P2RX7 functions as a putative biomarker of gastric cancer and contributes to worse prognosis

Wang, Lili; Li, Yun; Tingran, Wei; Wu, Xia; Sun, Ying

doi:10.1177/1535370219846492

Cited by 20 publications

(15 citation statements)

References 25 publications

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“…Considering these differences, our results of P2Y2R and P2X4R relative expression could provide an idea about the progression of gastric cancer. This relationship between P2Y2R and P2X4R gene expression remarks the potential of purinergic signaling as a prospective biomarker for gastric cancer progression, as similar studies have reported for P2X7R, whose overexpression is related to tumor size, metastatic potential, and overall survival in human colorectal and gastric cancer [41,42]. The opposite effects observed after P2Y2R or P2X4R activation can be explained by the different signaling pathways that these receptors can trigger: P2Y2R is a Gαq-coupled receptor that increases intracellular calcium and activates protein kinase C but also can activate other signaling pathways such as PI3K-Akt [43] or ERK1/2 phosphorylation via a protein kinase C (PKC)-dependent mechanism [44,45].…”

Section: Discussionsupporting

confidence: 77%

“…Interestingly, it has been reported in this work that the expression of P2Y6R is diminished in GC-derived cells and gastric tumors [ 52 ]. Another receptor that has been linked with GC is P2X7R, whose expression is increased in gastric tumors and associated with lower survival of GC patients [ 42 ]. Adenosine and ATP inhibit cell proliferation and induced apoptosis in lung cancer [ 53 , 54 ].…”

Section: Discussionmentioning

confidence: 99%

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Purinergic P2Y2 and P2X4 Receptors Are Involved in the Epithelial-Mesenchymal Transition and Metastatic Potential of Gastric Cancer Derived Cell Lines

et al. 2021

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Gastric cancer (GC) is a major health concern worldwide, presenting a complex pathophysiology that has hindered many therapeutic efforts so far. In this context, purinergic signaling emerges as a promising pathway for intervention due to its known role in cancer cell proliferation and migration. In this work, we explored in more detail the role of purinergic signaling in GC with several experimental approaches. First, we measured extracellular ATP concentrations on GC-derived cell lines (AGS, MKN-45, and MKN-74), finding higher levels of extracellular ATP than those obtained for the non-tumoral gastric cell line GES-1. Next, we established the P2Y2 and P2X4 receptors (P2Y2R and P2X4R) expression profile on these cells and evaluated their role on cell proliferation and migration after applying overexpression and knockdown strategies. In general, a P2Y2R overexpression and P2X4R downregulation pattern were observed on GC cell lines, and when these patterns were modified, concomitant changes in cell viability were observed. These modifications on gene expression also modified transepithelial electrical resistance (TEER), showing that higher P2Y2R levels decreased TEER, and high P2X4R expression had the opposite effect, suggesting that P2Y2R and P2X4R activation could promote and suppress epithelial-mesenchymal transition (EMT), respectively. These effects were confirmed after treating AGS cells with UTP, a P2Y2R-agonist that modified the expression patterns towards mesenchymal markers. To further characterize the effects of P2Y2R activation on EMT, we used cDNA microarrays and observed that UTP induced important transcriptional changes on several cell processes like cell proliferation induction, apoptosis inhibition, cell differentiation induction, and cell adhesion reduction. These results suggest that purinergic signaling plays a complex role in GC pathophysiology, and changes in purinergic balance can trigger tumorigenesis in non-tumoral gastric cells.

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Section: Discussionsupporting

confidence: 77%

Section: Discussionmentioning

confidence: 99%

Purinergic P2Y2 and P2X4 Receptors Are Involved in the Epithelial-Mesenchymal Transition and Metastatic Potential of Gastric Cancer Derived Cell Lines

et al. 2021

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“…Inhibition of COX-2 in MDA-MB-231 cells through upstream inhibition of the nuclear factor κB (NF-κB) signaling suppressed its invasiveness ( Kim et al, 2014 ). The p42/44 MAPK signaling is upstream of the NF-κB-mediated COX-2 expression ( Akundi et al, 2005 ), and has been shown to be activated following P2 receptor stimulation ( Parvathenani et al, 2003 ; Yang et al, 2004 ; Lili et al, 2019 ). Similarly, p38 MAPK is essential for COX-2 synthesis, either directly through downstream activation of transcription factors ( Fiebich et al, 2000 ; Akundi et al, 2005 ), or through stabilization of COX-2 mRNA post-transcription, thereby prolonging the effect of COX-2 or inflammation for a much longer period ( Lasa et al, 2000 ; Harper and Tyson-Capper, 2008 ).…”

