While the progression from early stage to middle stage LSCC can be potentially induced by the alteration of tumor microenvironment caused by oxidative stress induced by the stimulation of nicotine derived nitrosaminoketone (NNK), the dysfunctions of ERBB4, PDPN, and EMR2 signaling, the regulation of miR-9-2, the epigenetic modifications of GATA3, FOXL1, and CDH3, the DNA methylation of PDPN, and the dysregulation of cellular functions, such as proliferation, cell mobility, and cell adhesion. This evidence concerns the gene PDPN and neoplasm.