ΔNp63γ/SRC/Slug signalling axis promotes epithelial-to-mesenchymal transition in squamous cancers

Kirtiman Srivastava, Adam Pickard, Stephanie Craig, Gerard Quinn, Shauna Lambe, Jacqueline James, Dennis McCance, Simon McDade

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Purpose: To investigate the regulation of epithelial-to-mesenchymal transition (EMT) in Head and Neck Squamous Cell Carcinoma (HNSCC) and its importance in tumour invasion. Experimental design: We use a 3D invasive organotypic raft culture model of human foreskin keratinocytes expressing the E6/E7 genes of the Human Papilloma Virus-16, coupled with bioinformatics and immunohistochemical analysis of patient samples to investigate the role played by EMT in invasion and identify effectors and upstream regulatory pathways. Results: We identify SNAI2 (Slug) as a critical effector of EMT activated downstream of TP63 overexpression in Head and Neck Squamous Cell Carcinoma (HNSCC). Splice-form specific depletion and rescue experiments further identify the ΔNp63γ isoform as both necessary and sufficient to activate the SRC signalling axis and SNAI2-mediated EMT and invasion. Moreover, elevated SRC levels are associated with poor outcome in HNSCC patients in the cancer genome atlas dataset. Importantly, the effects on EMT and invasions and SNAI2 expression can be reversed by genetic or pharmacological inhibition of SRC. Conclusion:Overexpression of ΔNp63γ modulates cell invasion by inducing targetable SRC-Slug-evoked EMT in HNSCC, which can be reversed by inhibitors of the SRC signalling.
LanguageEnglish
Pages3917-3927
Number of pages11
JournalClinical Cancer Research
Volume24
Issue number16
DOIs
Publication statusPublished - 08 May 2018

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Gastropoda
Epithelial-Mesenchymal Transition
Neoplasms
Papillomaviridae
Foreskin
Atlases
Computational Biology
Keratinocytes
Protein Isoforms
Research Design
Genome
Pharmacology
Carcinoma, squamous cell of head and neck
Genes

Keywords

  • Human papilloma virus (HPV)
  • P63
  • Keratinocytes
  • Slug
  • Src
  • EMT

Cite this

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title = "ΔNp63γ/SRC/Slug signalling axis promotes epithelial-to-mesenchymal transition in squamous cancers",
abstract = "Purpose: To investigate the regulation of epithelial-to-mesenchymal transition (EMT) in Head and Neck Squamous Cell Carcinoma (HNSCC) and its importance in tumour invasion. Experimental design: We use a 3D invasive organotypic raft culture model of human foreskin keratinocytes expressing the E6/E7 genes of the Human Papilloma Virus-16, coupled with bioinformatics and immunohistochemical analysis of patient samples to investigate the role played by EMT in invasion and identify effectors and upstream regulatory pathways. Results: We identify SNAI2 (Slug) as a critical effector of EMT activated downstream of TP63 overexpression in Head and Neck Squamous Cell Carcinoma (HNSCC). Splice-form specific depletion and rescue experiments further identify the ΔNp63γ isoform as both necessary and sufficient to activate the SRC signalling axis and SNAI2-mediated EMT and invasion. Moreover, elevated SRC levels are associated with poor outcome in HNSCC patients in the cancer genome atlas dataset. Importantly, the effects on EMT and invasions and SNAI2 expression can be reversed by genetic or pharmacological inhibition of SRC. Conclusion:Overexpression of ΔNp63γ modulates cell invasion by inducing targetable SRC-Slug-evoked EMT in HNSCC, which can be reversed by inhibitors of the SRC signalling.",
keywords = "Human papilloma virus (HPV), P63, Keratinocytes, Slug, Src, EMT",
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ΔNp63γ/SRC/Slug signalling axis promotes epithelial-to-mesenchymal transition in squamous cancers. / Srivastava, Kirtiman; Pickard, Adam; Craig, Stephanie; Quinn, Gerard; Lambe, Shauna; James, Jacqueline; McCance, Dennis; McDade, Simon.

In: Clinical Cancer Research, Vol. 24, No. 16, 08.05.2018, p. 3917-3927.

Research output: Contribution to journalArticle

TY - JOUR

T1 - ΔNp63γ/SRC/Slug signalling axis promotes epithelial-to-mesenchymal transition in squamous cancers

AU - Srivastava, Kirtiman

AU - Pickard, Adam

AU - Craig, Stephanie

AU - Quinn, Gerard

AU - Lambe, Shauna

AU - James, Jacqueline

AU - McCance, Dennis

AU - McDade, Simon

PY - 2018/5/8

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N2 - Purpose: To investigate the regulation of epithelial-to-mesenchymal transition (EMT) in Head and Neck Squamous Cell Carcinoma (HNSCC) and its importance in tumour invasion. Experimental design: We use a 3D invasive organotypic raft culture model of human foreskin keratinocytes expressing the E6/E7 genes of the Human Papilloma Virus-16, coupled with bioinformatics and immunohistochemical analysis of patient samples to investigate the role played by EMT in invasion and identify effectors and upstream regulatory pathways. Results: We identify SNAI2 (Slug) as a critical effector of EMT activated downstream of TP63 overexpression in Head and Neck Squamous Cell Carcinoma (HNSCC). Splice-form specific depletion and rescue experiments further identify the ΔNp63γ isoform as both necessary and sufficient to activate the SRC signalling axis and SNAI2-mediated EMT and invasion. Moreover, elevated SRC levels are associated with poor outcome in HNSCC patients in the cancer genome atlas dataset. Importantly, the effects on EMT and invasions and SNAI2 expression can be reversed by genetic or pharmacological inhibition of SRC. Conclusion:Overexpression of ΔNp63γ modulates cell invasion by inducing targetable SRC-Slug-evoked EMT in HNSCC, which can be reversed by inhibitors of the SRC signalling.

AB - Purpose: To investigate the regulation of epithelial-to-mesenchymal transition (EMT) in Head and Neck Squamous Cell Carcinoma (HNSCC) and its importance in tumour invasion. Experimental design: We use a 3D invasive organotypic raft culture model of human foreskin keratinocytes expressing the E6/E7 genes of the Human Papilloma Virus-16, coupled with bioinformatics and immunohistochemical analysis of patient samples to investigate the role played by EMT in invasion and identify effectors and upstream regulatory pathways. Results: We identify SNAI2 (Slug) as a critical effector of EMT activated downstream of TP63 overexpression in Head and Neck Squamous Cell Carcinoma (HNSCC). Splice-form specific depletion and rescue experiments further identify the ΔNp63γ isoform as both necessary and sufficient to activate the SRC signalling axis and SNAI2-mediated EMT and invasion. Moreover, elevated SRC levels are associated with poor outcome in HNSCC patients in the cancer genome atlas dataset. Importantly, the effects on EMT and invasions and SNAI2 expression can be reversed by genetic or pharmacological inhibition of SRC. Conclusion:Overexpression of ΔNp63γ modulates cell invasion by inducing targetable SRC-Slug-evoked EMT in HNSCC, which can be reversed by inhibitors of the SRC signalling.

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