The Roles of Beclin 1 Expression in Gastric Cancer: A Marker for Carcinogenesis, Aggressive Behaviors and Favorable Prognosis, and a Target of Gene Therapy

Beclin 1 is encoded by Becn1, and plays a role in tumorigenesis, neurodegeneration, apoptosis and autophagy. Here, the aggressive phenotypes and relevant proteins were examined after Beclin 1 expression was altered in gastric cancer cells. We also observed the effects of Beclin 1 on gastric carcinogenesis using Becn1 knockout mice. Finally, clinicopathological significances of Beclin 1 expression were analyzed using meta- and bioinformatics analyses. Becn1 overexpression was found to inhibit proliferation, glucose metabolism, migration and invasion of gastric cancer cells, whereas its knockdown caused the opposite effects. Beclin 1 suppressed the tumor growth by decreasing proliferation and increasing apoptosis. The heterozygous abrogation of Becn1 in gastric pit, parietal and chief cells could not cause any epithelial lesion. Beclin 1-mediated chemoresistance was closely linked to the autophagy, Bax underexpression, and the overexpression of Bcl-2, LRP1, MDR1, and ING5. Bioinformatics analysis showed higher Becn1 mRNA expression in intestinal- than diffuse-type carcinomas (P<0.05), and in male than female gastric cancer patients (P<0.05). Becn1 hyperexpression was positively associated with both overall and progression-free survival rates of the cancer patients (P<0.05). Meta-analysis showed that down-regulated Beclin 1 expression in gastric cancer was positively with lymph node metastasis, TNM staging, dedifferentiation and poor prognosis (P<0.05). Becn1-related signal pathways in gastric cancer included prostate, lung, renal, colorectal, endometrial and thyroid cancers, glioma, and leukemia, the metabolism of amino acid, lipid and sugar, and some signal pathways of insulin, MAPK, TRL, VEGF, JAK-STAT, chemokine, p53, lysosome, peroxidome and ubiquitin-mediated protein degradation (P<0.05). These suggested that Beclin 1 might be considered as a potential marker of gastric carcinogenesis, aggressiveness and prognostic prediction, and as a target of gene therapy in gastric cancer.

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Reduced Kiss‑1 expression is associated with clinical aggressive feature of gastric cancer patients and promotes migration and invasion in gastric cancer cells

Oncology Reports ◽

10.3892/or.2020.7676 ◽

2020 ◽

Vol 44 (3) ◽

pp. 1149-1157

Author(s):

Chao Li ◽

Li Yuan ◽

Shuangshuang Han ◽

Mingda Xuan ◽

Dehua Liu ◽

...

Keyword(s):

Gastric Cancer ◽

Cancer Cells ◽

Cancer Patients ◽

Migration And Invasion ◽

Gastric Cancer Cells ◽

Gastric Cancer Patients

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Down-regulation of HIF-1α inhibits the proliferation, migration, and invasion of gastric cancer by inhibiting PI3K/AKT pathway and VEGF expression

Bioscience Reports ◽

10.1042/bsr20180741 ◽

2018 ◽

Vol 38 (6) ◽

Cited By ~ 13

Author(s):

Jingjing Zhang ◽

Jun Xu ◽

Yonghong Dong ◽

Bo Huang

Keyword(s):

Gastric Cancer ◽

Cancer Cells ◽

Cancer Patients ◽

Akt Pathway ◽

Migration And Invasion ◽

Vegf Expression ◽

Gastric Cancer Cells ◽

Tumor Tissues ◽

Sirna Silencing ◽

Gastric Cancer Patients

In view of the high incidence of gastric cancer and the functions of hypoxia-inducible factor 1α (HIF-1α), our study aimed to investigate the functionality of HIF-1α in gastric cancer, and to explore the diagnostic and prognostic values of HIF-1α for this disease. Expression of HIF-1α in tumor tissues and adjacent healthy tissues as well as serum collected from both gastric cancer patients and normal healthy controls was detected by qRT-PCR. Survival analysis was performed using Kaplan–Meier method. HIF-1α siRNA silencing cell lines were established. Effects of HIF-1α siRNA silencing as well as PI3K activator sc3036 on proliferation, migration, and invasion of gastric cancer cells were detected by Cell counting kit (CCK-8) assay, and Transwell migration and invasion assay. Effects of HIF-1α siRNA silencing on AKT and VEGF were detected by Western blot. Expression of HIF-1α was significantly down-regulated in tumor tissues than in adjacent healthy tissues in most gastric cancer patients. Serum levels of HIF-1α were also higher in gastric cancer patients than in normal healthy people. Serum HIF-1α showed promising diagnostic and prognostic values for gastric cancer. HIF-1α siRNA silencing inhibited the proliferation, migration, and invasion of gastric cancer cells, while PI3K activator sc3036 treatment reduced those inhibitory effects. Down-regulation of HIF-1α can inhibit the proliferation, migration, and invasion of gastric cancer possibly by inhibiting PI3K/AKT pathway and VEGF expression.

