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

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.

SUBMITTER: Wawrzyniak D

PROVIDER: S-EPMC7440653 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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

Wawrzyniak Dariusz D Grabowska Małgorzata M Głodowicz Paweł P Kuczyński Konrad K Kuczyńska Bogna B Fedoruk-Wyszomirska Agnieszka A Rolle Katarzyna K

PloS one 20200820 8

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 ...[more]

PMID: 32817625

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Project description:Objective:Cancer-associated fibroblasts (CAFs) in the tumor microenvironment are involved in cancer development and progression, including breast cancer (BC). Up-regulation of CCL17 was observed in BC and predicted a decrease in overall survival, suggesting an important role of CCL17 in BC development. Nonetheless, little is known about the role of CCL17 in the interaction between CAFs and BC. Materials and methods:Real-time quantitative PCR, Western blot, and enzyme-linked immunosorbent assay were performed to examine C-C motif chemokine ligand 17 (CCL17) and C-C motif chemokine receptor 4 (CCR4) levels in BC tissues and CAFs. Cell proliferation, migration, and invasion of CAFs co-cultured with or without BC cell lines were measured by Cell Counting Kit-8 and Transwell analysis. Expression of CCL17, CCR4, dual specificity phosphatase 6 (DUSP6), matrix metallopeptidase 13 (MMP13), extracellular signal-regulated kinase (ERK) 1/2, and phosphor-ERK1/2 (p-ERK1/2) in BC cell lines co-cultured with or without CAFs was measured by Western blotting. Results:We found that BC tissues and CAFs demonstrated higher levels of CCL17 compared with adjacent-normal breast tissues and adjacent-normal fibroblasts (NFs), respectively. CCL17 expression is correlated with lymph nodes, TNM stage and tumor size of BC patients. CCL17 knockdown significantly inhibited CCL17 release, CCR4 expression, and the cell proliferation of CAFs, while CCL17 overexpression demonstrated an inverse effect in NFs. Co-culture with CAFs induced the increases in cell proliferation, migration, invasion, and the expression of CCL17, CCR4, MMP13, and p-ERK1/2 in MCF-7 and MDA-MB-231 cells were markedly reversed by CCL17 knockdown in CAFs. Meanwhile, co-culture with NFs induced the malignant phenotype of MCF-7 cells was markedly enhanced by CCL17 overexpression in NFs. Moreover, DUSP6, a negative regulator of ERK1/2, was dose-dependent decrease in response to recombinant CCL17 and inhibited cell migration, invasion, MMP13 expression, and ERK1/2 activation in MCF-7 cells. Conclusion:The findings of this study suggest that CCL17 may function as a novel biomarker as well as potential therapeutic target against BC and CAF-secreted CCL17 promotes BC cell migration and invasion through the DUSP6-dependent ERK1/2 pathway.

Project description:Down Syndrome (DS) Cell Adhesion Molecules (DSCAMs) are transmembrane proteins of the immunoglobulin superfamily. Human DSCAM is located within the DS critical region of chromosome 21 (duplicated in Down Syndrome patients), and mutations or copy-number variations of this gene have also been associated to Fragile X syndrome, intellectual disability, autism, and bipolar disorder. The DSCAM paralogue DSCAM-like 1 (DSCAML1) maps to chromosome 11q23, implicated in the development of Jacobsen and Tourette syndromes. Additionally, a spontaneous mouse DSCAM deletion leads to motor coordination defects and seizures. Previous research has revealed roles for DSCAMs in several neurodevelopmental processes, including synaptogenesis, dendritic self-avoidance, cell sorting, axon growth and branching. However, their functions in embryonic mammalian forebrain development have yet to be completely elucidated. In this study, we revealed highly dynamic spatiotemporal patterns of Dscam and Dscaml1 expression in definite cortical layers of the embryonic mouse brain, as well as in structures and ganglionic eminence-derived neural populations within the embryonic subpallium. However, an in-depth histological analysis of cortical development, ventral forebrain morphogenesis, cortical interneuron migration, and cortical-subcortical connectivity formation processes in Dscam and Dscaml1 knockout mice (Dscam del17 and Dscaml1 GT ) at several embryonic stages indicated that constitutive loss of Dscam and Dscaml1 does not affect these developmental events in a significant manner. Given that several Dscam- and Dscaml1-linked neurodevelopmental disorders are associated to chromosomal region duplication events, we furthermore sought to examine the neurodevelopmental effects of Dscam and Dscaml1 gain of function (GOF). In vitro, ex vivo, and in vivo GOF negatively impacted neural migration processes important to cortical development, and affected the morphology of maturing neurons. Overall, these findings contribute to existing knowledge on the molecular etiology of human neurodevelopmental disorders by elucidating how dosage variations of genes encoding adhesive cues can disrupt cell-cell or cell-environment interactions crucial for neuronal migration.

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

Publications

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

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