DKK1 Promotes Epithelial–Mesenchymal Transition and Cisplatin Resistance in Gastric Cancer via Activation of the PI3K/AKT Pathway

Abstract

Chemotherapy is a classical method of cancer treatment. Cisplatin-based chemotherapy is a traditional and essential therapeutic approach in gastric cancer treatment. However, the development of drug resistance during treatment is a major obstacle that limits their further application, and molecular changes have occurred in the development of drug resistance. Here, we found that Dickkopf-related protein 1 (DKK1) is highly expressed in gastric cancer and related to poor prognosis in gastric cancer patients through public database mining. Next, we also identified that DKK1 is highly expressed in CDDP-resistant gastric cancer cell lines, supporting the notion that DKK1 is a necessary regulator of CDDP resistance. In terms of mechanistic research, our data reveal that DKK1 was able to activate the PI3K/AKT pathway and affect epithelial-to-mesenchymal transition, further contributing to CDDP resistance. Genetic knockdown and pharmacological inhibition of DKK1 recovered CDDP sensitivity both in vitro and in vivo. Therefore, our study highlights the potential of targeted inhibition of DKK1 to reverse CDDP resistance and alleviate metastatic properties in gastric cancer.

Environmental Exposure to Persistent Organic Pollutants and Its Association with Endometriosis Risk: Implications in the Epithelial–Mesenchymal Transition Process

“…Interestingly, we have found that higher concentrations of some OCPs, PCBs as well as ΣPOPs were positively correlated with the gene expression of a variety of promoters related to these signaling pathways such as PDGFRα, HMGA1, HOXA10, CCR1, FOXM1 or FUT8 genes. A similar trend was observed for DKK1, though the available evidence attributes a dual role to DKK1 during the EMT process [57,58]. These results are in line with previous studies suggesting up-regulation of PDGFRα gene expression in estrogen-dependent cells, such as epithelial mammary cells exposed to a pesticide mixture [83].…”

“…For instance, HMGA1, FOXM1, RXRA, FUT-8, POU5F1, or HOXA10 gene products promote EMT, while DUSP6 and AGR2 gene products decreased EMT via the TGF-β signaling pathway [49][50][51][52][53][54][55][56]. Similarly, DDK1, CDK1, or SOX2 and CCR1 or CHUK have been shown to regulate Wnt-driven and Notch/NF-κB-driven EMT, respectively [57][58][59][60][61][62]. Other soluble factors, such as the RRM2 gene product, promote EMT by targeting JAK2/STAT3 intracellular cascade [63].…”