Department of Medicine, Pingdingshan University, Chongwen Rd., Xincheng District, Pingdingshan, 467092, China.
Department of Gynecotokology, Pingdingshan First People's Hospital, Pingdingshan, 410402, China.
Mol Biol Rep. 2022 Jan;49(1):267-278. doi: 10.1007/s11033-021-06868-y. Epub 2021 Nov 30.
Noncatalytic region of tyrosine kinase 1 (NCK1) plays a key role in extracellular matrix degradation, which is required for the metastasis of triple-negative breast cancer (TNBC). However, the role NCK1 plays in the metastatic progression of TNBC is unknown.
Based on online databases, NCK1 was found to be highly expressed in TNBC as compared to normal breast-like subjects, which was also confirmed using TNBC cells and a tissue microarray. NCK1 expression gradually decreased with increased tumor stage. High NCK1 expression displayed a poor prognosis in lymph node-positive metastatic TNBC patients, but not in lymph node-negative patients. Using transwell assays and immunoblotting, we confirmed that NCK1 overexpression promoted, while NCK1 downregulation inhibited migration capabilities, as well as the expression of matrix metalloproteinases (MMP2/9), uridylyl phosphate adenosine, and plasminogen activator inhibitor-1 in TNBC cells. Mechanistically, NCK1 upregulation mediated the activation of MMP2/9 through ERK1/2 activity. Signal transducer and activator of transcription 3 (STAT3) was positively correlated with NCK1. STAT3 could directly bind to the promoter region of NCK1 to promote its expression and was accompanied by the elevation of MMP2/9 and ERK1/2 signaling, which were partially abolished by the knockdown of NCK1 in TNBC cells.
NCK1 may serve as a diagnostic and prognostic marker of metastatic TNBC. STAT3 upregulation promoted the expression of NCK1, which subsequently induced the migration and activity of MMPs in a ERK1/2 signaling-dependent manner in TNBC cells. NCK1 is a promising target for improving TNBC migration.
酪氨酸激酶 1（NCK1）的非催化区在细胞外基质降解中发挥关键作用，这是三阴性乳腺癌（TNBC）转移所必需的。然而，NCK1 在 TNBC 转移进展中的作用尚不清楚。
基于在线数据库，与正常乳腺样标本相比，NCK1 在 TNBC 中表达较高，这也得到了 TNBC 细胞和组织微阵列的证实。NCK1 的表达随肿瘤分期的增加而逐渐降低。高 NCK1 表达的淋巴结阳性转移性 TNBC 患者预后较差，但淋巴结阴性患者则不然。通过 Transwell 测定和免疫印迹，我们证实 NCK1 过表达促进，而 NCK1 下调抑制了 TNBC 细胞的迁移能力，以及基质金属蛋白酶（MMP2/9）、尿嘧啶核苷酸磷酸腺苷和纤溶酶原激活物抑制剂-1 的表达。在机制上，NCK1 的上调通过 ERK1/2 活性介导 MMP2/9 的激活。信号转导和转录激活因子 3（STAT3）与 NCK1 呈正相关。STAT3 可以直接结合 NCK1 的启动子区域促进其表达，并伴随着 MMP2/9 和 ERK1/2 信号的升高，这在 TNBC 细胞中被 NCK1 的敲低部分阻断。
NCK1 可能是转移性 TNBC 的诊断和预后标志物。STAT3 的上调促进了 NCK1 的表达，随后在 ERK1/2 信号依赖性方式诱导了 TNBC 细胞中 MMPs 的迁移和活性。NCK1 是改善 TNBC 迁移的有前途的靶点。
