Abstract
Cutaneous squamous cell carcinoma (cuSCC) is the second most common skin cancer and commonly arises in chronically UV-exposed skin or chronic wounds. Since UV exposure and chronic wounds are the two most prominent environmental factors that lead to cuSCC initiation, we undertook this study to test whether more acute molecular responses to UV and wounding overlapped with molecular signatures of cuSCC. We reasoned that transcriptional signatures in common between acutely UV-exposed skin, wounded skin, and cuSCC tumors, might enable us to identify important pathways contributing to cuSCC. We performed transcriptomic analysis on acutely UV-exposed human skin and integrated those findings with datasets from wounded skin and our transcriptomic data on cuSCC using functional pair analysis, GSEA, and pathway analysis. Integrated analyses revealed significant overlap between these three datasets, thus highlighting deep molecular similarities these biological processes, and we identified Oncostatin M (OSM) as a potential common upstream driver. Expression of OSM and its downstream targets correlated with poorer overall survival in head and neck SCC patients. In vitro, OSM promoted invasiveness of keratinocytes and cuSCC cells and suppressed apoptosis of irradiated keratinocytes. Together, these results support the concept of using an integrated, biologically-informed approach to identify potential promoters of tumorigenesis.
Highlights
Cutaneous squamous cell carcinoma is the second most common skin cancer and commonly arises in chronically UV-exposed skin or chronic wounds
Since UV exposure and chronic wounds are the two most prominent environmental factors that lead to Cutaneous squamous cell carcinoma (cuSCC) initiation, we sought to ask whether signatures of more acute molecular responses of skin to UV exposure and wounding would potentially overlap with signatures of established cuSCC
We demonstrated a direct effect of Oncostatin M (OSM) on keratinocyte and cuSCC migration and invasion, and we defined a role for OSM on UV-induced apoptosis
Summary
Cutaneous squamous cell carcinoma (cuSCC) is the second most common skin cancer and commonly arises in chronically UV-exposed skin or chronic wounds. Since UV exposure and chronic wounds are the two most prominent environmental factors that lead to cuSCC initiation, we sought to ask whether signatures of more acute molecular responses of skin to UV exposure and wounding would potentially overlap with signatures of established cuSCC. This notion is predicated on the previously established concept that molecular signatures of acute UV exposure are relevant to subsequent pathway alterations in established tumors[6,7]. Through integrated transcriptomic analyses of related data sets, we identified a consensus set of deregulated molecular pathways and a potential driver of cuSCC development
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