DKK3 blocked translocation of β-catenin/EMT induced by hypoxia and improved gemcitabine therapeutic effect in pancreatic cancer Bxpc-3 cell.
DKK3 blocked translocation of β-catenin/EMT induced by hypoxia and improved gemcitabine therapeutic effect in pancreatic cancer Bxpc-3 cell.
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DOI：
10.1111/jcmm.12675
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发表时间：
2015-12
影响因子：
5.3
通讯作者：
Qin W
中科院分区：
文献类型：
--
作者：
Guo Q;Qin W
Wnt/β-catenin信号通路在胰腺癌的发生和进展中被激活。Dickkopf相关蛋白3（DKK 3）是人类Dickkopf家族的成员，也是Wnt配体活性的拮抗剂。然而，DKK 3在胰腺癌中的这一通路中的功能很少为人所知。我们检测了DKK 3在6个人胰腺癌细胞系、75个胰腺癌和75个邻近非癌组织中的表达。Dickkopf相关蛋白3在胰腺癌细胞系中经常沉默和甲基化（3/6）。胰腺癌组织中DKK 3的表达明显低于癌旁正常胰腺组织。此外，DKK 3的异位表达抑制胰腺癌Bxpc-3细胞中缺氧诱导的β-连环蛋白核转位。DKK 3的强制表达通过逆转上皮-间充质转化（EMT）显著抑制缺氧条件下胰腺癌Bxpc-3细胞的迁移和干细胞样表型。在胰腺癌异种移植模型中，DKK 3的稳定表达使胰腺癌Bxpc-3细胞对吉西他滨敏感，延迟肿瘤生长并增强吉西他滨的治疗效果。因此，我们从我们的发现中得出结论，DKK 3是一种肿瘤抑制因子，并通过诱导胰腺癌Bxpc-3细胞中的细胞凋亡和调节β-连环蛋白/EMT信号传导来改善吉西他滨的治疗效果。
The Wnt/β‐catenin signalling pathway is activated in pancreatic cancer initiation and progression. Dickkopf‐related protein 3 (DKK3) is a member of the human Dickkopf family and an antagonist of Wnt ligand activity. However, the function of DKK3 in this pathway in pancreatic cancer is rarely known. We examined the expression of DKK3 in six human pancreatic cancer cell lines, 75 pancreatic cancer and 75 adjacent non‐cancerous tissues. Dickkopf‐related protein 3 was frequently silenced and methylation in pancreatic cancer cell lines (3/6). The expression of DKK3 was significantly lower in pancreatic cancer tissues than in adjacent normal pancreas tissues. Further, ectopic expression of DKK3 inhibits nuclear translocation of β‐catenin induced by hypoxia in pancreatic cancer Bxpc‐3 cell. The forced expression of DKK3 markedly suppressed migration and the stem cell‐like phenotype of pancreatic cancer Bxpc‐3 cell in hypoxic conditions through reversing epithelial–mesenchymal transition (EMT). The stable expression of DKK3 sensitizes pancreatic cancer Bxpc‐3 cell to gemcitabine, delays tumour growth and augments gemcitabine therapeutic effect in pancreatic cancer xenotransplantation model. Thus, we conclude from our finding that DKK3 is a tumour suppressor and improved gemcitabine therapeutic effect through inducing apoptosis and regulating β‐catenin/EMT signalling in pancreatic cancer Bxpc‐3 cell.