CircITGA7 Suppresses Gastric Cancer Progression Through miR-1471/MTDH Axis

In recent years, there have been reports about the involvement of circular RNAs (circRNAs) in the pathogenesis of gastric cancer (GC), but the molecular mechanism in cell proliferation, invasion, and migration is still unclear. Based on The Cancer Genome Atlas (TCGA) database, we analyzed differentially expressed circRNAs between GC and non-tumor tissues. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis were used to clarify the functional role in GC. Here, we showed that circITGA7 was lowly expressed in GC tissues based on the TCGA database. In vitro, silencing the expression of circITGA7 increased cell proliferation and metastasis, whereas overexpression did the opposite. Mechanistically, miR-1471 has circITGA7 as a sponge, and miR-1471 has metadherin (MTDH) as a target gene. Consequently, functional analysis showed that the tumor suppressor effect of circITGA7 was the result of regulating the miR-1471/MTDH axis. Overall, the circITGA7/miR-1471/MTDH signaling pathway may play a crucial role in GC, providing a new potential mechanism involved in GC progression.

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CircGSK3B promotes RORA expression and suppresses gastric cancer progression through the prevention of EZH2 trans-inhibition

Journal of Experimental & Clinical Cancer Research ◽

10.1186/s13046-021-02136-w ◽

2021 ◽

Vol 40 (1) ◽

Author(s):

Xianxiong Ma ◽

Hengyu Chen ◽

Lei Li ◽

Feng Yang ◽

Chuanqing Wu ◽

...

Keyword(s):

Gastric Cancer ◽

Cancer Progression ◽

Gene Expression Regulation ◽

Migration And Invasion ◽

Circular Rnas ◽

Loss Of Function ◽

Invasion And Migration ◽

And Migration

Abstract Background Circular RNAs (circRNAs) are a class of non-coding RNA that play critical roles in the development and pathogenesis of various cancers. The circRNA circGSK3B (hsa_circ_0003763) has been shown to enhance cell proliferation, migration, and invasion in hepatocellular carcinoma. However, the specific functions and underlying mechanistic involvement of circGSK3B in gastric cancer (GC) have not yet been explored. Our study aimed to investigate the effect of circGSK3B on the progression of GC and to identify any potential mechanisms underlying this process. Methods CircRNA datasets associated with GC were obtained from the PubMed, GEO, and ArrayExpress databases, and circRNAs were validated via RT-qPCR and Sanger sequencing. Biotin-labeled RNA pull-down, mass spectrometry, RNA immunoprecipitation, and in vitro binding assays were employed to determine proteins demonstrating interactions with circGSK3B. Gene expression regulation was assessed through RT-qPCR, chromatin immunoprecipitation, and western blot assays. Gain- and loss-of-function assays were used to analyze any effects of circGSK3B and its partner regulatory molecule (EZH2) on the proliferation, invasion, and migration abilities of GC cells both in vitro and in vivo. Results CircGSK3B was mainly identified in the nucleus. This circRNA was present at a reduced concentration in GC tissues and cell lines. Overexpression of circGSK3B was shown to inhibit the growth, invasion, and metastasis of GC cells both in vitro and in vivo. Mechanistically, circGSK3B directly interacted with EZH2, acting to suppress the binding of EZH2 and H3K27me3 to the RORA promoter, and leading to an elevation in RORA expression and ultimately the suppression of GC progression. Conclusions CircGSK3B acts as a tumor suppressor, reducing EZH2 trans-inhibition and GC progression. This demonstrates the potential use of this RNA as a therapeutic target for GC.

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Knockdown of PGM1 Synergistically Enhances Anticancer Effects of Orlistat in Gastric Cancer Under Glucose Deprivation

10.21203/rs.3.rs-650761/v1 ◽

2021 ◽

Author(s):

Bo Cao ◽

Huan Deng ◽

Hao Cui ◽

Ruiyang Zhao ◽

Hanghang Li ◽

...

