Our novel findings showed that either a low or high NNK dose can cause a significant upregulation of “oncomirs” miR-21 and miR-155 and downregulation of “tumor suppressor” miR-422a, as well as a decrease in hMSH2 and hMLH1 at both transcriptional and protein expression levels in exposed lung and head and neck squamous cancer cells. This evidence concerns the gene MSH2 and neoplasm.