Lysophosphatidic acid induces the migration and invasion of SGC-7901 gastric cancer cells through the LPA2 and Notch signaling pathways

Ren, Zhiheng; Zhang, Chen-Li; Ma, Linna; Zhang, Xiao; Shi, Suhua; Tang, Deng; Xu, Jianrong; Yan, Hu; Wang, Binsheng; Zhang, Fangfang; Zheng, Haixue

doi:10.3892/ijmm.2019.4186

Cited by 28 publications

(24 citation statements)

References 58 publications

(56 reference statements)

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“…We showed that LPA enhanced the migration and invasion of OSCC cells in a variety of in vitro assays, including 3D organotypic assays of invasion. These results are consistent with previous reports in other tumour types (Hwang et al, 2016;Jourquin et al, 2006;Ren et al, 2019), including OSCC (Brusevold et al, 2014). The effect of LPA on the response of OSCC cells to irradiation was also examined in the present study using clonogenic survival assays and we showed that cells pre-treated with LPA were more resistant to irradiation.…”

Section: Discussionsupporting

confidence: 93%

Figure 4: The effects of LPA on OSCC migration are mediated through COX-2.

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Section: Discussionsupporting

confidence: 93%

Figure 4: The effects of LPA on OSCC migration are mediated through COX-2.

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“…LPA is now emerging as an important factor in TME, which could promote tumor growth, migration, invasion, metastasis and angiogenesis. LPA markedly increased cell migration and invasion mainly via acting through LPAR 1-3 [35,37], however, the role of LPA/LPAR in DNA replication has not been discussed before. Here, we for the rst time reveal that LPA promotes DNA replication through upregulating geminin protein expression in gastric cancer cells.…”

Section: Discussionmentioning

confidence: 99%

“…The submucosal connective tissue-type mast cells is one source of the production of lysophosphatidic acid in gastrointestinal tract [34]. The most notable role of LPA in gastric cancer development is to mediate cell migration and invasion, which acting through diverse downstream effectors [35][36][37][38][39]. Meanwhile, LPA also stimulates gastric cancer cell proliferation through upregulating sphingosine kinase 1 transcription [40].…”

Section: Introductionmentioning

confidence: 99%

Lysophosphatidic Acid-induced EGFR Transactivation Promotes Gastric Cancer DNA Replication Through Up-Regulation of Geminin

Zhao¹,

Gezi²,

Tian³

et al. 2020

Preprint

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BackgroundLysophosphatidic 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 has not yet been investigated.MethodsFirst, diverse public databases were analyzed to explore the genetic abnormalities affecting geminin. Next, an LPA gradient treatment was performed on gastric cancer cells, followed by detecting geminin expression variation using western blot analysis. Finally, RNAi technology or inhibitors were used to block the biological activity of related factors in the GPCR induced EGFR transactivation signaling pathway to verify whether the effect of LPA evoked gastric cancer DNA replication is dependent on geminin upregulation.ResultsWe found that LPA specifically up-regulated expression of an essential replication negative regulator geminin in early S phase in gastric cancer cell lines, and that the deletion of geminin selectively induced DNA re-replication. Neither of these phenomena has been observed in normal gastric epithelial cells, indicating LPA-induced geminin up-regulation is restricted to tumor cells. Using RNAi or specific inhibitors to block the 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. Taken together, our results suggested that LPA mediated DNA replication and S-phase cell-cycle progression through a LPAR3/MMPs/EGFR/PI3K/mTOR signaling axis in gastric cancer. ConclusionsOur research is for the first time to study the regulatory effect of LPA-induced EGFR transactivation in DNA replication of tumor cells, and to uncover a novel mechanism for regulating the stability of geminin through LPA and related downstream signaling pathways. All of which will provide potential targets for the development of signaling pathways and tumor cell-specific EGFR transactivation inhibitor for the treatment of gastric cancer.

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“…Thrombin acts on PAR1, 2 and 4, and has been shown to affect cancer progression via activation of the PAR pathway (53,54). Most lysophosphatidic acid receptors (LPARs) are GPCRs and several studies have shown that the activation of the LPAR signaling axis is involved in cell proliferation and invasion in several types of cancer (55)(56)(57)(58). Recent studies have shown that activation of GPCR30 (GPR30) results in cancer cell growth, including in breast cancer-associated fibroblasts, thyroid cancer cells, ovarian cancer cells, GPCR, G-protein coupled receptor; SNX27, sorting nexin 27; PTHR, a receptor of parathyroid hormone or parathyroid hormone-related protein (PTHrP); β1-AR, β-adrenergic receptor 1; β2-AR, β-adrenergic receptor 2; mGluRs, metabotropic glutamate receptors; GIRKs, G protein-coupled inwardly rectifying K + channels; FZDs, frizzled receptors; PARs, protease-activated receptors; LPARs, lysophosphatidic acid receptors.…”

Section: O Th Er Ca N Cer-a Sso Cia Ted Gpcr S D Epen D En T O Nmentioning

confidence: 99%