AUTHOR=Zhao Haile , Gezi Gezi , Tian Xiaoxia , Jia Peijun , Morigen Morigen , Fan Lifei 

TITLE=Lysophosphatidic Acid–Induced EGFR Transactivation Promotes Gastric Cancer Cell DNA Replication by Stabilizing Geminin in the S Phase

JOURNAL=Frontiers in Pharmacology

VOLUME=12

YEAR=2021

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2021.706240

DOI=10.3389/fphar.2021.706240

ISSN=1663-9812

ABSTRACT=<p>Geminin, an inhibitor of the DNA replication licensing factor, chromatin licensing and DNA replication factor (Cdt) 1, is essential for the maintenance of genomic integrity. As a multifunctional protein, geminin is also involved in tumor progression, but the molecular details are largely unknown. Here, we found that lysophosphatidic acid (LPA)–induced upregulation of geminin was specific to gastric cancer cells. LPA acted <italic>via</italic> LPA receptor (LPAR) 3 and matrix metalloproteinases (MMPs) signaling to transactivate epidermal growth factor receptor (EGFR) (Y1173) and thereby stabilize geminin expression level during the S phase. LPA also induced the expression of deubiquitinating protein (DUB) 3, which prevented geminin degradation. These results reveal a novel mechanism underlying gastric cancer progression that involves the regulation of geminin stability by LPA-induced EGFR transactivation and provide potential targets for the signaling pathway and tumor cell–specific inhibitors.</p>