STAT3-induced NCK1 elevation promotes migration of triple-negative breast cancer cells via regulating ERK1/2 signaling.

Abstract

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.