The Roal Of DKK Protein In Wnt/ β-Catenin Pathway In Stomach Cancer

Studies showed that the formation of wnt signaling induced inactivation of Wnt inhibitorsplays an important role in gastric cancer. Including the Wnt signaling pathways, is Wnt/β-Catenin pathway. β-Catenin acts as a Wnt pathway regulator, in the presence of Wnt ligands,β-Catenin accumulates in the cytoplasm ØOE following it enters into nucleus, where it acts asa transcription regulator and causing expression of the Wnt target genes. In the absence ofwnt ligands, cytoplasmic β-Catenin phosphorylated and then degradated, thus preventcancer. Several studies demonstrated some Wnt target genes include proteins of theDickkopf or (DKK), Axin and Nemo Kinase, etc inhibits Wnt signaling. DKK proteins, areproteins that play an important role in signaling pathways and are essential forembryogenesis and postnatal development, exemplified by DKK1 are a secretedglycoprotein of cancer cells that acts as an inhibitor of Wnt signaling pathway. DKK1 isligands antagonists of low-density lipoprotein (LDL)-receptor-related proteins 5 and 6 (LRP5and LRP6) and through binding to LRP5 and LRP6 blocked Wnt interaction with this complexvia inducing LRP6 internalization/degradation by transmembrane Kremen (Krm) proteins andthus led to the β-Catenin destruction and prevent its accumulation in the cell and causeddelay in proliferation. This Wnt antagonists are the early upregulated. In response toactivation of the Wnt signaling, it starts a negative feedback regulating. However, in certaintumor cells, DKK1 epigenetic silensing through promoter hypermethylated or loss of itsheterozygosity, produced a Wnt/DKK negative feedback of unstable. So supported tocontinuous activation of Wnt/β-Catenin signaling. These discussions suggest that in additionto the DKK1 regulated Wnt signaling pathway through a negative feedback mechanism alsoacts as a tumor suppressor, can have a strong oncogenic role in some tumors, such as lung,esophagus, breast, myeloma and stomach.

کلیدواژه ها:

DKK1 ، Wnt signaling ، β-Catenin ، Gastric cancer ، Tumor suppresure