MeCP2 confers 5-fluorouracil resistance in gastric cancer via upregulating the NOX4/PKM2 pathway.
MeCP2 confers 5-fluorouracil resistance in gastric cancer via upregulating the NOX4/PKM2 pathway.
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DOI：
10.1186/s12935-022-02489-y
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发表时间：
2022-02-18
影响因子：
5.8
通讯作者：
Zhao L
中科院分区：
文献类型：
--
作者：
Qin Y;Ma X;Guo C;Cai S;Ma H;Zhao L
越来越多的证据表明，异常甲基化与胃癌 (GC) 的 5-氟尿嘧啶 (5-FU) 耐药性有关。我们前期的工作发现，甲基CpG结合蛋白2（MeCP2）通过与特定基因启动子区域的甲基化位点结合，影响下游信号通路，从而促进GC进展。然而，MeCP2在GC 5-FU耐药中的功能和分子机制仍不清楚。我们检测了 5-FU 耐药性 GC 细胞中 MeCP2 的表达，并检查了 MeCP2 沉默时的细胞行为。通过染色质免疫沉淀（ChIP）-qRT-PCR、荧光素酶报告基因测定、临床组织样本分析和体内致瘤性测定来探讨其分子机制。 MeCP2 在 5-FU 耐药的 GC 细胞中上调。 MeCP2 的敲低增强了细胞对 5-FU 的敏感性。此外，MeCP2通过与NOX4的启动子结合促进细胞中NOX4的转录。沉默NOX4可以挽救MeCP2过表达对GC细胞5-FU敏感性的诱导作用，并减少MeCP2过表达5-FU耐药GC细胞中NOX4和PKM2的表达。此外，我们的体内实验表明，MeCP2 敲低增强了肿瘤中 5-FU 的敏感性。 MeCP2 通过上调 NOX4/PKM2 通路赋予 GC 细胞 5-FU 耐药性，这可能为 GC 带来一种有前途的治疗策略。在线版本包含可在 10.1186/s12935-022-02489-y 获取的补充材料。
Increasing evidence suggests that aberrant methylation is involved in 5-fluorouracil (5-FU) resistance in gastric cancer (GC). Our previous work has identified that Methyl-CpG binding protein 2 (MeCP2) promotes GC progression by binding to the methylation sites of promoter regions of specific genes to affect the downstream signaling pathways. However, the function and molecular mechanisms of MeCP2 in GC 5-FU resistance remain unclear. We detected the expression of MeCP2 in 5-FU-resistant GC cells and examined cell behaviors when MeCP2 was silenced. The molecular mechanisms were explored through chromatin immunoprecipitation (ChIP)-qRT-PCR, luciferase reporter assay, clinical tissue samples analysis, and in vivo tumorigenicity assay. MeCP2 was up-regulated in 5-FU-resistant GC cells. Knockdown of MeCP2 enhanced the sensitivity of the cells to 5-FU. Moreover, MeCP2 promoted NOX4 transcription in the cells by binding to the promoter of NOX4. Silencing NOX4 rescued the inductive effect of MeCP2 overexpression on 5-FU sensitivity of GC cells and reduced the expression of NOX4 and PKM2 in MeCP2 overexpressed 5-FU-resistant GC cells. In addition, our in vivo experiments demonstrated that MeCP2 knockdown enhanced 5-FU sensitivity in tumors. MeCP2 confers 5-FU resistance in GC cells via upregulating the NOX4/PKM2 pathway, which may lead to a promising therapeutic strategy for GC. The online version contains supplementary material available at 10.1186/s12935-022-02489-y.
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影响因子：
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作者：
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影响因子：
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