Keyword(s):

Gastric Cancer ◽

Cell Proliferation ◽

Lipid Metabolism ◽

Fatty Acid Synthase ◽

Enrichment Analysis ◽

Glucose Deprivation ◽

Metabolic Reprogramming ◽

The Cancer Genome Atlas

Abstract Background Phosphoglucomutase 1 (PGM1) acts as an important regulator in glucose metabolism. However, the role of PGM1 in gastric cancer (GC) remains unclear. This study aims to investigate the role of PGM1 and develop novel regimens based on metabolic reprogramming in GC. MethodsCorrelation and enrichment analysis of PGM1 was conducted based on The Cancer Genome Atlas database. Data derived from the Kaplan-Meier Plotter database were analyzed for correlations between PGM1 expression and survival time of GC patients. CCK-8, EdU, flow cytometry assays, generation of subcutaneous tumor and lung metastasis mouse models were used to determine growth and metastasis in vitro and in vivo. Cell glycolysis was detected by a battery of glycolytic indicators, including lactate, pyruvic acid, ATP production and glucose uptake. Fatty Acid Synthase (FASN) activity and detection of lipid regulators levels by western blot were used to reflect on the cell lipid metabolism. ResultsCorrelation and enrichment analysis suggested that PGM1 was closely associated with cell proliferation and metabolism. PGM1 was overexpressed in GC tissues and cell lines. High PGM1 expression served as an indicator of shorter survival for specific subpopulation of GC patients, which was also correlated with some clinicopathological features, including T stage and TNM stage. Under low glucose conditions, knockdown of PGM1 significantly suppressed cell proliferation and glycolysis levels, whereas lipid metabolism was enhanced. Orlistat, as a drug that was designed to inhibit FASN activity for obesity treatment, effectively induced apoptosis, suppressed FASN activity. However, orlistat conversely increased glycolytic levels in GC cells. Orlistat exhibited more significant inhibitive effects on GC progression after knockdown of PGM1 under glucose deprivation due to combination of glycolysis and lipid metabolism. ConclusionsDownregulation of PGM1 expression under glucose deprivation synergistically enhanced anti-cancer effects of orlistat. This combination application may serve as a novel strategy for GC treatment.

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Inhibition of Carnitine Palmitoyl Transferase 1A-induced Fatty Acid Oxidation Suppresses Cell Progression in Gastric Cancer

10.21203/rs.3.rs-37846/v1 ◽

2020 ◽

Author(s):

Liqiang Wang ◽

Changfeng Li ◽

Yumei Song ◽

ZhenKun Yan

Keyword(s):

Gastric Cancer ◽

Cell Proliferation ◽

Cancer Progression ◽

Molecular Mechanisms ◽

High Rate ◽

Acid Oxidation ◽

Cell Proliferation And Migration ◽

And Migration ◽

Proliferation And Migration

Abstract Background: Gastric cancer (GC) has a high rate of metastasis which thereason leading to death. Carnitine palmitoyltransferase 1a (CPT1A) has been reported to play a critical obstacle to various types of cancer progression, which is an attractive focus in anti-cancer therapy. However, the underlying molecular mechanisms of CPT1A involved in GC have not been clarified unclear.Methods: To determine the expression of CPT1A in human GC tissues and cells and illustrate whether it is correlated with the clinical pathologic characteristics and prognosis in GC patients. Its roles and potential mechanisms in regulating tumor growth and invasion were evaluated by CPT1A knockdown/overexpression of GC cells in vitro.Results: Marked upregulation of CPT1A protein expression was observed in GC cells and tissues, which was associated with grade, pathological stage, lymph node metastasis and poor prognosis in patients with GC. CPT1A overexpression also promoted the proliferation, invasion, EMT process of GC cells. In addition, CPT1A upregulation activated GC cell FAO via increasing NADP+/NADPH ratio, whereasinhibiting of FAO abolished the effects of CPT1A on GC cell proliferation and migration.Conclusion: Our results examine that CPT1A-mediated FAO activation increases GC cell proliferation and migration, supporting that CPT1A is a useful prognostic biomarker and an attractive focus for GC.

