Aberrant activation of the Hedgehog signalling pathway in squamous cell carcinoma of the vulva as a potential target for cancer therapy
Abstract In a previous study, we showed that the Hedgehog (Hh) signalling pathway is aberrantly activated in vulval squamous cell carcinoma (VSCC). In this study, we further validated our findings on a prospective cohort of primary VSCC cases, where immunohistochemical staining confirmed that key Hh...
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2021-09-01
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doaj-05f946613f6a40b3894bfa12183184292021-09-05T11:33:35ZengNature Publishing GroupScientific Reports2045-23222021-09-0111111710.1038/s41598-021-96940-1Aberrant activation of the Hedgehog signalling pathway in squamous cell carcinoma of the vulva as a potential target for cancer therapyJason K. W. Yap0Khalil Uddin1Rachel Pounds2Danielle O’Neill3Sean Kehoe4Raji Ganesan5Christopher W. Dawson6Birmingham Cancer Research UK Cancer Centre, Institute of Cancer and Genomic Sciences, University of BirminghamBirmingham Cancer Research UK Cancer Centre, Institute of Cancer and Genomic Sciences, University of BirminghamBirmingham Cancer Research UK Cancer Centre, Institute of Cancer and Genomic Sciences, University of BirminghamBirmingham Cancer Research UK Cancer Centre, Institute of Cancer and Genomic Sciences, University of BirminghamBirmingham Cancer Research UK Cancer Centre, Institute of Cancer and Genomic Sciences, University of BirminghamBirmingham Women’s NHS Foundation TrustDepartment of Microbiology & Infection, Warwick Medical School, University of WarwickAbstract In a previous study, we showed that the Hedgehog (Hh) signalling pathway is aberrantly activated in vulval squamous cell carcinoma (VSCC). In this study, we further validated our findings on a prospective cohort of primary VSCC cases, where immunohistochemical staining confirmed that key Hh pathway components were overexpressed in VSCC compared to normal vulval epithelium. We also undertook a series of in vitro studies to determine the extent of Hh pathway activation in VSCC-derived cell lines, and examine the consequences of pathway inhibition on the growth of these cells. We found that of six cell lines tested, four displayed elevated baseline Hh pathway activity that was dependent on SHH ligand, or in one case, a PTCH1 gene mutation. Hh signalling appeared necessary to sustain cell growth, as SHH ligand depletion with Robotikinin or SMO inhibition, either with chemical inhibitors (Itraconazole or LDE-225) or SMO-specific siRNA, attenuated GLI1 activity and cell proliferation in both monolayer and organotypic raft culture. Furthermore, treatment of Hh-dependent cell lines with SMO inhibitors sensitised cells to Cisplatin. Findings from our study offer us the opportunity to explore further the development of targeted chemotherapy for women with VSCC driven by aberrant Hh activation.https://doi.org/10.1038/s41598-021-96940-1 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Jason K. W. Yap Khalil Uddin Rachel Pounds Danielle O’Neill Sean Kehoe Raji Ganesan Christopher W. Dawson |
spellingShingle |
Jason K. W. Yap Khalil Uddin Rachel Pounds Danielle O’Neill Sean Kehoe Raji Ganesan Christopher W. Dawson Aberrant activation of the Hedgehog signalling pathway in squamous cell carcinoma of the vulva as a potential target for cancer therapy Scientific Reports |
author_facet |
Jason K. W. Yap Khalil Uddin Rachel Pounds Danielle O’Neill Sean Kehoe Raji Ganesan Christopher W. Dawson |
author_sort |
Jason K. W. Yap |
title |
Aberrant activation of the Hedgehog signalling pathway in squamous cell carcinoma of the vulva as a potential target for cancer therapy |
title_short |
Aberrant activation of the Hedgehog signalling pathway in squamous cell carcinoma of the vulva as a potential target for cancer therapy |
title_full |
Aberrant activation of the Hedgehog signalling pathway in squamous cell carcinoma of the vulva as a potential target for cancer therapy |
title_fullStr |
Aberrant activation of the Hedgehog signalling pathway in squamous cell carcinoma of the vulva as a potential target for cancer therapy |
title_full_unstemmed |
Aberrant activation of the Hedgehog signalling pathway in squamous cell carcinoma of the vulva as a potential target for cancer therapy |
title_sort |
aberrant activation of the hedgehog signalling pathway in squamous cell carcinoma of the vulva as a potential target for cancer therapy |
publisher |
Nature Publishing Group |
series |
Scientific Reports |
issn |
2045-2322 |
publishDate |
2021-09-01 |
description |
Abstract In a previous study, we showed that the Hedgehog (Hh) signalling pathway is aberrantly activated in vulval squamous cell carcinoma (VSCC). In this study, we further validated our findings on a prospective cohort of primary VSCC cases, where immunohistochemical staining confirmed that key Hh pathway components were overexpressed in VSCC compared to normal vulval epithelium. We also undertook a series of in vitro studies to determine the extent of Hh pathway activation in VSCC-derived cell lines, and examine the consequences of pathway inhibition on the growth of these cells. We found that of six cell lines tested, four displayed elevated baseline Hh pathway activity that was dependent on SHH ligand, or in one case, a PTCH1 gene mutation. Hh signalling appeared necessary to sustain cell growth, as SHH ligand depletion with Robotikinin or SMO inhibition, either with chemical inhibitors (Itraconazole or LDE-225) or SMO-specific siRNA, attenuated GLI1 activity and cell proliferation in both monolayer and organotypic raft culture. Furthermore, treatment of Hh-dependent cell lines with SMO inhibitors sensitised cells to Cisplatin. Findings from our study offer us the opportunity to explore further the development of targeted chemotherapy for women with VSCC driven by aberrant Hh activation. |
url |
https://doi.org/10.1038/s41598-021-96940-1 |
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