NDRG1一举多得广谱抑癌基因

Oncotarget. 2015 Nov 3;6(34):35522-41.doi: 10.18632/oncotarget.5849.

Themolecular effect of metastasis suppressors on Src signaling and tumorigenesis:new therapeutic targets.

转移抑制基因N-myc下游调节基因1（N-myc downstream regulated gene 1 ，NDRG1)是许多肿瘤细胞多个信号的关键调节基因。NDRG1通过多个通路调节细胞信号抑制肿瘤细胞侵犯和转移，这些信号通路包括 (1)  PI3K/ AKT和Ras/MAPK/ERK ; (2)转化生长因子-β (TGF-β), 导致PTEN和SMAD4上调; (3)Ras; (4) β-catenin 和 WNT;  (5)Rho相关包含蛋白激酶1(ROCK1)/轻链肌球蛋白磷酸化2 (pMLC2).

一类新开发的药物是缩氧硫脲类药。其作用原理是选择性靶向肿瘤细胞不断增加的铁需求。铁在肿瘤细胞增殖和DNA合成起关键作用，根据新生肿瘤细胞铁转运蛋白受体1表达显著升高，表明肿瘤细胞铁需求不断增加并加强铁的摄取。缩氧硫脲类药结合肿瘤细胞的鉄和铜，也形成氧化还原复合体导致下游信号的连锁反应，并改变各种蛋白的表达涉及细胞周期控制，如细胞周期蛋白家族及依赖的激酶。重要的是，这类缩氧硫脲类药物上调NDRG1表达。铁螯合剂通过HIF-1α依赖和独立机制上调NDRG1，对于减少铁是必须的。 一类螯合剂已经开发，还包括双甲酮缩氧硫脲类(DpT)的配体，如Dp44mT、DpC，体内外实验对肿瘤具有抑制能力。Dp44mT和DpC 显著提高NDRG1 表达，接着导致src活性的抑制，表明其治疗效果。DpC计划2015进行临床实验。

（此外，已经上市的铁螯合剂还有地拉罗司分散片用于因需要长期输血而引致铁质积聚的患者（如患有地中海贫血症或其他罕见的贫血症）适用于两岁以上儿童及成人服用。）

其他研究有：

The IronChelator, Dp44mT, Effectively Inhibits Human Oral Squamous Cell Carcinoma CellGrowth in Vitro and in Vivo.

铁螯合剂Dp44mT, 去铁敏(DFO), 地拉罗司上调NDRG1和NDRG3抑制细胞周期蛋白D抑制口腔鳞癌。

Knockdown ofNDRG1 promote epithelial-mesenchymal transition of colorectal cancer via NF-κBsignaling.

NDRG1防止转移结直肠癌EMT而转移，弱化NF-κB信号。

NDRG1Controls Gastric Cancer Migration and Invasion through Regulating MMP-9.

NDRG1与胃癌分化、侵犯程度、TNM分期、淋巴结转移相关。当NDRG1静默，MMP-9增加表达，胃癌进展和侵犯。表明NDRG1抑制胃癌侵犯转移通过抑制MMP-9表达。

Thepotential of deferasirox as a novel therapeutic modality in gastric cancer.

地拉罗司治疗胃癌的效果是通过上调NDRG1，阻滞细胞周期，抑制c-myc和mtor表达，诱导细胞凋亡。

Targetingthe Metastasis Suppressor, N-Myc Downstream Regulated Gene-1, with NovelDi-2-Pyridylketone Thiosemicarbazones: Suppression of Tumor Cell Migration andCell-Collagen Adhesion by Inhibiting Focal Adhesion Kinase/Paxillin Signaling.

缩氧硫脲类药上调NDRG1，降低FAK/桩蛋白磷酸化，抑制肿瘤细胞迁移及细胞胶原质粘附

Valproicacid inhibits the invasion of PC3 prostate cancer cells by upregulating themetastasis suppressor protein NDRG1.

组蛋白去乙酰化抑制剂丙戊酸上调NDRG1抑制前列腺癌侵犯

TheMetastasis Suppressor, N-MYC Downstream-regulated Gene-1 (NDRG1),Down-regulates the ErbB Family of Receptors to Inhibit Downstream OncogenicSignaling Pathways.