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HEATR1 promotes proliferation in gastric cancer in vitro and in vivo

Acta Biochimica et Biophysica Sinica ◽

10.1093/abbs/gmaa077 ◽

2020 ◽

Vol 52 (9) ◽

pp. 1030-1039

Author(s):

Jun Zhao ◽

Yiping Zhu ◽

Qingsheng Fu ◽

Yimei Zhu ◽

Guohai Zhao

Keyword(s):

Gastric Cancer ◽

Cell Proliferation ◽

Cancer Progression ◽

Xenograft Model ◽

The Cancer Genome Atlas ◽

Antibody Array ◽

Mouse Xenograft Model ◽

In Vivo Growth

Abstract HEAT repeat-containing protein 1 (HEATR1) is related to the progression of several cancers. However, the role of HEATR1 in gastric cancer (GC) remains unknown. In the present study, we aimed to detect the expression of HEATR1 in GC and identify its role. The expressions of HEATR1 in GC tissues were analyzed using The Cancer Genome Atlas database and by western blot analysis and immunohistochemistry. Furthermore, the HEATR1 expressions in GC cell lines MGC-803 and AGS were knocked down by using lentivirus-mediated HEATR1 shRNA. Cell proliferation and apoptosis were detected by CCK-8 and Caspase-Glo® 3/7 assays, respectively. PathScan® Signaling Antibody Array kit and Kyoto Encyclopedia of Genes and Genomes enrichment were used to study the pathways related to HEATR1. The influence of HEATR1 shRNA on the in vivo growth of GC cells was assessed by establishing a nude mouse xenograft model and conducting bioluminescence imaging. Our results showed that HEATR1 was highly expressed in GC tissues. Higher expression of HEATR1 is related to cancer progression and metastasis. Knocking down HEATR1 significantly suppressed the cell proliferation and colony formation and promoted cell apoptosis. The expression levels of phosphorylated p53, p38 MAPK, Chk2, and IKBa in shHEATR1-transfected MGC-803 cells exceeded those in shCtrl-transfected cells. HEATR1 shRNA treatment also significantly inhibited tumor growth in the mouse model. This study suggested that HEATR1 may be an oncogene and a target for GC therapy.

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EphA2–YES1–ANXA2 pathway promotes gastric cancer progression and metastasis

Oncogene ◽

10.1038/s41388-021-01786-6 ◽

2021 ◽

Author(s):

Linfeng Mao ◽

Weijie Yuan ◽

Kaimei Cai ◽

Chen Lai ◽

Changhao Huang ◽

...

Keyword(s):

Gastric Cancer ◽

Tyrosine Kinase ◽

Cancer Progression ◽

Cell Invasion ◽

Receptor Tyrosine Kinase ◽

Invasion And Migration ◽

Calcium Dependent ◽

And Migration ◽

Gastric Cancer Progression

AbstractErythropoietin-producing hepatocellular receptor A2 (EphA2) is a key member of the receptor tyrosine kinase (RTK) family, while YES Proto-Oncogene 1 (YES1) is a non-receptor tyrosine kinase (nRTK) and annexin A2 (ANXA2) belongs to the calcium-dependent phospholipid-binding protein family annexins. Here, we show that EphA2, YES1, and ANXA2 form a signal axis, in which YES1 activated by EphA2 phosphorylates ANXA2 at Tyr24 site, leading to ANXA2 activation and increased ANXA2 nuclear distribution in gastric cancer (GC) cells. Overexpression (OE) of YES1 increases, while knockdown (KD) of YES1 or ANXA2 decreases GC cell invasion and migration in vitro and tumor growth in mouse models. Reexpression of wildtype (WT) rather than mutant ANXA2 (Tyr24F) in ANXA2 knockdown (ANXA2-KD) GC cells restores YES1-induced cell invasion and migration, while neither WT nor mutant ANXA2 (Tyr24F) can restore cell invasion and migration in YES1-KD GC cells. In addition, the activation of EphA2–YES1–ANXA2 pathway is correlated with poor prognosis. Thus, our results establish EphA2–YES1–ANXA2 axis as a novel pathway that drives GC invasion and metastasis, targeting this pathway would be an efficient way for the treatment of GC.

