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

Abstract

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 via 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.

The Emerging Role of LPA as an Oncometabolite

“…LPA, via LPAR1 and 3, activates the epidermal growth factor receptor (EGFR)/PI3K/mammalian target of rapamycin (mTOR) and Aurora kinase pathways to promote geminin expression and stabilisation, which subsequently regulate DNA replication, cell cycle progression and proliferation of ovarian cancer cells [107]. A similar mechanism of LPA/geminincontrolled cell cycle progression has also been described in gastric cancer cells [108]. Of note, the induction of PI3K/AKT/mTOR/S6K1 signalling by LPA/LPAR5 interactions and concomitant increase in cell proliferation have also been noted in the cases of thyroid and oesophageal squamous cell carcinoma, as described previously {Zhao, 2021 #148} {Liu, 2021 #149}.…”

Lysophosphatidic acid suppresses apoptosis of high-grade serous ovarian cancer cells by inducing autophagy activity and promotes cell-cycle progression via EGFR-PI3K/Aurora-AThr288-geminin dual signaling pathways

“…The pellet was resuspended with 20 μL 5× SDS sample buffer. Proteins were then detected by immunoblotting assay ( Zhao et al, 2021 ).…”

“…A HiScript II 1st Strand cDNA Synthesis Kit (+gDNA wiper) (Vazyme Biotech) was used to generate the cDNA template. qRT-PCR was performed with TransStart Tip Green qPCR SuperMix (TransGen Biotech) on a LightCycler 480 II system (Roche, Basel, Switzerland) ( Zhao et al, 2021 ). Oligonucleotide sequences (Sangon Biotech) are described in Table S2.…”

“…DNA was visualized by staining with DAPI (1:5,000 in water). The immunofluorescence analysis was visualized with a laser scanning confocal microscope (LSM 710, CarlZeiss, Wetzlar, Germany) ( Zhao et al, 2021 ).…”