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

2021 ◽  
Vol 12 ◽  
Author(s):  
Haile Zhao ◽  
Gezi Gezi ◽  
Xiaoxia Tian ◽  
Peijun Jia ◽  
Morigen Morigen ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Dna Replication ◽  
Cancer Progression ◽  
Lysophosphatidic Acid ◽  
Growth Factor Receptor ◽  
S Phase ◽  
Gastric Cancer Cells ◽  
Egfr Transactivation ◽  
Lpa Receptor ◽  
Multifunctional Protein

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.

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

2020 ◽  
Author(s):  
Haile Zhao ◽  
Gezi Gezi ◽  
Xiaoxia Tian ◽  
Peijun Jia ◽  
Morigen Morigen ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Dna Replication ◽  
Cancer Cells ◽  
Signaling Pathways ◽  
Signaling Pathway ◽  
Tumor Cells ◽  
S Phase ◽  
Gastric Cancer Cells ◽  
Related Factors ◽  
Egfr Transactivation

Abstract 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.

scholarly journals Migration of gastric cancer cells in response to lysophosphatidic acid is mediated by LPA receptor 2

2013 ◽  
Vol 5 (3) ◽  
pp. 1048-1052 ◽  
Author(s):  
DEZHI YANG ◽  
WENHUA YANG ◽  
QIAN ZHANG ◽  
YAN HU ◽  
LIANG BAO ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cancer Cells ◽  
Lysophosphatidic Acid ◽  
Gastric Cancer Cells ◽  
Lpa Receptor

scholarly journals MTA2 sensitizes gastric cancer cells to PARP inhibition by induction of DNA replication stress

2021 ◽  
Vol 14 (10) ◽  
pp. 101167
Author(s):  
Jinwen Shi ◽  
Xiaofeng Zhang ◽  
Jin'e Li ◽  
Wenwen Huang ◽  
Yini Wang ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Dna Replication ◽  
Cancer Cells ◽  
Replication Stress ◽  
Parp Inhibition ◽  
Gastric Cancer Cells ◽  
Dna Replication Stress

scholarly journals MBP-1 Suppresses Growth and Metastasis of Gastric Cancer Cells through COX-2

2009 ◽  
Vol 20 (24) ◽  
pp. 5127-5137 ◽  
Author(s):  
Kai-Wen Hsu ◽  
Rong-Hong Hsieh ◽  
Chew-Wun Wu ◽  
Chin-Wen Chi ◽  
Yan-Hwa Wu Lee ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Tumor Progression ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Epithelial Mesenchymal Transition ◽  
Suppressive Effect ◽  
Migration And Invasion ◽  
Gastric Cancer Cells ◽  
Mesenchymal Transition ◽  
Cox 2

The c-Myc promoter binding protein 1 (MBP-1) is a transcriptional suppressor of c-myc expression and involved in control of tumorigenesis. Gastric cancer is one of the most frequent neoplasms and lethal malignancies worldwide. So far, the regulatory mechanism of its aggressiveness has not been clearly characterized. Here we studied roles of MBP-1 in gastric cancer progression. We found that cell proliferation was inhibited by MBP-1 overexpression in human stomach adenocarcinoma SC-M1 cells. Colony formation, migration, and invasion abilities of SC-M1 cells were suppressed by MBP-1 overexpression but promoted by MBP-1 knockdown. Furthermore, the xenografted tumor growth of SC-M1 cells was suppressed by MBP-1 overexpression. Metastasis in lungs of mice was inhibited by MBP-1 after tail vein injection with SC-M1 cells. MBP-1 also suppressed epithelial-mesenchymal transition in SC-M1 cells. Additionally, MBP-1 bound on cyclooxygenase 2 (COX-2) promoter and downregulated COX-2 expression. The MBP-1-suppressed tumor progression in SC-M1 cells were through inhibition of COX-2 expression. MBP-1 also exerted a suppressive effect on tumor progression of other gastric cancer cells such as AGS and NUGC-3 cells. Taken together, these results suggest that MBP-1–suppressed COX-2 expression plays an important role in the inhibition of growth and progression of gastric cancer.