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FGFR2 Promotes Gastric Cancer Progression by Inhibiting the Expression of Thrombospondin4 via PI3K-Akt-Mtor Pathway

Cellular Physiology and Biochemistry ◽

10.1159/000494590 ◽

2018 ◽

Vol 50 (4) ◽

pp. 1332-1345 ◽

Cited By ~ 14

Author(s):

Tingting Huang ◽

Dian Liu ◽

Yihua Wang ◽

Piao Li ◽

Li Sun ◽

...

Keyword(s):

Gastric Cancer ◽

Cancer Progression ◽

Clinical Stage ◽

Xenograft Model ◽

Mtor Pathway ◽

Invasion And Migration ◽

And Migration ◽

The Relationship

Background/Aims: Fibroblast growth factor receptor 2 (FGFR2) has attracted considerable interest as a therapeutic target in gastric cancer (GC). There is growing evidence to suggest that the bioavailability of the potent pro-tumor function of FGFR2 is associated with thrombospondins (TSPs). As a follow-on from our previous study, here we evaluated the potential clinical significance and mechanism of the relationship between FGFR2 and TSP4 in GC. Methods: Expression levels of FGFR2 and TSP4 were detected by immunohistochemistry in GC tissue microarray slides. SGC7901 and MKN28 cell lines were used to confirm the relationship between FGFR2 and TSP4. In vitro cell viability, colony formation, and invasion and migration assays were performed to evaluate the effect of FGFR2-TSP4 axis on tumor cell activities. The mechanism of TSP4 regulated by FGFG2 was explored via small molecular inhibitors in vitro and a xenograft model. Results: FGFR2 was shown to be markedly overexpressed in GC tissues and was correlated with a high risk of lymph node metastasis, late clinical stage, and poor prognosis. Low TSP4 expression was associated with shorter overall survival (OS) and advanced stage in GC patients. Interestingly, correlation analysis indicated that FGFR2 was negatively associated with TSP4. Indeed, in vitro and in vivo experiments suggested FGFR2 activation could downregulate TSP4 expression, which played an important role in the proliferation, invasion and migration of GC cells. We also found involvement of the PI3K-AKT-mTOR pathway in the FGFR2-TSP4 axis. Conclusion: The FGFR2 signal promotes human GC progression through the downregulation of TSP4 via PI3K-AKT-mTOR pathway. Our findings provide a foundation for further investigating promising therapeutic strategies for GC overexpressing FGFR2.

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microRNA-4488 in extracellular vesicles derived from marrow mesenchymal stem cells suppresses ABHD8 to inhibit ovarian cancer progression

10.21203/rs.3.rs-125335/v1 ◽

2020 ◽

Author(s):

Lei Chang ◽

Junying Zhou ◽

Wanjia Tian ◽

Mengyu Chen ◽

Ruixia Guo ◽

...

