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Background Tenascin-C (Tn-C) is an extracellular matrix protein with multiple functions that is present at low levels in normal tissues, but which is highly present in various tumours. The mRNA expression and protein level of Tn-C including its various isoforms have not been investigated comprehensively so far in cutaneous squamous cell carcinoma (SCC) and the precursor lesion actinic keratosis (AK). Objectives To assess the dysregulated expression and splice variants of Tn-C in cutaneous squamous cell dysplasia and carcinoma. Methods Biopsies from 66 patients (or representative subsets) that comprised 25 specimens from normal skin, 19 AK and 22 cutaneous SCC were analysed for Tn-C splice variants using splice-specific primers. The amount of Tn-C mRNA was investigated by quantitative real-time reverse transcription–polymerase chain reaction. In addition, the presence of Tn-C protein was analysed in sections of paraffin-embedded tissues using immunohistochemistry. Results The large Tn-C splice variant was present in only 5% of normal skin samples, in comparison with 63% of AK ( P < 0·001) and 88% of SCC ( P < 0·001). Tn-C mRNA expression was significantly increased in AK and SCC compared with normal skin ( P < 0·001). The corresponding proteins were rarely detected in cells of the vascular epithelial layers and perifollicular layers of some normal skin specimens, and their spatial localization expanded into the papillary dermis of AK. The largest amount and the widest distribution were found in samples of SCC, in which Tn-C was located in the basal cells at the tumour invasion front and additionally in the papillary dermis and reticular dermis. Conclusions Tn-C is present in the dermis, its expression is increased during skin cancer development, and the large splice variant is characteristic for AK and SCC, which may prove useful for diagnostic approaches in cutaneous SCC. [ABSTRACT FROM AUTHOR]