In summary, we first explored that PRR14 was high expressed in human cSCC, and its overexpression was associated with tumor thickness, TNM stage and differentiation, suggesting that PRR14 might be a potential poor prognosis factor for cSCC; and the activator role of PRR14 in cSCC carcinogenesis maybe partial through PI3K/Akt/mTOR signal pathway, suggesting that PRR14 might be a new therapeutic target for cSCC treatment. Here, PRR14 is linked to skin squamous cell carcinoma.