scholarly journals Growth inhibitory effects of gastric cancer cells with an increase in S phase and alkaline phosphatase activity repression by aloe-emodin

2007 ◽  
Vol 6 (1) ◽  
pp. 85-88 ◽  
Author(s):  
Junming Guo ◽  
Bingxiu Xiao ◽  
Shun Zhang ◽  
Donghai Liu ◽  
Yiping Liao ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Alkaline Phosphatase ◽  
Cancer Cells ◽  
Phosphatase Activity ◽  
Alkaline Phosphatase Activity ◽  
S Phase ◽  
Inhibitory Effects ◽  
Gastric Cancer Cells ◽  
Growth Inhibitory ◽  
Aloe Emodin

The Role of Cancer-associated Fibroblasts in Tumorigenesis of Gastric Cancer

2018 ◽  
Vol 24 (28) ◽  
pp. 3297-3302 ◽  
Author(s):  
Zhilong Ma ◽  
Min Chen ◽  
Xiaohu Yang ◽  
Bin Xu ◽  
Zhenshun Song ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cancer Progression ◽  
Tumor Biology ◽  
Vital Role ◽  
Cancer Associated Fibroblasts ◽  
Gastric Cancer Cells ◽  
Stromal Fibroblasts ◽  
Tumor Microenvironments ◽  
Tumorigenesis And Progression

Cancer-associated fibroblasts (CAFs) are an important cell type present in solid tumor microenvironments, including that of gastric cancer. They play a vital role in the promotion of tumorigenesis, angiogenesis, and cancer progression through paracrine signaling and modulation of the extracellular matrix. However, the exact molecular mechanism underlying the interaction between gastric cancer cells and stromal fibroblasts remains poorly understood. Recent studies have demonstrated that various factors, such as gene and microRNA variations, are involved in this process. This review discusses recent advances in understanding how these factors are regulated in CAFs and how they affect tumor biology, which may improve our understanding of their role in gastric cancer tumorigenesis and progression and provide new promising targets for therapeutic strategies.

scholarly journals miR-335-5p Suppresses Gastric Cancer Progression by Targeting MAPK10

2020 ◽  
Author(s):  
Yi Gao ◽  
Yanfeng Wang ◽  
Xiaofei Wang ◽  
Changan Zhao ◽  
Fenghui Wang ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cell Cycle ◽  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Progression ◽  
Target Gene ◽  
Luciferase Reporter ◽  
Gastric Cancer Cells ◽  
Aberrant Expression ◽  
Related Target

Abstract Background: In recent years, many microRNAs(miRNAs) involved in cancer progression. The aberrant expression of miR-335-5p in tumorigenesis has been demonstrated. The present study aimed to investigate the molecular mechanisms underlying miR-335-5p- regulated MAPK10 expression in human gastric cancer（GC）.Methods: The quantitative real-time PCR was used to study the level of miR-335-5p expression in gastric cancer cell lines and tissues. Subsequently, the MTT and cloning formation assays were used to detect cell proliferation, while transwell and wound-healing assays were used to identify invasion and migration of the gastric cancer cells. The correlation between the miR-335-5p and the cell cycle-related target gene mitogen‑activated protein kinase 10 (MAPK10) in gastric cancer was analyzed based on the website. In addition, the target gene of miR-335-5p was detected by luciferase reporter assay, qRT-PCR, and western blotting.Results: The miR-335-5p level was down-regulated in GC tissues and cell lines. Furthermore, miR-335-5p inhibited proliferation, migration of gastric cancer cells, and induced apoptosis. During the G1/S phase, miR-335-5p arrested the cycle of gastric cancer cells in vitro. The correlation between the miR-335-5p and the cell cycle-related target gene MAPK10 in GC was analyzed, MAPK10 was directly targeted by the miR-335-5p.Conclusion: These data suggested that miR-335-5p acts as a tumor suppressor, and go through the MAPK10 to inhibit the GC progression.

scholarly journals CircPTK2 Suppresses the Progression of Gastric Cancer by Targeting the MiR-196a-3p/AATK Axis

