We recently characterized SEC62 as an oncogene in non-small-cell lung cancer (NSCLC). Here we aimed to gain further insight into the molecular mechanisms of the cancer-related functions of this oncogene. We performed 2D-DIGE proteome analysis of tumor material from patients with NSCLC and of HEK293 cells stably overexpressing plasmid-encoded SEC62, combined with investigation of the Sec62 interactome. Furthermore, we analyzed the proteomic effects of siRNA-mediated depletion of the Sec62-interacting protein Sec63. We identified a comprehensive list of differentially regulated proteins, providing new insights into the molecular mechanisms of the cancer-related functions of Sec62 in cell migration, drug resistance, and Ca2+-homeostasis.