Dkk3 inhibits the aggressiveness and mitigates chemoresistance through low lipid droplet formation in gastric cancer: A biomarker and gene therapy target

Dkk3 is discovered through comparative studies of immortalized cells and their parental counterparts and might inhibit the aggressive phenotypes in malignant cells, demonstrating its tumor-suppressor activity. Here, we explored the clinicopathological significance of Dkk3 expression, the association between Dkk3 expression and immune microenvironment, and Dkk3-related signal pathways in gastric cancer (GC), and discovered the effects of Dkk3 on aggressiveness, chemoresistance and lipid droplet formation with molecular mechanisms investigated. Our data showed that plasma level of Dkk3 was low in GC and Dkk3 expression was negatively correlated with younger age, tumor size, depth of invasion, lymph node metastasis, clinicopathological stage and histological classification of GC. Additionally our study shows DKK3 have a potential impact on GC immunity by regulating immune cell infiltration. Overexpression of wild-type and no-signal peptide Dkk3 inhibited cell proliferation, promoted apoptotic and pyroptotic cell death, and suppressed invasion, migration and epithelialmesenchymal transition in GC cells. Furthermore, Dkk3 expression promoted chemosensitivity by weakening lipid droplet formation in GC cells. The Dkk3-related pathways included ECM (extracellular matrix)-receptor interactions, ECM constituents and organization, WP miRNA targets in ECM membrane receptors, focal adhesion, cAMP, calcium and integrin signaling pathways, basement membranes, spliceosome activity, mitochondrial oxidative phosphorylation, and ubiquitin-like protein binding. These results indicate that Dkk3 expression may serve as a valuable indicator to evaluate the pathological behaviors and immunotherapy of GC. Additionally, Dkk3 could potentially inhibit the aggressiveness regardless of signal peptide, and alleviate chemoresistance by low lipid droplet formation, making it become a valuable molecular target for gene therapy.