A novel regulatory function of CDKN1A/p21 in TNFα-induced matrix metalloproteinase 9-dependent migration and invasion of triple-negative breast cancer cells

Magdalena Zaremba-Czogalla; Anita Hryniewicz-Jankowska; Renata Tabola; Miroslaw Nienartowicz; Kamilla Stach; Jaroslaw Wierzbicki; Roberto Cirocchi; Piotr Ziolkowski; Sabina Tabaczar; Katarzyna Augoff

doi:10.1016/j.cellsig.2018.03.010

A novel regulatory function of CDKN1A/p21 in TNFα-induced matrix metalloproteinase 9-dependent migration and invasion of triple-negative breast cancer cells

Cell Signal. 2018 Jul:47:27-36. doi: 10.1016/j.cellsig.2018.03.010. Epub 2018 Mar 26.

Affiliations

¹ Department of Gastrointestinal and General Surgery, Medical University of Wroclaw, Poland.
² Laboratory of Cytobiochemistry, Biotechnology Faculty, University of Wroclaw, Poland.
³ Department of Biochemistry, Medical University of Wroclaw, Poland.
⁴ Department of Minimally Invasive Surgery and Proctology, Wroclaw Medical University, Wroclaw, Poland.
⁵ Department of General and Oncological Surgery, University of Perugia, Italy.
⁶ Department of Pathology, Wroclaw Medical University, Wroclaw, Poland.
⁷ Department of Gastrointestinal and General Surgery, Medical University of Wroclaw, Poland. Electronic address: katarzyna.augoff@umed.wroc.pl.

PMID: 29588220
DOI: 10.1016/j.cellsig.2018.03.010

Abstract

Metastasis is the leading cause of mortality in patients with highly invasive cancers and, as such, is a major problem for medicine. It has been increasingly recognized that cancer-related inflammation plays an important role in promoting invasion and the metastatic process in which cell motility and upregulation of proteolytic enzymes are crucial events. TNFα is a proinflammatory cytokine known to stimulate synthesis of MMP9, a zinc- and calcium-dependent endopeptidase contributing to the regulation of ECM remodeling and cell signaling. However, the precise molecular mechanism of TNFα-induced MMP9 gene expression in cancers is still not fully understood. This study shows that TNFα-induced cell migration and invasion involve ERK1/2-dependent up-regulation of CDKN1A/p21 expression in highly aggressive breast cancer cells and that CDKN1A/p21 plays an important regulatory role in TNFα-induced MMP9 gene expression, indicating an unknown function of CDKN1A/p21 as a regulator of proteolytic activity in cancer cells.

Keywords: Breast cancer; CDKN1A/p21((WAF1/CIP1/SDI1)); Cell migration; MMP9; TNFα.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cell Line, Tumor
Cell Movement / drug effects
Cyclin-Dependent Kinase Inhibitor p21 / antagonists & inhibitors
Cyclin-Dependent Kinase Inhibitor p21 / genetics
Cyclin-Dependent Kinase Inhibitor p21 / metabolism*
Female
Humans
Matrix Metalloproteinase 9 / metabolism*
Mitogen-Activated Protein Kinase 1 / metabolism
Mitogen-Activated Protein Kinase 3 / metabolism
Phosphorylation / drug effects
RNA Interference
RNA, Small Interfering / metabolism
Signal Transduction / drug effects
Triple Negative Breast Neoplasms / metabolism
Triple Negative Breast Neoplasms / pathology
Tumor Necrosis Factor-alpha / pharmacology*
Up-Regulation / drug effects*

Substances

Cyclin-Dependent Kinase Inhibitor p21
RNA, Small Interfering
Tumor Necrosis Factor-alpha
Mitogen-Activated Protein Kinase 1
Mitogen-Activated Protein Kinase 3
Matrix Metalloproteinase 9