The Effects And Molecular Mechanism Of Lysophosphatidic Acid In Gastric Cancer Cell DNA Replication Initiation

Lysophosphatidic acid（LPA）is one of the simplest active phospholipid molecules.Binding to its receptors on the cell surface,LPA initiates various intracellular signal cascades,involving in numerous biological processes,such as cell proliferation,migration,and apoptosis.If abnormalities occur in the processes of LPA production,receptor expression or signal transduction,it may induce certain diseases and even contribute to the occurrence,development and metastasis of cancer.However,whether the initiation of DNA replication is regulated by LPA have not yet been investigated.We found that LPA specifically up-regulated of Geminin expression in gastric cancer cell lines,and that the deletion of Geminin protein induced DNA re-replication in gastric cancer cell lines.Nither of these phenomenon has been observed in normal gastric epithelial cells,indicating these phenomenon are restricted to tumor cells.Using RNAi technology or inhibitor to block the biological activity of related factors in the signaling pathway,we found that LPA acts through LPAR₃ and downstream coupled MMPs signaling to trans-activate EGFR,increasing the expression level of Geminin in S phase.On the other hand,LPA stimulation induced the up-regulation of de-ubiquitinating enzyme 3（DUB3）in a short time and inhibited the ubiquitination degradation of Geminin to enhance Geminin stability and positively regulate the DNA replication initiation in gastric cancer cells.Our research is an important supplement to the function of LPA in the tumor microenvironment and the initial regulatory mechanism of tumor cell DNA replication,providing a potential target for the treatment of gastric cancer.