Wnt signaling modulator DKK4 inhibits colorectal cancer metastasis through an AKT/Wnt/β-catenin negative feedback pathway.
Wnt signaling modulator DKK4 inhibits colorectal cancer metastasis through an AKT/Wnt/β-catenin negative feedback pathway.
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Wnt 信号调节剂 DKK4 通过 AKT/Wnt/β-catenin 负反馈途径抑制结直肠癌转移
DOI：
10.1016/j.jbc.2022.102545
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发表时间：
2022-11
期刊：
影响因子：
--
通讯作者：
Lu Y
中科院分区：
文献类型：
--
作者：
Liang J;Sun L;Li Y;Liu W;Li D;Chen P;Wang X;Hui J;Zhou J;Liu H;Cao T;Pang M;Guo M;Wang X;Zhao X;Lu Y
Wnt/β-catenin信号通路的异常激活涉及大多数恶性肿瘤，特别是结直肠癌（CRC）的发生和进展。DKK 4是Wnt/β-catenin通路的经典抑制分子，但其在结直肠癌中的作用尚不明确，其分子机制尚不清楚。在此，我们分别通过定量PCR和免疫组化分析确定了23个CRC细胞系和229个CRC组织中DKK 4表达显著上调。我们对组织样本的分析表明，DKK 4高表达的CRC患者的生存时间长于中低表达的患者。我们通过细胞计数试剂盒-8测定、transwell测定以及皮下和转移性小鼠肿瘤模型检测了DKK 4对细胞增殖和转移的影响，并且我们发现DKK 4沉默促进了CRC细胞在体外和体内的转移。我们的RNA-seq分析显示，在AKT和Wnt信号传导中起重要作用的AKT 2、FZD 6和JUN在DKK 4敲低后显著增加。DKK 4通过抑制CRC中的FZD 6和AKT 2/s552 β-catenin来抑制Wnt/β-catenin信号传导。进一步的实验表明重组Wnt 3a和LiCl可以诱导DKK 4的表达。此外，我们的生物信息学分析和荧光素酶报告基因检测确定了CRC细胞中DKK 4的转录后调节因子。总之，DKK 4在CRC中升高，并通过Wnt 3a/DKK 4/AKT/s552 β-连环蛋白调节轴的新负反馈机制抑制细胞转移，以限制CRC中Wnt活性的过度激活。因此，DKK 4修复可作为潜在的CRC治疗策略。
Aberrant activation of the Wnt/β-catenin signaling pathway is implicated in most malignant cancers, especially in the initiation and progression of colorectal cancer (CRC). DKK4 is a classical inhibitory molecule of the Wnt/β-catenin pathway, but its role in CRC is ambiguous, and the molecular mechanism remains unclear. Here, we determined DKK4 expression was significantly upregulated in 23 CRC cell lines and 229 CRC tissues when analyzed by quantitative PCR and immunohistochemistry, respectively. Our analysis of tissue samples indicated the survival time of CRC patients with high DKK4 expression was longer than that of patients with medium-low DKK4 expression. We examined the effects of DKK4 on cell proliferation and metastasis by cell counting kit-8 assays, transwell assays, and subcutaneous and metastatic mouse tumor models, and we discovered that DKK4 silencing promoted the metastasis of CRC cells both in vitro and in vivo. Our RNA-seq analysis revealed that AKT2, FZD6, and JUN, which play important roles in AKT and Wnt signaling, were significantly increased after DKK4 knockdown. DKK4 represses Wnt/β-catenin signaling by repressing FZD6 and AKT2/s552 β-catenin in CRC. Further experiments revealed recombinant Wnt3a and LiCl could induce DKK4 expression. Moreover, our bioinformatics analysis and luciferase reporter assays identified posttranscriptional regulators of DKK4 in CRC cells. In summary, DKK4 is elevated in CRC and inhibits cell metastasis by a novel negative feedback mechanism of the Wnt3a/DKK4/AKT/s552 β-catenin regulatory axis to restrict overactivation of Wnt activity in CRC. Therefore, DKK4 restoration may be applied as a potential CRC therapeutic strategy.
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影响因子：
5.3
作者：
Lou X;Meng Y;Hou Y
通讯作者：
Hou Y
影响因子：
3.7
作者：
Dong, Jun;Xu, Xiqiang;Tan, Bingyi
通讯作者：
Tan, Bingyi
Dickkopf 相关蛋白 2 表观遗传失活，通过拮抗 Wnt/β-Catenin 信号传导抑制结直肠癌生长和肿瘤转移
影响因子：
--
作者：
Wang, Can;Yue, Yujuan;Ren, Guosheng
通讯作者：
Ren, Guosheng
DOI：
10.1083/jcb.200710050
发表时间：
2008-03-24
期刊：
The Journal of cell biology
影响因子：
--
作者：
Gan XQ;Wang JY;Xi Y;Wu ZL;Li YP;Li L
通讯作者：
Li L
影响因子：
254.7
作者：
Siegel, Rebecca L.;Miller, Kimberly D.;Jemal, Ahmedin
通讯作者：
Jemal, Ahmedin