2021 ◽  
Vol 11 ◽  
Author(s):  
Ling Gao ◽  
Tingting Xia ◽  
Mingde Qin ◽  
Xiaofeng Xue ◽  
Linhua Jiang ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Circular Rnas ◽  
High Morbidity ◽  
Gastric Cancer Cells ◽  
Mirna Sponges ◽  
Gastric Cancer Cell Proliferation

BackgroundGastric cancer is a type of malignant tumor with high morbidity and mortality. It has been shown that circular RNAs (circRNAs) exert critical roles in gastric cancer progression via working as microRNA (miRNA) sponges to regulate gene expression. However, the role and potential molecular mechanism of circRNAs in gastric cancer remain largely unknown.MethodsCircPTK2 (hsa_circ_0005273) was identified by bioinformatics analysis and validated by RT-qPCR assay. Bioinformatics prediction, dual-luciferase reporter, and RNA pull-down assays were used to determine the interaction between circPTK2, miR-196a-3p, and apoptosis-associated tyrosine kinase 1 (AATK).ResultsThe level of circPTK2 was markedly downregulated in gastric cancer tissues and gastric cancer cells. Upregulation of circPTK2 significantly suppressed the proliferation, migration, and invasion of gastric cancer cells, while circPTK2 knockdown exhibited opposite effects. Mechanically, circPTK2 could competitively bind to miR-196a-3p and prevent miR-196a-3p to reduce the expression of AATK. In addition, overexpression of circPTK2 inhibited tumorigenesis in a xenograft mouse model of gastric cancer.ConclusionCollectively, circPTK2 functions as a tumor suppressor to suppress gastric cancer cell proliferation, migration, and invasion through regulating the miR-196a-3p/AATK axis, suggesting that circPTK2 may serve as a novel therapeutic target for gastric cancer.

scholarly journals PKM2 Is the Target of a Multi-Herb-Combined Decoction During the Inhibition of Gastric Cancer Progression

2021 ◽  
Vol 11 ◽  
Author(s):  
Qingmin Sun ◽  
Mengyun Yuan ◽  
Hongxing Wang ◽  
Xingxing Zhang ◽  
Ruijuan Zhang ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cancer Progression ◽  
Cancer Metastasis ◽  
Nuclear Translocation ◽  
Aerobic Glycolysis ◽  
Metabolic Reprogramming ◽  
Migration And Invasion ◽  
Dependent Manner ◽  
Gastric Cancer Cells ◽  
Mesenchymal Transition

Gastric cancer is the third leading cause of cancer death worldwide. Traditional Chinese medicine (TCM) is increasingly extensively applied as a complementary therapy for gastric cancer (GC) in China, which shows unique advantages in preventing gastric cancer metastasis. Previous study indicates modified Jian-pi-yang-zheng (mJPYZ) decoction inhibit the progression of gastric cancer by regulating tumor-associated macrophages (TAM). However, it is unclear whether mJPYZ can affect metabolic reprogramming of gastric cancer cells. Here, we showed that mJPYZ effectively attenuated GC cells proliferation, migration and invasion. Meantime, mJPYZ reduced the aerobic glycolysis level of GC cells in vivo and in vitro by regulating the expression and nuclear translocation of PKM2. Overexpression of PKM2 that could reverse the inhibitory effect of mJPYZ, migration and epithelial to mesenchymal transition (EMT). Our results showed PKM2/HIF-1α signaling was the key metabolic regulator of mJPYZ in GC cells. In summary, our present study suggested that abnormal PKM2 is required for maintaining the malignant phenotype of GC cells. The TCM decoction mJPYZ inhibited GC cells growth and EMT by reducing of glycolysis in PKM2 dependent manner. This evidence expanded our understanding of the anti-tumor mechanism of mJPYZ and further indicated mJPYZ a potential anti-tumor agent for GC patients.Chemical Compounds Studied in this ArticleRutin (PubChem CID: 5280805); Lobetyolin (PubChem CID: 53486204); Calycosin-7-glucoside (PubChem CID: 71571502); Formononetin (PubChem CID: 5280378); Calycosin (PubChem CID: 5280448); Ononin (PubChem CID: 442813); P-Coumaric Acid (PubChem CID: 637542).

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