Down-regulation of tenascin-C inhibits breast cancer cells development by cell growth, migration, and adhesion impairment.

Dariusz Wawrzyniak,Małgorzata Grabowska,Agnieszka Fedoruk-Wyszomirska,Bogna Kuczyńska,Katarzyna Rolle,Konrad Kuczyński,Paweł Głodowicz,Lucia R Languino

doi:10.1371/journal.pone.0237889

Dariusz Wawrzyniak, Małgorzata Grabowska + Show 6 more

Open Access

https://doi.org/10.1371/journal.pone.0237889

Copy DOI

Abstract

Tenascin-C (TNC) is an extracellular matrix (ECM) glycoprotein that plays an important role in cell proliferation, migration, and tumour invasion in various cancers. TNC is one of the main protein overexpressed in breast cancer, indicating a role for this ECM molecule in cancer pathology. In this study we have evaluated the TNC loss-off-function in breast cancer cells. In our approach, we used dsRNA sharing sequence homology with TNC mRNA, called ATN-RNA. We present the data showing the effects of ATN-RNA in MDA-MB-231 cells both in monolayer and three-dimensional culture. Cells treated with ATN-RNA were analyzed for phenotypic alterations in proliferation, migration, adhesion, cell cycle, multi-caspase activation and the involvement in epithelial to mesenchymal transition (EMT) processes. As complementary analysis the oncogenomic portals were used to assess the clinical implication of TNC expression on breast cancer patient’s survival, showing the TNC overexpression associated with a poor survival outcome. Our approach applied first in brain tumors and then in breast cancer cell lines reveals that ATN-RNA significantly diminishes the cell proliferation, migration and additionally, reverses the mesenchymal cells phenotype to the epithelial one. Thus, TNC could be considered as the universal target in different types of tumors, where TNC overexpression is associated with poor prognosis.

Highlights

The tumor microenvironment is composed of the surrounding stromal cells, such as endothelial cells in blood vessels, immune cells, fibroblasts, and the extracellular matrix (ECM) [1, 2]
Based on the status of three important receptors conventionally used for breast cancer subtyping, i.e., estrogen receptor (ER), progesterone receptor (PR), and human epithelial receptor 2 (HER2), breast cancer is classified as luminal A, luminal B, HER2 positive and triple
We first compared the expression level of tenascin-C in 4 subtypes of breast cancer using GEPIA program (Fig A in S1 File). mRNA level of TNC were higher in triple-negative and HER2 subtypes compared to the luminal A and luminal B subtypes, which have a better prognosis for patient survival

Summary

Introduction

The tumor microenvironment is composed of the surrounding stromal cells, such as endothelial cells in blood vessels, immune cells, fibroblasts, and the extracellular matrix (ECM) [1, 2]. Down-regulation of tenascin-C inhibits breast cancer cells development and possibly more stable than those of the cell surface [4,5,6]. These proteins represent possible valuable targets for tumor imaging and therapy [4, 5]. ECM proteins such as fibronectin (FN) and tenascin have isoforms that are expressed in a tissue specific manner generated by alternative splicing of their primary transcripts. It is important for the development of neural stem cells [28, 29] and is suspected to be a potential marker for glioblastoma multiforme (GBM) stem cells (GSC) [30]

Methods

Results

Conclusion