Cancer Progression Gene Expression Profiling Identifies the Urokinase Plasminogen Activator Receptor as a Biomarker of Metastasis in Cutaneous Squamous Cell Carcinoma
Cutaneous squamous cell carcinoma (cSCC) of the head and neck region is the second most prevalent skin cancer, with metastases to regional lymph nodes occurring in 2%–5% of cases. To further our understanding of the molecular events characterizing cSCC invasion and metastasis, we conducted targeted...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-04-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2022.835929/full |
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| author | Elahe Minaei Elahe Minaei Simon A. Mueller Simon A. Mueller Bruce Ashford Bruce Ashford Bruce Ashford Bruce Ashford Amarinder Singh Thind Amarinder Singh Thind Jenny Mitchell Jay R. Perry Jay R. Perry Benjamin Genenger Benjamin Genenger Jonathan R. Clark Jonathan R. Clark Jonathan R. Clark Ruta Gupta Ruta Gupta Ruta Gupta Marie Ranson Marie Ranson |
| author_facet | Elahe Minaei Elahe Minaei Simon A. Mueller Simon A. Mueller Bruce Ashford Bruce Ashford Bruce Ashford Bruce Ashford Amarinder Singh Thind Amarinder Singh Thind Jenny Mitchell Jay R. Perry Jay R. Perry Benjamin Genenger Benjamin Genenger Jonathan R. Clark Jonathan R. Clark Jonathan R. Clark Ruta Gupta Ruta Gupta Ruta Gupta Marie Ranson Marie Ranson |
| author_sort | Elahe Minaei |
| collection | DOAJ |
| description | Cutaneous squamous cell carcinoma (cSCC) of the head and neck region is the second most prevalent skin cancer, with metastases to regional lymph nodes occurring in 2%–5% of cases. To further our understanding of the molecular events characterizing cSCC invasion and metastasis, we conducted targeted cancer progression gene expression and pathway analysis in non-metastasizing (PRI-) and metastasizing primary (PRI+) cSCC tumors of the head and neck region, cognate lymph node metastases (MET), and matched sun-exposed skin (SES). The highest differentially expressed genes in metastatic (MET and PRI+) versus non-metastatic tumors (PRI-) and SES included PLAU, PLAUR, MMP1, MMP10, MMP13, ITGA5, VEGFA, and various inflammatory cytokine genes. Pathway enrichment analyses implicated these genes in cellular pathways and functions promoting matrix remodeling, cell survival and migration, and epithelial to mesenchymal transition, which were all significantly activated in metastatic compared to non-metastatic tumors (PRI-) and SES. We validated the overexpression of urokinase plasminogen activator receptor (uPAR, encoded by PLAUR) in an extended patient cohort by demonstrating higher uPAR staining intensity in metastasizing tumors. As pathway analyses identified epidermal growth factor (EGF) as a potential upstream regulator of PLAUR, the effect of EGF on uPAR expression levels and cell motility was functionally validated in human metastatic cSCC cells. In conclusion, we propose that uPAR is an important driver of metastasis in cSCC and represents a potential therapeutic target in this disease. |
| first_indexed | 2024-04-13T04:06:26Z |
| format | Article |
| id | doaj.art-3fab7cd4a9ee461d85584ffcb91394a7 |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-04-13T04:06:26Z |
| publishDate | 2022-04-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-3fab7cd4a9ee461d85584ffcb91394a72022-12-22T03:03:14ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2022-04-011210.3389/fonc.2022.835929835929Cancer Progression Gene Expression Profiling Identifies the Urokinase Plasminogen Activator Receptor as a Biomarker of Metastasis in Cutaneous Squamous Cell CarcinomaElahe Minaei0Elahe Minaei1Simon A. Mueller2Simon A. Mueller3Bruce Ashford4Bruce Ashford5Bruce Ashford6Bruce Ashford7Amarinder Singh Thind8Amarinder Singh Thind9Jenny Mitchell10Jay R. Perry11Jay R. Perry12Benjamin Genenger13Benjamin Genenger14Jonathan R. Clark15Jonathan R. Clark16Jonathan R. Clark17Ruta Gupta18Ruta Gupta19Ruta Gupta20Marie Ranson21Marie Ranson22Illawarra Health and Medical Research Institute (IHMRI), Wollongong, NSW, AustraliaSchool of Chemistry and Molecular Bioscience, University of Wollongong, Wollongong, NSW, AustraliaDepartment of Head and Neck Surgery, Sydney Head and Neck Cancer Institute, Chris O’Brien Lifehouse, Sydney, NSW, AustraliaDepartment for Otorhinolaryngology, Head and Neck Surgery, Zurich University Hospital University of Zurich, Zurich, SwitzerlandIllawarra Health and Medical Research Institute (IHMRI), Wollongong, NSW, AustraliaDepartment of Head and Neck Surgery, Sydney Head and Neck Cancer Institute, Chris O’Brien Lifehouse, Sydney, NSW, AustraliaIllawarra and Shoalhaven Local Health District (ISLHD), Wollongong, NSW, AustraliaSchool of Medicine, University of Wollongong, Wollongong, NSW, AustraliaIllawarra Health and Medical Research Institute (IHMRI), Wollongong, NSW, AustraliaSchool of Medicine, University of Wollongong, Wollongong, NSW, AustraliaIllawarra and Shoalhaven Local Health District (ISLHD), Wollongong, NSW, AustraliaIllawarra Health and Medical Research Institute (IHMRI), Wollongong, NSW, AustraliaSchool of Chemistry