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Abnormal N-glycosylated CPXM1 promotes gastric cancer metastasis through ITGB2 / FAK pathway

10.21203/rs.3.rs-613113/v1 ◽

2021 ◽

Author(s):

Jun Du ◽

Mengxiang Zhu ◽

Wenwu Yan ◽

Jin Guo Wang

Keyword(s):

Gastric Cancer ◽

Cancer Cells ◽

Bioinformatics Analysis ◽

Abdominal Cavity ◽

Migration And Invasion ◽

Signal Pathways ◽

Malignant Phenotype ◽

Gastric Cancer Cells ◽

Glycosylation Sites

Abstract Background: To explore the molecular mechanism of CPXM1 in gastric cancer (GC) metastasis.Methods: Based on the difference in expression of CPXM1 mRNA in GC tissues and normal gastric mucosa tissues in public databases, rt-PCR, WB and IHC staining experiments were performed to verify the expression of CPXM1 in fresh GC tissues. Bioinformatics analysis predicts the possible signal pathways of co-expression genes in CPXM1 overexpression group. The malignant phenotypes of GC cells was verified by in vivo and in vitro experiments. Using tunicamycin to inhibit the N-glycosylation of CPXM1 and constructing mutations. The plasmid further validated the specific N-glycosylation sites that affect the malignant phenotype of gastric cancer cells.Results: CPXM1 mRNA expression was significantly increased in GC tissues. The results of IHC staining and WB indicated that there was no difference in the expression of CPXM1 at the protein level. Knocking down CPXM1 expression in HGC-27 cells can significantly inhibit its migration and invasion ability. Increasing the expression of CPXM1 in MGC-803 and BGC-823 cell lines can significantly promote its migration and invasion capabilities. CPXM1 can also promote the adhesion of GC cells and change the cytoskeleton structure. The results of in-vivo experiments show that CPXM1 can promote the metastasis of GC cells in the abdominal cavity of nude mice. Bioinformatics analysis showed that the co-expressed genes of the CPXM1 high expression group were mainly enriched in cell adhesion function, and the experimental results verified that CPXM1 may promote the adhesion and metastasis of gastric cancer cells through the ITGB2/FAK signaling pathway. Through N-glycosylation site prediction and WB results, it was found that CPXM1 had abnormal N-glycosylation in GC tissues. Tunicamycin can reverse the ability of CPXM1 that promote the invasion of GC cells. After respectively mutating the N-glycosylation sites on CPXM1, it was found that N210 site is the key site for CPXM1 to promote the adhesion and invasion of GC cells.Conclusion: CPXM1 is upgraded in GC. CPXM1 can promote the adhesion, migration and invasion of GC cells and change cytoskeleton structure. The N210 site on CPXM1 is a key site affecting the malignant phenotype of GC.

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DNAJA3/Tid1 Is Required for Mitochondrial DNA Maintenance and Regulates Migration and Invasion of Human Gastric Cancer Cells

Cancers ◽

10.3390/cancers12113463 ◽

2020 ◽

Vol 12 (11) ◽

pp. 3463

Author(s):

Sheng-Fan Wang ◽

Kuo-Hung Huang ◽

Wei-Chuan Tseng ◽

Jeng-Fan Lo ◽

Anna Fen-Yau Li ◽

...

