WNK1 Enhances Migration and Invasion in Breast Cancer Models.
WNK1 Enhances Migration and Invasion in Breast Cancer Models.
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DOI：
10.1158/1535-7163.mct-21-0174
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发表时间：
2021-10
影响因子：
5.7
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中科院分区：
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转移是乳腺癌患者死亡的主要原因。许多信号通路与癌症的侵袭性有关，但阻断少数蛋白质组分已成功减少转移。因此，鉴定可被小分子操纵的有助于入侵的蛋白质可能在抑制疾病传播方面是有价值的。无赖氨酸的蛋白激酶（K）1（WNK 1）已被认为诱导代表一系列癌症类型的细胞的迁移。对小鼠模型和患者数据的分析表明，WNK 1是与侵袭性乳腺癌独特相关的少数基因之一。在这里，我们提出的证据表明，抑制WNK 1减缓乳腺癌转移。我们发现，WNK 1的消耗或抑制减少了几种乳腺癌细胞系在伤口愈合试验中的迁移，并减少了胶原基质中的侵袭。此外，WNK 1缺失抑制了与转移有关的酪氨酸激酶AXL的表达。最后，我们证明了小鼠中的WNK抑制减弱了肿瘤进展和转移负荷。这些数据显示，在多种乳腺癌模型中，WNK 1耗尽后迁移、侵袭和转移减少，表明WNK 1有助于转移表型，并且WNK 1抑制可能为减弱侵袭性乳腺癌的进展提供治疗途径。
Metastasis is the major cause of mortality in patients with breast cancer. Many signaling pathways have been linked to cancer invasiveness, but blockade of few protein components has succeeded in reducing metastasis. Thus, identification of proteins contributing to invasion that are manipulable by small molecules may be valuable in inhibiting spread of the disease. The protein kinase with no lysine (K) 1 (WNK1) has been suggested to induce migration of cells representing a range of cancer types. Analyses of mouse models and patient data have implicated WNK1 as one of a handful of genes uniquely linked to invasive breast cancer. Here, we present evidence that inhibition of WNK1 slows breast cancer metastasis. We show that depletion or inhibition of WNK1 reduces migration of several breast cancer cell lines in wound healing assays and decreases invasion in collagen matrices. Furthermore, WNK1 depletion suppresses expression of AXL, a tyrosine kinase implicated in metastasis. Finally, we demonstrate that WNK inhibition in mice attenuates tumor progression and metastatic burden. These data showing reduced migration, invasion, and metastasis upon WNK1 depletion in multiple breast cancer models suggest that WNK1 contributes to the metastatic phenotype, and that WNK1 inhibition may offer a therapeutic avenue for attenuating progression of invasive breast cancers.