The top 10 significantly upregulated genes were highlighted, including S100A9, S100A8, SFN, S100A7, S100A2, SPRR2A, FABP5, ISG15, KRT6B, and KRT16. In specific, seven keratin encoded genes (KRT5, KRT6A, KRT6B, KRT6C, KRT14, KRT16, and KRT17), six genes (S100A2, S100A7, S100A7A, S100A8, and S100A9) from the S100 family, and five genes (SPRR2A, SPRR2B, SPRR2D, SPRR2F, and SPRR1B) from SPRR family were significantly upregulated in cSCC cells, indicating the pivotal function of these gene families in cSCC progression. Here, ISG15 is linked to skin squamous cell carcinoma.