Keyword(s):

Ovarian Cancer ◽

Cell Proliferation ◽

Cancer Cells ◽

Cancer Progression ◽

Luciferase Reporter ◽

Ovarian Cancer Cells ◽

Invasion And Migration ◽

And Migration

Abstract Background Extracellular vesicle (EV) that delivered microRNAs (miRNAs) have been found as the important biomarkers participating in the pathological mechanism of ovarian cancer. Consequently, this study sought to examine the underlying mechanism of mesenchymal stem cell (MSC)-derived EVs containing miR-4488 in ovarian cancer. Methods The normal ovarian tissues and ovarian cancer tissues were extracted, and the information of MSC-EV miRNA was obtained by Bioinformatics analysis. RT-qPCR and western blot analysis were applied to detect miR-4488 and α/β-hydrolase domain-containing (ABHD)8 expression followed by determination of relationship between miR-4488 and ABHD8 by dual-luciferase reporter assay. After transfection with different plasmids and treatment with DMSO or GW4869 (inhibitor of EV), the regulatory roles of MSC-EV-miR-4488 in invasion, proliferation, apoptosis, and migration of cancer cells were explored. Besides, xenograft tumor in nude mice was conducted to explore the role of miR-4488 and ABHD8 in ovarian cancer in vivo. Results miR-4488 was poorly expressed and ABHD8 was highly expressed in ovarian cancer cells and tissues. ABHD8 was a target gene of miR-4488 while the knockdown of ABHD8 resulted in the suppression of proliferation, invasion, and migration while promoting the apoptosis of cancer cells. Functionally, MSC-EV-derived miR-4488 inhibited the expression of ABHD8. Additionally, miR-4488 over-expressed in MSC-EVs inhibited the cell proliferation, invasion, and migration through down-regulation of ABHD8 expression. At last, these in vitro findings were also confirmed in vivo. Conclusion To summarize, miR-4488 overexpressed in MSC-EVs suppressed ABHD8 expression to inhibit the cancer cell proliferation, invasion, and migration, thus suppressing ovarian cancer.

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YB-1 Is Altered in Pregnancy-Associated Disorders and Affects Trophoblast in Vitro Properties via Alternation of Multiple Molecular Traits

International Journal of Molecular Sciences ◽

10.3390/ijms22137226 ◽

2021 ◽

Vol 22 (13) ◽

pp. 7226

Author(s):

Violeta Stojanovska ◽

Aneri Shah ◽

Katja Woidacki ◽

Florence Fischer ◽

Mario Bauer ◽

...

Keyword(s):

Cell Lines ◽

Cancer Progression ◽

Cell Function ◽

Trophoblast Cell ◽

Mrna Levels ◽

Trophoblast Cells ◽

Invasion And Migration ◽

And Migration ◽

Apoptosis And Inflammation

Cold shock Y-box binding protein-1 (YB-1) coordinates several molecular processes between the nucleus and the cytoplasm and plays a crucial role in cell function. Moreover, it is involved in cancer progression, invasion, and metastasis. As trophoblast cells share similar characteristics with cancer cells, we hypothesized that YB-1 might also be necessary for trophoblast functionality. In samples of patients with intrauterine growth restriction, YB-1 mRNA levels were decreased, while they were increased in preeclampsia and unchanged in spontaneous abortions when compared to normal pregnant controls. Studies with overexpression and downregulation of YB-1 were performed to assess the key trophoblast processes in two trophoblast cell lines HTR8/SVneo and JEG3. Overexpression of YB-1 or exposure of trophoblast cells to recombinant YB-1 caused enhanced proliferation, while knockdown of YB-1 lead to proliferative disadvantage in JEG3 or HTR8/SVneo cells. The invasion and migration properties were affected at different degrees among the trophoblast cell lines. Trophoblast expression of genes mediating migration, invasion, apoptosis, and inflammation was altered upon YB-1 downregulation. Moreover, IL-6 secretion was excessively increased in HTR8/SVneo. Ultimately, YB-1 directly binds to NF-κB enhancer mark in HTR8/SVneo cells. Our data show that YB-1 protein is important for trophoblast cell functioning and, when downregulated, leads to trophoblast disadvantage that at least in part is mediated by NF-κB.

