT-related proteins, reduced cell migration by 52–60%, and reduced cell invasion by 50–74%. Flank xenografts derived from KMT2C-expressing DGA organoids, compared to wild-type organoids, grew more slowly and lost their infiltrative leading edge. EMT can lead to the acquisition of cancer stem cell (CSC) phenotypes. KMT2C re-expression in DGA cell lines reduced spheroid formation by 77–78% and reversed CSC resistance to chemotherapy via promotion of DNA damage and apoptosis. KMT2C is frequently mutated in certain populations with DGA. KMT2C loss is associated with worse overall survival and promotes EMT.