Using analysis of oral SCC patient tumors, together with the proteomic and genomic analysis of the HNSCC patient data we reveal an important association of CD109 expression with the expression of IL6Rα, phosphoSTAT3, NRF2 and NRF2 target genes, demonstrating the clinical relevance of the CD109/IL6Rα/STAT3/NRF2/antioxidant pathway as an important molecular mechanism mediating SCC progression. This evidence concerns the gene IL6R and head and neck squamous cell carcinoma.