NOTCH1 signaling in oral squamous cell carcinoma via a TEL2/SERPINE1 axis

Vasiliki Salameti; Priyanka G Bhosale; Ashley Ames-Draycott; Kalle Sipilä; Fiona M Watt

doi:10.18632/oncotarget.27306

NOTCH1 signaling in oral squamous cell carcinoma via a TEL2/SERPINE1 axis

Vasiliki Salameti, Priyanka G Bhosale, Ashley Ames-Draycott, Kalle Sipilä, Fiona M Watt

Centre for Stem Cells and Regenerative Medicine, King's College London, London, SE1 9RT, UK
Department of Medical Physics and Biomedical Engineering, University College London, Gower Street, London WC1E 6BT, United Kingdom. Wellcome/EPSRC Centre for Interventional and Surgical Sciences, University College London, Charles Bell House, 67-73 Riding House Street, London W1W 7EJ, United Kingdom. These authors contributed equally to this work.

Research output: Contribution to journal › Article › peer-review

10 Citations (Scopus)

Abstract

Inactivating mutations in the EGF-like ligand binding domain of NOTCH1 are a prominent feature of the mutational landscape of oral squamous cell carcinoma (OSCC). In this study, we investigated NOTCH1 mutations in keratinocyte lines derived from OSCC biopsies that had been subjected to whole exome sequencing. One line, SJG6, was found to have truncating mutations in both NOTCH1 alleles, resulting in loss of NOTCH1 expression. Overexpression of the NOTCH1 intracellular domain (NICD) in SJG6 cells promoted cell adhesion and differentiation, while suppressing proliferation, migration and clonal growth, consistent with the previously reported tumour suppressive function of NOTCH1 in OSCC. Comparative gene expression profiling identified SERPINE1 as being downregulated on NICD overexpression and predicted an interaction between SERPINE1 and genes involved in cell proliferation and migration. Mechanistically, overexpression of NICD resulted in upregulation of ETV7/TEL2, which negatively regulates SERPINE1 expression. Knockdown of SERPINE1 phenocopied the effects of NICD overexpression in culture. Consistent with previous studies and our in vitro findings, there were inverse correlations between ETV7 and SERPINE1 expression and survival in OSCC primary tumours. Our results suggest that the tumour suppressive role of NOTCH1 in OSCC is mediated, at least in part, by inhibition of SERPINE1 via ETV7.

Original language	English
Pages (from-to)	6791-6804
Number of pages	14
Journal	Oncotarget
Volume	10
Issue number	63
DOIs	https://doi.org/10.18632/oncotarget.27306
Publication status	Published - 26 Nov 2019

Keywords

Cell adhesion
ETV7/TEL2
NOTCH1
Oral squamous cell carcinoma (OSCC)
SERPINE1

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.18632/oncotarget.27306

Cite this

@article{7acc1469a81047a98b108f6f6d99bc4e,

title = "NOTCH1 signaling in oral squamous cell carcinoma via a TEL2/SERPINE1 axis",

abstract = "Inactivating mutations in the EGF-like ligand binding domain of NOTCH1 are a prominent feature of the mutational landscape of oral squamous cell carcinoma (OSCC). In this study, we investigated NOTCH1 mutations in keratinocyte lines derived from OSCC biopsies that had been subjected to whole exome sequencing. One line, SJG6, was found to have truncating mutations in both NOTCH1 alleles, resulting in loss of NOTCH1 expression. Overexpression of the NOTCH1 intracellular domain (NICD) in SJG6 cells promoted cell adhesion and differentiation, while suppressing proliferation, migration and clonal growth, consistent with the previously reported tumour suppressive function of NOTCH1 in OSCC. Comparative gene expression profiling identified SERPINE1 as being downregulated on NICD overexpression and predicted an interaction between SERPINE1 and genes involved in cell proliferation and migration. Mechanistically, overexpression of NICD resulted in upregulation of ETV7/TEL2, which negatively regulates SERPINE1 expression. Knockdown of SERPINE1 phenocopied the effects of NICD overexpression in culture. Consistent with previous studies and our in vitro findings, there were inverse correlations between ETV7 and SERPINE1 expression and survival in OSCC primary tumours. Our results suggest that the tumour suppressive role of NOTCH1 in OSCC is mediated, at least in part, by inhibition of SERPINE1 via ETV7.",

