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 Nonlinear Hierarchical Effects of Housing Prices and Built Environment Based on Multiscale Life Circle—A Case Study of Chengdu 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) Ott-Antonsen ansatz truncation of a circular cumulant series 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.