and Molecular Bioscience, University of Wollongong, Wollongong, NSW, AustraliaIllawarra Health and Medical Research Institute (IHMRI), Wollongong, NSW, AustraliaSchool of Chemistry and Molecular Bioscience, University of Wollongong, Wollongong, NSW, AustraliaDepartment of Head and Neck Surgery, Sydney Head and Neck Cancer Institute, Chris O’Brien Lifehouse, Sydney, NSW, AustraliaRoyal Prince Alfred Institute of Academic Surgery, Sydney Local Health District, Sydney, NSW, AustraliaCentral Clinical School, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, AustraliaDepartment of Head and Neck Surgery, Sydney Head and Neck Cancer Institute, Chris O’Brien Lifehouse, Sydney, NSW, AustraliaCentral Clinical School, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, AustraliaNSW Health Pathology, Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Sydney, NSW, AustraliaIllawarra Health and Medical Research Institute (IHMRI), Wollongong, NSW, AustraliaSchool of Chemistry and Molecular Bioscience, University of Wollongong, Wollongong, NSW, AustraliaCutaneous squamous cell carcinoma (cSCC) of the head and neck region is the second most prevalent skin cancer, with metastases to regional lymph nodes occurring in 2%–5% of cases. To further our understanding of the molecular events characterizing cSCC invasion and metastasis, we conducted targeted cancer progression gene expression and pathway analysis in non-metastasizing (PRI-) and metastasizing primary (PRI+) cSCC tumors of the head and neck region, cognate lymph node metastases (MET), and matched sun-exposed skin (SES). The highest differentially expressed genes in metastatic (MET and PRI+) versus non-metastatic tumors (PRI-) and SES included PLAU, PLAUR, MMP1, MMP10, MMP13, ITGA5, VEGFA, and various inflammatory cytokine genes. Pathway enrichment analyses implicated these genes in cellular pathways and functions promoting matrix remodeling, cell survival and migration, and epithelial to mesenchymal transition, which were all significantly activated in metastatic compared to non-metastatic tumors (PRI-) and SES. We validated the overexpression of urokinase plasminogen activator receptor (uPAR, encoded by PLAUR) in an extended patient cohort by demonstrating higher uPAR staining intensity in metastasizing tumors. As pathway analyses identified epidermal growth factor (EGF) as a potential upstream regulator of PLAUR, the effect of EGF on uPAR expression levels and cell motility was functionally validated in human metastatic cSCC cells. In conclusion, we propose that uPAR is an important driver of metastasis in cSCC and represents a potential therapeutic target in this disease.https://www.frontiersin.org/articles/10.3389/fonc.2022.835929/fullcutaneous squamous cell carcinoma (cSSC)urokinase plasminogen activator receptor (uPAR)urokinase plasminogen activator (uPA)metastasismatrix metalloproteinase (MMP)extracellular matrix (ECM) |
| spellingShingle | Elahe Minaei Elahe Minaei Simon A. Mueller Simon A. Mueller Bruce Ashford Bruce Ashford Bruce Ashford Bruce Ashford Amarinder Singh Thind Amarinder Singh Thind Jenny Mitchell Jay R. Perry Jay R. Perry Benjamin Genenger Benjamin Genenger Jonathan R. Clark Jonathan R. Clark Jonathan R. Clark Ruta Gupta Ruta Gupta Ruta Gupta Marie Ranson Marie Ranson Cancer Progression Gene Expression Profiling Identifies the Urokinase Plasminogen Activator Receptor as a Biomarker of Metastasis in Cutaneous Squamous Cell Carcinoma Frontiers in Oncology cutaneous squamous cell carcinoma (cSSC) urokinase plasminogen activator receptor (uPAR) urokinase plasminogen activator (uPA) metastasis matrix metalloproteinase (MMP) extracellular matrix (ECM) |
| title | Cancer Progression Gene Expression Profiling Identifies the Urokinase Plasminogen Activator Receptor as a Biomarker of Metastasis in Cutaneous Squamous Cell Carcinoma |
| title_full | Cancer Progression Gene Expression Profiling Identifies the Urokinase Plasminogen Activator Receptor as a Biomarker of Metastasis in Cutaneous Squamous Cell Carcinoma |
| title_fullStr | Cancer Progression Gene Expression Profiling Identifies the Urokinase Plasminogen Activator Receptor as a Biomarker of Metastasis in Cutaneous Squamous Cell Carcinoma |
| title_full_unstemmed | Cancer Progression Gene Expression Profiling Identifies the Urokinase Plasminogen Activator Receptor as a Biomarker of Metastasis in Cutaneous Squamous Cell Carcinoma |
| title_short | Cancer Progression Gene Expression Profiling Identifies the Urokinase Plasminogen Activator Receptor as a Biomarker of Metastasis in Cutaneous Squamous Cell Carcinoma |
| title_sort | cancer progression gene expression profiling identifies the urokinase plasminogen activator receptor as a biomarker of metastasis in cutaneous squamous cell carcinoma |
| topic | cutaneous squamous cell carcinoma (cSSC) urokinase plasminogen activator receptor (uPAR) urokinase plasminogen activator (uPA) metastasis matrix metalloproteinase (MMP) extracellular matrix (ECM) |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2022.835929/full |
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