PDF(Pubmed)
Abstract：
The Wnt/β-catenin signaling pathway plays a pivotal role during embryogenesis and its deregulation is a key mechanism in the origin and progression of several tumors. Wnt antagonists have been described as key modulators of Wnt/β-catenin signaling in cancer, with Dickkopf-1 (DKK-1) being the most studied member of the DKK family. Although the therapeutic potential of DKK-1 inhibition has been evaluated in several diseases and malignancies, little is known in pediatric tumors. Only a few works have studied the genetic inhibition and function of DKK-1 in rhabdomyosarcoma. Here, for the first time, we report the analysis of the therapeutic potential of DKK-1 pharmaceutical inhibition in rhabdomyosarcoma, the most common soft tissue sarcoma in children. We performed DKK-1 inhibition via shRNA technology and via the chemical inhibitor WAY-2626211. Its inhibition led to β-catenin activation and the modulation of focal adhesion kinase (FAK), with positive effects on in vitro expression of myogenic markers and a reduction in proliferation and invasion. In addition, WAY-262611 was able to impair survival of tumor cells in vivo. Therefore, DKK-1 could constitute a molecular target, which could lead to novel therapeutic strategies in RMS, especially in those patients with high DKK-1 expression.
摘要：
Wnt/β-catenin信号通路在胚胎发生过程中起着关键作用，其失调是几种肿瘤起源和进展的关键机制。Wnt拮抗剂已被描述为癌症中Wnt/β-catenin信号传导的关键调节剂。Dickkopf-1（DKK-1）是DKK家族中研究最多的成员。虽然DKK-1抑制的治疗潜力已经在几种疾病和恶性肿瘤中进行了评估，在小儿肿瘤中鲜为人知。只有少数工作研究了横纹肌肉瘤中DKK-1的遗传抑制和功能。这里,第一次,我们报告了DKK-1药物抑制在横纹肌肉瘤中的治疗潜力分析，儿童最常见的软组织肉瘤。我们通过shRNA技术和化学抑制剂WAY-2626211进行了DKK-1抑制。其抑制导致β-连环蛋白激活和粘着斑激酶（FAK）的调节，对肌源性标志物的体外表达具有积极作用，并减少增殖和侵袭。此外,WAY-262611能够损害肿瘤细胞在体内的存活。因此,DKK-1可以构成分子靶标,这可能会导致RMS的新治疗策略，特别是在DKK-1高表达的患者中。