Keyword(s):

Gastric Cancer ◽

Cell Migration ◽

Cancer Cells ◽

Cancer Patients ◽

Migration And Invasion ◽

Gastric Cancer Cells ◽

Cell Migration And Invasion ◽

Gastric Cancers ◽

Gastric Cancer Patients

Background: Gastric cancer is a common health issue. Deregulated cellular energetics is regarded as a cancer hallmark and mitochondrial dysfunction might contribute to cancer progression. Tid1, a mitochondrial co-chaperone, may play a role as a tumor suppressor in various cancers, but the role of Tid1 in gastric cancers remains under investigated. Methods: The clinical TCGA online database and immunohistochemical staining for Tid1 expression in tumor samples of gastric cancer patients were analyzed. Tid1 knockdown by siRNA was applied to investigate the role of Tid1 in gastric cancer cells. Results: Low Tid1 protein-expressing gastric cancer patients had a poorer prognosis and higher lymph node invasion than high Tid1-expressing patients. Knockdown of Tid1 did not increase cell proliferation, colony/tumor sphere formation, or chemotherapy resistance in gastric cancer cells. However, Tid1 knockdown increased cell migration and invasion. Moreover, Tid1 knockdown reduced the mtDNA copy number of gastric cancer cells. In addition, the Tid1-galectin-7-MMP-9 axis might be associated with Tid1 knockdown–induced cell migration and invasion of gastric cancer cells. Conclusions: Tid1 is required for mtDNA maintenance and regulates migration and invasion of gastric cancer cells. Tid1 deletion may be a poor prognostic factor in gastric cancers and could be further investigated for development of gastric cancer treatments.

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Distinctive Prognostic Value and Cellular Functions of Osteopontin Splice Variants in Human Gastric Cancer

Cells ◽

10.3390/cells10071820 ◽

2021 ◽

Vol 10 (7) ◽

pp. 1820

Author(s):

Chengcheng Hao ◽

Yuxin Cui ◽

Jane Lane ◽

Shuqin Jia ◽

Jiafu Ji ◽

...

Keyword(s):

Gastric Cancer ◽

Cancer Cells ◽

Cell Lines ◽

Prognostic Value ◽

Splice Variants ◽

Tnm Staging ◽

Migration And Invasion ◽

Ros Production ◽

Gastric Cancer Cells ◽

Normal Tissues

Background: Osteopontin (OPN) splice variants are identified as predictors of tumour progression and therapeutic resistance in certain types of solid tumours. However, their roles in gastric cancer (GC) remain poorly characterized. The current study sought to assess the prognostic value of the three OPN splice variants (namely OPN-a, OPN-b, and OPN-c) in gastric cancer and their potential functions within gastric cancer cells. Methods: RNA extraction and reverse transcription were performed using our clinical cohort of gastric carcinomas and matched normal tissues (n = 324 matched pairs). Transcript levels were determined using real-time quantitative PCR. Three OPN splice variants overexpressed cell lines were created from the gastric cancer cell line HGC-27. Subsequently, biological functions, including cell growth, adhesion, migration, and invasion, were studied. The potential effects of OPN isoforms on cisplatin and 5-Fu were evaluated by detecting cellular reactive oxygen species (ROS) levels in the HGC-27-derived cell lines. Results: Compared with normal tissues, the expression levels of three splice variants were all elevated in gastric cancer tissues in an order of OPN-a > OPN-b > OPN-c. The OPN-a level significantly increased with increasing TNM staging and worse clinical outcome. There appeared to be a downregulation for OPN-c in increasing lymph node status (p < 0.05), increasing TNM staging, and poor differentiation. High levels of OPN-a and OPN-b were correlated with short overall survival and disease-free survival of gastric cancer patients. However, the low expression of OPN-c was significantly associated with a poor prognosis. Functional analyses further showed that ectopic expression of OPN-c suppressed in vitro proliferation, adhesiveness, migration, and invasion properties of HGC-27 cells, while the opposite role was seen for OPN-a. Cellular ROS detection indicated that OPN-a and OPN-c significantly promoted ROS production after treatment with 5-Fu comparing to OPN-vector, while only OPN-a markedly induced ROS production after treatment with cisplatin. Conclusion: Our results suggest that OPN splice variants have distinguished potential to predict the prognosis of gastric cancer. Three OPN variants exert distinctive functions in gastric cancer cells. Focusing on specific OPN isoforms could be a novel direction for developing diagnostic and therapeutic approaches in gastric cancer.

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CDX2 and Reg IV expression and correlation in gastric cancer

BMC Gastroenterology ◽

10.1186/s12876-021-01678-9 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Dandan Chai ◽

Huifen Du ◽

Kesheng Li ◽

Xueliang Zhang ◽

Xiaoqin Li ◽

...

