DNMT1 expression partially dictates 5-Azacytidine sensitivity and correlates with RAS/MEK/ERK activity in gastric cancer cells.
DNMT1 expression partially dictates 5-Azacytidine sensitivity and correlates with RAS/MEK/ERK activity in gastric cancer cells.
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DOI：
10.1080/15592294.2023.2254976
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发表时间：
2023-12
期刊：
影响因子：
3.7
通讯作者：
Fan, Daiming
中科院分区：
文献类型：
--
作者：
Chen, Zhangqian;Zhang, Lin;Yang, Yang;Liu, Haiming;Kang, Xiaoyu;Nie, Yongzhan;Fan, Daiming
虽然DNMTs抑制剂广泛用于骨髓增生异常综合征和白血病，但其在实体瘤中的应用受到低反应率和缺乏最佳组合策略的限制。在胃癌（GC）中，KRAS突变或MEK/ERK激活对DNMT抑制剂与MEK/ERK抑制剂联合使用的治疗意义仍然难以捉摸。在这项研究中，通过慢病毒转染稳定敲低DNMT 1表达导致GC细胞对5-氮杂胞苷的敏感性降低。KRAS突变型GC细胞中的KRAS敲低或GC细胞中通过EGF刺激的MEK/ERK活化增加DNMT 1表达，而Selumetinib抑制MEK/ERK活性导致DNMT 1表达降低。5-氮杂胞苷处理导致DNMTs蛋白水平急剧下降和MEK/ERK途径活性增加，改变了MEK/ERK抑制剂Selumetinib对GC细胞的活性。RAS依赖性基因表达特征和多个MEK/ERK依赖性基因的表达水平均与TCGA胃癌样品中的DNMT 1表达相关。总之，DNMT 1表达部分决定了5-氮杂胞苷的敏感性，并与GC细胞中的RAS/MEK/ERK活性相关。联合应用DNMTs抑制剂和MEK/ERK抑制剂可能是治疗胃癌的一个有希望的策略。
Though DNMTs inhibitors were widely used in myelodysplastic syndrome and leukaemia, their application in solid tumours has been limited by low response rate and lack of optimal combination strategies. In gastric cancer (GC), the therapeutic implication of KRAS mutation or MEK/ERK activation for combinational use of DNMTs inhibitors with MEK/ERK inhibitors remains elusive. In this study, stable knockdown of DNMT1 expression by lentiviral transfection led to decreased sensitivity of GC cells to 5-Azacytidine. KRAS knockdown in KRAS mutant GC cells or the MEK/ERK activation by EGF stimulation in GC cells increased DNMT1 expression, while inhibition of MEK/ERK activity by Selumetinib led to decreased DNMT1 expression. 5-Azacytidine treatment, which led to dramatic decline of DNMTs protein levels and increased activity of MEK/ERK pathway, altered the activity of MEK/ERK inhibitor Selumetinib on GC cells. Both RAS-dependent gene expression signature and expression levels of multiple MEK/ERK-dependent genes were correlated with DNMT1 expression in TCGA stomach cancer samples. In conclusion, DNMT1 expression partially dictates 5-Azacytidine sensitivity and correlates with RAS/MEK/ERK activity in GC cells. Combining DNMTs inhibitor with MEK/ERK inhibitor might be a promising strategy for patients with GC.
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影响因子：
6.4
作者：
Liao, Xiaoyun;Siu, Michelle Kwan-Yee;Cheung, Annie Nga-Yin
通讯作者：
Cheung, Annie Nga-Yin
DOI：
10.1073/pnas.0700153104
发表时间：
2007-07-24
影响因子：
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作者：
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通讯作者：
Thorgeirsson SS
影响因子：
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作者：
Overman MJ;Morris V;Moinova H;Manyam G;Ensor J;Lee MS;Eng C;Kee B;Fogelman D;Shroff RT;LaFramboise T;Mazard T;Feng T;Hamilton S;Broom B;Lutterbaugh J;Issa JP;Markowitz SD;Kopetz S
通讯作者：
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