Section: Discussionmentioning

confidence: 99%

Extracellular ATP Mediates Cancer Cell Migration and Invasion Through Increased Expression of Cyclooxygenase 2

2021

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The tumor microenvironment plays a major role in the ability of the tumor cells to undergo metastasis. A major player of tumors gaining metastatic property is the inflammatory protein, cyclooxygenase 2 (COX-2). Several tumors show upregulation of this protein, which has been implicated in mediating metastasis in various cancer types such as of colon, breast and lung. In this report, we show that the concentration of extracellular ATP (eATP) is increased in response to cell death mediated by chemotherapeutic agents such as doxorubicin. By using three different cell-lines—HeLa (cervical), IMR-32 (neuronal) and MCF-7 (breast)—we show that this eATP goes on to act on purinergic (P2) receptors. Among the various P2 receptors expressed in these cells we identified P2X7, in IMR-32 and MCF-7 cells, and P2Y12, in HeLa cells, as important in modulating cell migration and invasion. Downstream of the P2 receptor activation, both p42/44 mitogen-activated protein kinase (MAPK) and the p38 MAPK are activated in these cells. These result in an increase in the expression of COX-2 mRNA and protein. We also observe an increase in the activity of matrix metalloproteinase 2 (MMP-2) enzyme in these cells. Blocking the P2 receptors not only blocks migration and invasion, but also COX-2 synthesis and MMP-2 activity. Our results show the link between purinergic receptors and COX-2 expression. Increased levels of ATP in the tumor microenvironment, therefore, leads to increased COX-2 expression, which, in turn, affords migratory and invasive properties to the tumor. This provides P2 receptor-based anti-inflammatory drugs (PBAIDs) a potential opportunity to be explored as cancer therapeutics.

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“…Additional studies published have revealed that the P2X7 receptor is highly correlated with the growth of cancers, including GC, when ATP acts as an extracellular messenger. 21,22 TCGA database results showed that P2X7 is clearly related to an unfavorable prognosis in GC patients (Figure S1B) and is highly expressed in tumor tissues of GC patients (Figure S1A). It has been proposed that ATP5B activated the FAK/ AKT/MMP2 pathway through ATP binding its receptor P2X7.…”

Section: Atp Activates the Fak/akt/mmp2 Signaling Pathway Through Its Receptor P2x7mentioning

confidence: 99%

ATP5B promotes the metastasis and growth of gastric cancer by activating the FAK/AKT/MMP2 pathway

Wang

Chang

et al. 2021

The FASEB Journal

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Adenosine triphosphate (ATP) in the tumor microenvironment serves a vital role during tumor progression. ATP synthase F1 β subunit (ATP5B) is one of the most important subunits of ATP synthase and increases cellular ATP levels. ATP5B reportedly participates in carcinogenesis in several tumors. However, the regulatory mechanisms of ATP5B remain poorly understood in gastric cancer (GC). Here, we determined that high ATP5B expression in tumor tissues of GC is positively correlated with age, the tumor size, the TNM stage, lymph node metastasis, and patients’ poor prognosis. The overexpression of ATP5B in GC cells elevated the cellular ATP content and promoted migration, invasion and proliferation. The levels of MMP2 expression, phosphorylated FAK, and phosphorylated AKT were increased after ATP5B overexpression in GC cells. Additionally, ATP5B overexpression increased the extracellular ATP level through the secretion of intracellular ATP and activated the FAK/AKT/MMP2 signaling pathway. ATP5B‐induced downstream pathway activation was induced through the plasma membrane P2X7 receptor. Inhibitors of P2X7, FAK, AKT, and MMP2 suppressed the proliferative, migratory, and invasive capabilities of GC cells. In conclusion, our experiments indicate that ATP5B contributes to tumor progression of GC via FAK/AKT/MMP2 pathway. ATP5B, therefore, may be a biomarker of poor prognosis and a potential therapeutic target for GC.

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P2RX7 functions as a putative biomarker of gastric cancer and contributes to worse prognosis

Cited by 20 publications

References 25 publications

Purinergic P2Y2 and P2X4 Receptors Are Involved in the Epithelial-Mesenchymal Transition and Metastatic Potential of Gastric Cancer Derived Cell Lines

Purinergic P2Y2 and P2X4 Receptors Are Involved in the Epithelial-Mesenchymal Transition and Metastatic Potential of Gastric Cancer Derived Cell Lines

Extracellular ATP Mediates Cancer Cell Migration and Invasion Through Increased Expression of Cyclooxygenase 2

ATP5B promotes the metastasis and growth of gastric cancer by activating the FAK/AKT/MMP2 pathway

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