To determine the effects of CNN2 knockdown on the molecular phenotype of NSCLC cells, global RNA-Seq-based transcriptomic analysis was performed in parallel with global tandem mass tag multiplexing-based proteomic analysis in A549 cells transduced with shCtrl or shCNN2 . Knockdown of CNN2 resulted in 3,980 DEGs and 539 DEPs in A549 cells (Limma-moderated t-test). Venn analysis of these DEPs and DEGs revealed 222 differentially expressed targets at both mRNA and protein levels. After which, the DEGs and DEPs were mapped based on their log2-fold change values to profile the consistency of up- or downregulation at mRNA and protein levels. This mapping revealed four distinct groups of differentially expressed targets: (i) The ‘same’ group represents differentially expressed targets with the same trend at the mRNA level and protein level; (ii) the ‘opposite’ group represents differentially expressed targets with an opposite trend at the mRNA level and protein level; (iii) the ‘transcript_only’ group represents differentially expressed targets at the mRNA level but not at the protein level; and (iv) the ‘protein_only’ group represents differentially expressed targets at the protein level but not at the mRNA level. To improve understanding of the biological relevance of DEGs and DEPs, functional enrichment analysis was performed on GO and KEGG pathway enrichment analysis. The GO analysis revealed significant enrichment for several GO-BP, including wound healing, DNA replication, neutrophil degranulation and mitotic cytokinesis; several GO-MF, including protein domain-specific binding, cadherin binding and actin binding; and several GO-CC, including focal adhesion, membrane raft and centrosome . Breaking down the GO-BP analysis by group, it was found that the ‘same’ group consistently showed significant enrichment for neutrophil degranulation, wound healing, DNA replication and mitotic cytokinesis . KEGG analysis revealed significant enrichment for several KEGG pathways, including proteoglycans in cancer, actin cytoskeleton regulation and cell cycle. Partitioning the KEGG analysis by group revealed that the ‘same’ group consistently showed significant enrichment for proteoglycans in cancer, actin cytoskeleton regulation and cell cycle . Consistent with the role of CNN2 as a regulatory actin-binding protein, these combined results suggest that CNN2 may play a role in regulating actin cytoskeleton-mediated DNA replication and cell cycle progression in NSCLC cells.