CTEN Induces Tumour Cell Invasion and Survival and Is Prognostic in Radiotherapy-Treated Head and Neck Cancer
Head and neck squamous cell carcinoma (HNSCC) is a heterogenous disease treated with surgery and/or (chemo) radiotherapy, but up to 50% of patients with late-stage disease develop locoregional recurrence. Determining the mechanisms underpinning treatment resistance could identify new therapeutic tar...
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| Format: | Article |
| Language: | English |
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MDPI AG
2020-10-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/12/10/2963 |
| _version_ | 1797551142447611904 |
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| author | Jason C. Fleming Jeongmin Woo Karwan Moutasim Christopher J. Hanley Steven J. Frampton Oliver Wood Matthew Ward Christopher H. Woelk Christian H. Ottensmeier Sassan Hafizi Dae Kim Gareth J. Thomas |
| author_facet | Jason C. Fleming Jeongmin Woo Karwan Moutasim Christopher J. Hanley Steven J. Frampton Oliver Wood Matthew Ward Christopher H. Woelk Christian H. Ottensmeier Sassan Hafizi Dae Kim Gareth J. Thomas |
| author_sort | Jason C. Fleming |
| collection | DOAJ |
| description | Head and neck squamous cell carcinoma (HNSCC) is a heterogenous disease treated with surgery and/or (chemo) radiotherapy, but up to 50% of patients with late-stage disease develop locoregional recurrence. Determining the mechanisms underpinning treatment resistance could identify new therapeutic targets and aid treatment selection. C-terminal tensin-like (CTEN) is a member of the tensin family, upregulated in several cancers, although its expression and function in HNSCC are unknown. We found that CTEN is commonly upregulated in HNSCC, particularly HPV<sup>−ve</sup> tumours. In vitro CTEN was upregulated in HPV<sup>−ve</sup> (<i>n</i> = 5) and HPV<sup>+ve</sup> (<i>n</i> = 2) HNSCC cell lines. Stable shRNA knockdown of CTEN in vivo significantly reduced tumour growth (SCC-25), and functional analyses in vitro showed that CTEN promoted tumour cell invasion, colony formation and growth in 3D-culture (SCC-25, Detroit 562). RNA sequencing of SCC-25 cells following CTEN siRNA knockdown identified 349 differentially expressed genes (logFC > 1, <i>p</i> < 0.05). Gene ontology analysis highlighted terms relating to cell locomotion and apoptosis, consistent with in vitro findings. A membrane-based antibody array confirmed that CTEN regulated multiple apoptosis-associated proteins, including HSP60 and cleaved caspase-3. Notably, in a mixed cohort of HPV<sup>+ve</sup> and HPV<sup>−ve</sup> HNSCC patients (<i>n</i> = 259), we found a significant, independent negative association of CTEN with prognosis, limited to those patients treated with (chemo)radiotherapy, not surgery, irrespective of human papillomavirus (HPV) status. These data show that CTEN is commonly upregulated in HNSCC and exerts several functional effects. Its potential role in modulating apoptotic response to therapy suggests utility as a predictive biomarker or radio-sensitising target. |
| first_indexed | 2024-03-10T15:39:31Z |
| format | Article |
| id | doaj.art-76eaf9e8e35c4815bfc006dc21b6342f |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T15:39:31Z |
| publishDate | 2020-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-76eaf9e8e35c4815bfc006dc21b6342f2023-11-20T16:55:06ZengMDPI AGCancers2072-66942020-10-011210296310.3390/cancers12102963CTEN Induces Tumour Cell Invasion and Survival and Is Prognostic in Radiotherapy-Treated Head and Neck CancerJason C. Fleming0Jeongmin Woo1Karwan Moutasim2Christopher J. Hanley3Steven J. Frampton4Oliver Wood5Matthew Ward6Christopher H. Woelk7Christian H. Ottensmeier8Sassan Hafizi9Dae Kim10Gareth J. Thomas11Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton SO17 1BJ, UKClinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton SO17 1BJ, UKCancer Sciences, Faculty of Medicine, University of Southampton, Southampton SO17 1BJ, UKCancer Sciences, Faculty of Medicine, University