Keyword(s):

Gastric Cancer ◽

Cell Migration ◽

Cancer Cells ◽

Real Time ◽

Real Time Pcr ◽

Ectopic Expression ◽

Rank Correlation ◽

Migration And Invasion ◽

Gastric Cancer Cells ◽

Cell Migration And Invasion

Abstract Background Ectopic expression of CDX2 is associated with the development and progression of gastric cancer. Previous studies showed that CDX2 may be an upstream regulator of Reg IV expression in gastric cancer, and our previous report showed that Reg IV upregulated SOX9 expression and enhanced cell migration and invasion in gastric cancer cells. However, the regulatory roles of CDX2 have not been clarified in gastric cancer, and the correlation between CDX2 and Reg IV requires further study. Methods CDX2 and Reg IV were examined in gastric cancer specimens and paired adjacent tissues via real-time PCR and immunohistochemistry (IHC). The association between CDX2 and Reg IV was assessed using the χ2-test and Spearman’s rank correlation. To verify their relationship, knockdown and exogenous expression of CDX2 or Reg IV were performed in AGS and MKN-45 gastric cancer cells, and their expression was subsequently analyzed via a real-time PCR and western blotting. Wound-healing and Transwell assays were used to examine migration and invasion in AGS and MKN-45 cells following CDX2 silencing or overexpression. Results A positive correlation was observed between CDX2 and Reg IV expression at the mRNA and protein levels in gastric cancer tissues. CDX2 silencing significantly downregulated Reg IV expression, and CDX2 overexpression significantly upregulated Reg IV expression in AGS and MKN-45 cells. Neither Reg IV silencing nor overexpression had any effect on CDX2 protein expression in AGS or MKN-45 cells, even though both affected the expression of CDX2 mRNA. Functionally, CDX2 silencing significantly inhibited cell migration and invasion, and CDX2 overexpression significantly promoted cell migration and invasion in AGS and MKN-45 cells. Conclusions Our findings demonstrate that CDX2 expression was positively correlated with that of Reg IV in gastric cancer, and CDX2 promoted cell migration and invasion through upregulation of Reg IV expression in AGS and MKN-45 cells.

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Sevoflurane represses the migration and invasion of gastric cancer cells by regulating forkhead box protein 3

Journal of International Medical Research ◽

10.1177/03000605211005936 ◽

2021 ◽

Vol 49 (4) ◽

pp. 030006052110059

Author(s):

Fangfang Yong ◽

Hemei Wang ◽

Chao Li ◽

Huiqun Jia

Keyword(s):

Gastric Cancer ◽

Cell Migration ◽

Cancer Cells ◽

Cell Lines ◽

Migration And Invasion ◽

Control Group ◽

Gastric Cancer Cells ◽

Cell Migration And Invasion ◽

Forkhead Box ◽

Induced Apoptosis

Objective Previous studies suggested that sevoflurane exerts anti-proliferative, anti-migratory, and anti-invasive effects on cancer cells. To determine the role of sevoflurane on gastric cancer (GC) progression, we evaluated its effects on the proliferation, migration, and invasion of SGC7901, AGS, and MGC803 GC cells. Methods GC cells were exposed to different concentrations of sevoflurane (1.7, 3.4, or 5.1% v/v). Cell viability, migration, and invasion were evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and Transwell assays. Immunohistochemical staining and immunoblotting were performed to analyze forkhead box protein 3 (FOXP3) protein expression in tissue specimens and cell lines, respectively. Results FOXP3 was downregulated in human GC specimens and cell lines. Functionally, FOXP3 overexpression significantly inhibited the proliferation, migration, and invasion of GC cells and accelerated their apoptosis. Moreover, sevoflurane significantly blocked GC cell migration and invasion compared with the findings in the control group. However, FOXP3 silencing neutralized sevoflurane-induced apoptosis and the inhibition of GC cell migration and invasion. Sevoflurane-induced apoptosis and the suppression of migration and invasion might be associated with FOXP3 overactivation in GC cells. Conclusions Sevoflurane activated FOXP3 and prevented GC progression via inhibiting cell migration and invasion in vitro.

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

Molecular Biology of the Cell ◽

10.1091/mbc.e09-05-0386 ◽

2009 ◽

Vol 20 (24) ◽

pp. 5127-5137 ◽

Cited By ~ 27

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.

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