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

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

  • Mol Biol Rep. 2022 Jan;49(1):267-278. doi: 10.1007/s11033-021-06868-y.
Peina He 1 Jianyun Sheng 2 Jinxu Qi 1 Xianguang Bai 1 Jiaxin Li 1 Fubao Wang 2 Yamin Yuan 1 Xinhua Zheng 3
Affiliations

Affiliations

  • 1 Department of Medicine, Pingdingshan University, Chongwen Rd., Xincheng District, Pingdingshan, 467092, China.
  • 2 Department of Gynecotokology, Pingdingshan First People's Hospital, Pingdingshan, 410402, China.
  • 3 Department of Medicine, Pingdingshan University, Chongwen Rd., Xincheng District, Pingdingshan, 467092, China. zhengxinhua0406@163.com.
Abstract

Background: 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.

Methods and results: 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.

Conclusions: 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.

Keywords

ERK1/2; Matrix metalloproteinases; Migration; Noncatalytic region of tyrosine kinase 1; STAT3; Triple-negative breast cancer.

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