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Knockdown CYP2S1 inhibits lung cancer cells proliferation and migration

Cancer Biomarkers ◽

10.3233/cbm-210189 ◽

2021 ◽

pp. 1-9

Author(s):

Huan Guo ◽

Baozhen Zeng ◽

Liqiong Wang ◽

Chunlei Ge ◽

Xianglin Zuo ◽

...

Keyword(s):

Lung Cancer ◽

Cell Proliferation ◽

Cell Growth ◽

Cancer Cells ◽

Molecular Mechanisms ◽

Lung Cancer Cells ◽

Invasion And Migration ◽

And Migration

BACKGROUND: The incidence of lung cancer in Yunnan area ranks firstly in the world and underlying molecular mechanisms of lung cancer in Yunnan region are still unclear. We screened a novel potential oncogene CYP2S1 used mRNA microassay and bioinformation database. The function of CYP2S1 in lung cancer has not been reported. OBJECTIVE: To investigate the functions of CYP2S1 in lung cancer. METHODS: Immunohistochemistry and Real-time PCR were used to verify the expression of CYP2S1. Colony formation and Transwell assays were used to determine cell proliferation, invasion and migration. Xenograft assays were used to detected cell growth in vivo. RESULTS: CYP2S1 is significantly up-regulated in lung cancer tissues and cells. Knockdown CYP2S1 in lung cancer cells resulted in decrease cell proliferation, invasion and migration in vitro. Animal experiments showed downregulation of CYP2S1 inhibited lung cancer cell growth in vivo. GSEA analysis suggested that CYP2S1 played functions by regulating E2F targets and G2M checkpoint pathway which involved in cell cycle. Kaplan-Meier analysis indicated that patients with high CYP2S1 had markedly shorter event overall survival (OS) time. CONCLUSIONS: Our data demonstrate that CYP2S1 exerts tumor suppressor function in lung cancer. The high expression of CYP2S1 is an unfavorable prognostic marker for patient survival.

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ALG3 Contributes to the Malignant Biological Properties of Oral Squamous Cell Carcinoma Cells Through Regulating CDK-Cyclin Pathway

10.21203/rs.3.rs-46867/v1 ◽

2020 ◽

Author(s):

Peihong Shao ◽

Chengshi Wei ◽

Yun Wang

Keyword(s):

Western Blot ◽

Colony Formation ◽

Enrichment Analysis ◽

Biological Properties ◽

The Cancer Genome Atlas ◽

Cell Counting ◽

Invasion And Migration ◽

Elevated Expression ◽

Cancer Genome Atlas ◽

And Migration

Abstract Background: In this study, we planned to investigate the function and potential mechanisms of Alpha-1,3-mannosyltransferase (ALG3) in oral squamous cell carcinoma (OSCC). Methods: Data from The Cancer Genome Atlas (TCGA) was used to analyze ALG3 expression and its effect on the prognosis of patients with OSCC. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis was applied to explore the signaling pathways related to ALG3. In OSCC cells, ALG3 expression was measured by qPCR and western blot. Cell counting kit-8, colony formation, and transwell assays were implemented to detect the effects of ALG3 on the malignant biological properties OSCC cells. The expression of key proteins related to CDK-Cyclin pathway was detected by western blot. Results: The expression of ALG3 in OSCC samples was higher than that of the control samples, and the increase of ALG3 expression was related to unfavorable prognosis of OSCC patients. Additionally, the elevated expression of ALG3 was associated with pathological stage, lymph node metastasis and primary lesion in OSCC patients. ALG3 depletion blocked the growth, colony formation, invasion and migration of OSCC cells, while over-expression ALG3 reversed these phenomena. Moreover, exhaustion of ALG3 resulted in decreased expression of MCM7, CCNB2, CDK1 and PCNA, while these phenomena were inversed after ALG3 up-regulation. Conclusions: The enhancement of ALG3 expression promoted the aggressive biological behaviors of OSCC cells probably by promoting CDK-Cyclin pathway.

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