keywords = "Cell adhesion, ETV7/TEL2, NOTCH1, Oral squamous cell carcinoma (OSCC), SERPINE1",

author = "Vasiliki Salameti and Bhosale, {Priyanka G} and Ashley Ames-Draycott and Kalle Sipil{\"a} and Watt, {Fiona M}",

year = "2019",

month = nov,

day = "26",

doi = "10.18632/oncotarget.27306",

language = "English",

volume = "10",

pages = "6791--6804",

journal = "Oncotarget",

issn = "1949-2553",

publisher = "Impact Journals",

number = "63",

}

TY - JOUR

T1 - NOTCH1 signaling in oral squamous cell carcinoma via a TEL2/SERPINE1 axis

AU - Salameti, Vasiliki

AU - Bhosale, Priyanka G

AU - Ames-Draycott, Ashley

AU - Sipilä, Kalle

AU - Watt, Fiona M

PY - 2019/11/26

Y1 - 2019/11/26

N2 - Inactivating mutations in the EGF-like ligand binding domain of NOTCH1 are a prominent feature of the mutational landscape of oral squamous cell carcinoma (OSCC). In this study, we investigated NOTCH1 mutations in keratinocyte lines derived from OSCC biopsies that had been subjected to whole exome sequencing. One line, SJG6, was found to have truncating mutations in both NOTCH1 alleles, resulting in loss of NOTCH1 expression. Overexpression of the NOTCH1 intracellular domain (NICD) in SJG6 cells promoted cell adhesion and differentiation, while suppressing proliferation, migration and clonal growth, consistent with the previously reported tumour suppressive function of NOTCH1 in OSCC. Comparative gene expression profiling identified SERPINE1 as being downregulated on NICD overexpression and predicted an interaction between SERPINE1 and genes involved in cell proliferation and migration. Mechanistically, overexpression of NICD resulted in upregulation of ETV7/TEL2, which negatively regulates SERPINE1 expression. Knockdown of SERPINE1 phenocopied the effects of NICD overexpression in culture. Consistent with previous studies and our in vitro findings, there were inverse correlations between ETV7 and SERPINE1 expression and survival in OSCC primary tumours. Our results suggest that the tumour suppressive role of NOTCH1 in OSCC is mediated, at least in part, by inhibition of SERPINE1 via ETV7.

AB - Inactivating mutations in the EGF-like ligand binding domain of NOTCH1 are a prominent feature of the mutational landscape of oral squamous cell carcinoma (OSCC). In this study, we investigated NOTCH1 mutations in keratinocyte lines derived from OSCC biopsies that had been subjected to whole exome sequencing. One line, SJG6, was found to have truncating mutations in both NOTCH1 alleles, resulting in loss of NOTCH1 expression. Overexpression of the NOTCH1 intracellular domain (NICD) in SJG6 cells promoted cell adhesion and differentiation, while suppressing proliferation, migration and clonal growth, consistent with the previously reported tumour suppressive function of NOTCH1 in OSCC. Comparative gene expression profiling identified SERPINE1 as being downregulated on NICD overexpression and predicted an interaction between SERPINE1 and genes involved in cell proliferation and migration. Mechanistically, overexpression of NICD resulted in upregulation of ETV7/TEL2, which negatively regulates SERPINE1 expression. Knockdown of SERPINE1 phenocopied the effects of NICD overexpression in culture. Consistent with previous studies and our in vitro findings, there were inverse correlations between ETV7 and SERPINE1 expression and survival in OSCC primary tumours. Our results suggest that the tumour suppressive role of NOTCH1 in OSCC is mediated, at least in part, by inhibition of SERPINE1 via ETV7.

KW - Cell adhesion

KW - ETV7/TEL2

KW - NOTCH1

KW - Oral squamous cell carcinoma (OSCC)

KW - SERPINE1

UR - http://www.scopus.com/inward/record.url?scp=85075592957&partnerID=8YFLogxK

U2 - 10.18632/oncotarget.27306

DO - 10.18632/oncotarget.27306

M3 - Article

C2 - 31827722

AN - SCOPUS:85075592957

SN - 1949-2553

VL - 10

SP - 6791

EP - 6804

JO - Oncotarget

JF - Oncotarget

IS - 63

ER -

NOTCH1 signaling in oral squamous cell carcinoma via a TEL2/SERPINE1 axis

Abstract

Keywords

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this