NDRG1下调ErbB家族成员抑制下游致癌信号

Antimetastaticeffect of fluvastatin on breast and hepatocellular carcinoma cells in relationto SGK1 and NDRG1 genes.

氟伐斯汀抗乳腺癌和肝癌转移通过下调SGK1、上调NDRG1和AMPKA2

Themetastasis suppressor, NDRG1, inhibits "stemness" of colorectalcancer via down-regulation of nuclearβ-catenin and CD44.

NDRG1下调β-catenin 和CD44抑制结直肠癌干细胞性

NDRG1overexpressing gliomas are characterized by reduced tumor vascularization andresistance to antiangiogenic treatment.

NDRG1过表达的胶质瘤肿瘤血管减少，对抗血管药物耐药。因为NDRG1本身就是抗血管生成因子。

Downregulationof N-myc downstream regulated gene 1 caused by the methylation of CpG islandsof NDRG1 promoter promotes proliferation and invasion of prostate cancer cells.

前列腺癌因NDRG1启动子cpg岛甲基化导致NDRG1下调促肿瘤细胞增殖和侵犯。

NDRG1attenuates epithelial-mesenchymal transition of nasopharyngeal cancer cells viablocking Smad2 signaling.

NDRG1抑制smad2而抑制鼻咽癌细胞EMT.

Theproto-oncogene c-Src and its downstream signaling pathways are inhibited by themetastasis suppressor, NDRG1.

NDRG1抑制c-Src激活及其下游信号通路

Overexpressionof N-myc downstream-regulated gene 1 inhibits human glioma proliferation andinvasion via phosphoinositide 3-kinase/AKT pathways.

过表达NDRG1抑制胶质瘤增殖和侵犯通过抑制PI3K/AKT信号通路。

Theanticancer effects of desferrioxamine on human breast adenocarcinoma andhepatocellular carcinoma cells.

去铁敏治疗乳腺癌和肝癌

Ironchelation: inhibition of key signaling pathways in the induction of theepithelial mesenchymal transition in pancreatic cancer and other tumors. 铁螯合剂抑制EMT

Expandinghorizons in iron chelation and the treatment of cancer: role of iron in theregulation of ER stress and the epithelial-mesenchymal transition. 铁螯合剂调节内质网压力和抑制EMT

Aprolyl-hydroxylase inhibitor, ethyl-3,4-dihydroxybenzoate, induces cellautophagy and apoptosis in esophageal squamous cell carcinoma cells viaup-regulation of BNIP3 and N-myc downstream-regulated gene-1.鼻咽癌

N-mycdownstream-regulated gene 1 downregulates cell proliferation, invasiveness, andtumorigenesis in human oral squamous cell carcinoma.口腔鳞癌

N-mycdownstream regulated gene 1 acts as a tumor suppressor in ovarian cancer.卵巢癌

Themetastasis suppressor, N-myc downstream-regulated gene 1 (NDRG1), inhibitsstress-induced autophagy in cancer cells.抑制自噬

NDRG1as a molecular target to inhibit the epithelial-mesenchymal transition: thecase for developing inhibitors of metastasis.

抑制EMT

SET-mediatedNDRG1 inhibition is involved in acquisition of epithelial-to-mesenchymaltransition phenotype and cisplatin resistance in human lung cancer cell.

MicroRNA-769-3pdown-regulates NDRG1 and enhances apoptosis in MCF-7 cells duringreoxygenation.

Thesilencing of N-myc downstream-regulated gene-1 in an orthotopic pancreaticcancer model leads to more aggressive tumor growth and metastases.

以上几篇文章采用反证法抑制NDRG1导致肿瘤侵犯转移。

Themetastasis suppressor NDRG1 modulates the phosphorylation and nucleartranslocation of β-catenin through mechanisms involving FRAT1 and PAK4.

NDRG1对β-catenin抑制作用设及基因FRAT1（频繁重排晚期T细胞淋巴瘤1）、PAK4（P21活化激酶4）.

Molecularfunctions of the iron-regulated metastasis suppressor, NDRG1, and its potentialas a molecular target for cancer therapy.

Proteomicsidentified nuclear N-myc downstream-regulated gene 1 as a prognostic tissuebiomarker candidate in renal cell carcinoma.

Themetastasis suppressor, N-myc downregulated gene 1 (NDRG1), is a prognosticbiomarker for human colorectal cancer.

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