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

Lysophosphatidic acid（LPA）is the simplest active phospholipid molecule.LPA purified and identified from the ascites of patients with ovarian cancer has extensive tumor-promoting activities.Studies have shown that LPA can stimulate proliferation,migration and invasion of ovarian cancer cells by activating a series of G protein-coupled receptors.However,there are few reports about the research on LPA regulating the DNA replication in ovarian cancer cells.In this work,we take ovarian cancer cell lines as the research object,and use Western Blotting,RT-q PCR,Immunoprecipitation,Inhibitor treatment,CCK-8,ELISA,Flow cytometry and other research methods to clarify the regulatory mechanism of high expression of LPA on DNA replication in ovarian tumor microenvironment.We showed that LPA can induce up-regulation of the transcription and translation of geminin in ovarian cancer cells A2780 and OVCAR5.In ovarian cancer cell line with high EGFR expression,LPA binds to its specific receptor LPAR₃ and induces transactivation of EGFR through MMPs.The activated EGFR induces the activation of downstream PI3K/m TOR pathway,thereby up-regulating the expression of geminin.We also proved that LPA binds to its receptor LPAR₃ in a short period of time,and then increases the DNA content in S+G2/M phase of cells through MMPs,EGFR,and PI3K/m TOR pathway downstream of EGFR,thereby regulating the DNA replication in OVCAR5cells.On the other hand,LPA can also stabilize the expression of geminin by promoting the phosphorylation of Aurora-A kinase in Thr288.In summary,in ovarian cancer cells with high EGFR expression,LPA-induced EGFR transactivation to regulate the expression level of geminin and promote the DNA replication.This subject studied the regulation of EGFR transactivation induced by LPA in the tumor microenvironment on the DNA replication in ovarian cancer cells,and explored the mechanism by which LPA and related downstream signaling pathways regulate the stability of geminin.We also provide new potential targets and a theoretical basis for the development of signaling pathways and tumor cell-specific EGFR transactivation inhibitor drugs.