of Southampton, Southampton SO17 1BJ, UKCancer Sciences, Faculty of Medicine, University of Southampton, Southampton SO17 1BJ, UKCancer Sciences, Faculty of Medicine, University of Southampton, Southampton SO17 1BJ, UKCancer Sciences, Faculty of Medicine, University of Southampton, Southampton SO17 1BJ, UKClinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton SO17 1BJ, UKCancer Sciences, Faculty of Medicine, University of Southampton, Southampton SO17 1BJ, UKSchool of Pharmacy & Biomedical Sciences, University of Portsmouth, Portsmouth PO1 2DT, UKSt. George’s University Hospitals NHS Foundation Trust, Tooting, London SW17 0QT, UKCancer Sciences, Faculty of Medicine, University of Southampton, Southampton SO17 1BJ, UKHead and neck squamous cell carcinoma (HNSCC) is a heterogenous disease treated with surgery and/or (chemo) radiotherapy, but up to 50% of patients with late-stage disease develop locoregional recurrence. Determining the mechanisms underpinning treatment resistance could identify new therapeutic targets and aid treatment selection. C-terminal tensin-like (CTEN) is a member of the tensin family, upregulated in several cancers, although its expression and function in HNSCC are unknown. We found that CTEN is commonly upregulated in HNSCC, particularly HPV<sup>−ve</sup> tumours. In vitro CTEN was upregulated in HPV<sup>−ve</sup> (<i>n</i> = 5) and HPV<sup>+ve</sup> (<i>n</i> = 2) HNSCC cell lines. Stable shRNA knockdown of CTEN in vivo significantly reduced tumour growth (SCC-25), and functional analyses in vitro showed that CTEN promoted tumour cell invasion, colony formation and growth in 3D-culture (SCC-25, Detroit 562). RNA sequencing of SCC-25 cells following CTEN siRNA knockdown identified 349 differentially expressed genes (logFC > 1, <i>p</i> < 0.05). Gene ontology analysis highlighted terms relating to cell locomotion and apoptosis, consistent with in vitro findings. A membrane-based antibody array confirmed that CTEN regulated multiple apoptosis-associated proteins, including HSP60 and cleaved caspase-3. Notably, in a mixed cohort of HPV<sup>+ve</sup> and HPV<sup>−ve</sup> HNSCC patients (<i>n</i> = 259), we found a significant, independent negative association of CTEN with prognosis, limited to those patients treated with (chemo)radiotherapy, not surgery, irrespective of human papillomavirus (HPV) status. These data show that CTEN is commonly upregulated in HNSCC and exerts several functional effects. Its potential role in modulating apoptotic response to therapy suggests utility as a predictive biomarker or radio-sensitising target.https://www.mdpi.com/2072-6694/12/10/2963head and neck cancertensinCTENinvasionapoptosisradiotherapy |
| spellingShingle | Jason C. Fleming Jeongmin Woo Karwan Moutasim Christopher J. Hanley Steven J. Frampton Oliver Wood Matthew Ward Christopher H. Woelk Christian H. Ottensmeier Sassan Hafizi Dae Kim Gareth J. Thomas CTEN Induces Tumour Cell Invasion and Survival and Is Prognostic in Radiotherapy-Treated Head and Neck Cancer Cancers head and neck cancer tensin CTEN invasion apoptosis radiotherapy |
| title | CTEN Induces Tumour Cell Invasion and Survival and Is Prognostic in Radiotherapy-Treated Head and Neck Cancer |
| title_full | CTEN Induces Tumour Cell Invasion and Survival and Is Prognostic in Radiotherapy-Treated Head and Neck Cancer |
| title_fullStr | CTEN Induces Tumour Cell Invasion and Survival and Is Prognostic in Radiotherapy-Treated Head and Neck Cancer |
| title_full_unstemmed | CTEN Induces Tumour Cell Invasion and Survival and Is Prognostic in Radiotherapy-Treated Head and Neck Cancer |
| title_short | CTEN Induces Tumour Cell Invasion and Survival and Is Prognostic in Radiotherapy-Treated Head and Neck Cancer |
| title_sort | cten induces tumour cell invasion and survival and is prognostic in radiotherapy treated head and neck cancer |
| topic | head and neck cancer tensin CTEN invasion apoptosis radiotherapy |
| url | https://www.mdpi.com/2072-6694/12/10/2963 |
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