The prevalence of non-melanoma skin cancer (basal cell carcinoma and squamous cell carcinoma (SCC)) is growing. Cutaneous SCC is clinically recognised and often manifested as actinic keratosis (AK). AK is recognised as an early stage in a development of skin cancer. The aim of this study was to investigate molecular signalling pathways involved in AK progression to SCC. We collected 25 clinically diagnosed AK lesions, 9 of which were confirmed to be AK by histopatolology. Half of the lesion was processed for whole transcriptome sequencing. All lesions were histopathologically diagnosed within the AK to squamous cell carcinoma progression lineage. From the bioinformatics analysis, we observed a several specific signalling pathways that were modulated from AK to SCC. We confirmed a subset of proteins by immunohistochemistry (IF) to validate the relevant expression profiles in addition to phosphorylation status. We found that the focal adhesion pathway, MAPK signalling pathway and the branched amino acid metabolic pathway had several key regulator genes differentially expressed between AK, SCC and normal skin samples. Particularity, one of the key regulators for focal adhesion, PTEN showed a significant 1.5 folds decreased in expression in SCC compared to AK and a 1.9 fold decrease from SCC and normal (p<0.05). We performed IF for phospho-PTEN (pPTEN), PTEN and phospho-Akt and Akt which are negatively regulated by PTEN. Results from IF supported the finding in RNA-Seq that PTEN was highly expressed in AK compared to SCC. In addition, the expression of phospho-PTEN was localized mainly in nucleus and stratum corneum (SC) in AK whereas in SCC, it was localised mainly in cytoplasm but not in SC. Phospho-Akt was switched off in both AK and SCC compared to normal skin. Our results indicate that the expression and localization of phosphor-PTEN in tumour sections that represent the different stages of human skin carcinogenesis. It also suggests that PTEN expression might be used as marker distinguishing AK from SCC.