Effect of Spag5 on proliferation and sensitivity to DNA-damaging chemotherapy.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e15556-e15556
Author(s):  
Wangjun Liao ◽  
Lezhong Yuan ◽  
Yuhao Luo ◽  
Huanrong Ma
Keyword(s):  
Gastric Cancer ◽  
Comet Assay ◽  
Tumor Growth ◽  
Cell Viability ◽  
Protein Level ◽  
Mrna Level ◽  
The Cancer Genome Atlas ◽  
Tumor Growth Rate ◽  
Cancer Tissue

e15556 Background: Chemotherapy based on DNA-damaging anti-cancer drugs remains the most predominant treatment for advanced gastric cancer. The predictors for their sensitivity are under development. Our data showed that sperm-associated antigen 5 (Spag5) contributed to cancer cell proliferation and decreased DNA-damaging drug sensitivity in vivo and vitro. Methods: Spag5 mRNA expression were compared in The Cancer Genome Atlas (TCGA) and GEO datasets (GSE56807, GSE63089, GSE65801), while protein level were detected in 52 patients diagnosed with gastric cancer in Nanfang Hospital by immunohistochemistry. BGC-823 and MGC-803 were transfected with spag5 and control siRNA and then subjected to MTT and EDU assay to verify proliferation rate. Cell viability and apoptosis were tested in spag5-silenced BGC-823 and MGC-803 treated with oxaliplatin, epirubicin and 5-fluorouracil independently. DNA-damaged were detected by comet assay and yH2ax level with western blot. Treatment of oxaliplatin was given intraperitoneally to nude mice carrying xerographs of Shspag5 or control BGC-823 cells every three days. Results: Spag5 mRNA level was significantly upregulated in cancer tissues compared with paired normal tissues in all of the datasets. Immunohistochemistry shows higher protein level of spag5 in paired cancer tissue. Knockdown of Spag5 BGC-823 and MGC-803 showed a significantly decreased proliferation in both MTT and EDU assay. Spag5 silencing led to increase vulnerability to oxaliplatin, epirubicin and 5-fluorouracil, thus less cell viability and more apoptosis. Spag5 knockdown BGC-823 and MGC-803 subjected to DNA-damaging drugs showed upregulated yH2ax level and increased DNA damage in comet assay. Tumor growth rate were significantly reduced in shspag5 group and treatment of oxaliplatin led to relatively higher inhibition of tumor growth. Conclusions: Spag5 serves as a candidate to predict proliferation and chemosensitivity to DNA-damaging chemotherapy.

scholarly journals Downregulation of B3GNT6 Predicts Poor Outcome in Colorectal Cancer Patients

2020 ◽  
Author(s):  
Chen Yang ◽  
Changhao Huang ◽  
Pengwei Zeng ◽  
Heyuan Huang ◽  
Zhikang Chen ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Overall Survival ◽  
Cancer Patients ◽  
Prognostic Marker ◽  
Protein Level ◽  
Mrna Level ◽  
The Cancer Genome Atlas ◽  
Cancer Tissue ◽  
Poor Overall Survival ◽  
Colorectal Cancer Patients

Abstract Background: B3GNT6 encodes the core 3 synthase in O-glycan biosynthesis. It is commonly expressed in the GI tract, while its clinical significance in colorectal cancer remains largely unknown.Methods: We gathered mRNA transcriptomic sequencing data from 3 Gene Expression Omnibus (GEO) datasets (GSE37182, GSE39582, GSE103512) and The Cancer Genome Atlas (TCGA) to compare the B3GNT6 mRNA level between colorectal cancer tissues and normal tissues and to evaluate its value as a prognostic marker. We further validated this in protein level using online database Human Protein Atlas and with immunohistochemical staining of B3GNT6 with our own cohort. Results: B3GNT6 expression was downregulated in colorectal cancer tissue compared with that in normal tissue in both mRNA and in protein level. Downregulation of B3GNT6 was associated with poor overall survival of colorectal cancer in GSE39582 and in TCGA database. Low B3GNT6 mRNA level was significantly associated with chromosome stable (CIN negative) and KRAS mutated group colorectal cancer patient. GSEA revealed that low B3GNT6 level in colorectal cancer is associated with upregulated proteasome activity.Conclusions: Downregulated B3GNT6 was correlated with poor overall survival of colorectal cancer patients. B3GNT6 could be used as a good prognostic marker in colorectal cancer.

Effect of miR-206 Derived from Bone Marrow Mesenchymal Stem Cells (BMSCs) on CD8 Expression in Gastric Cancer

2022 ◽  
Vol 12 (5) ◽  
pp. 920-925
Author(s):  
He Bai ◽  
Jian He
Keyword(s):  
Gastric Cancer ◽  
Tumor Growth ◽  
Signaling Pathway ◽  
Scratch Test ◽  
Tumor Evolution ◽  
Cancer Tissue ◽  
Gastric Cancer Cells ◽  
Cell Behaviors ◽  
Novel Target

The BMSCs are one of the components of tumor micro-environment and participate in tumor evolution. Our study aimed to discuss the effect of exosome derived from BMSC on gastric cancer cells. Tumor and para-tumor tissues were isolated to measure miR-206 level by RT-PCR. Gastric cancer cell behaviors were analyzed using MTT assay and scratch test. Gastric cancer model was established and treated TIGIT inhibitor to assess its role in the tumor growth in vivo. The miR-206 in exosome from BMSCs in cancer tissue was detected. CD8 expression excreted by DC could be induced after miR-206 treatment possibly through regulating the signaling pathway of TIGIT/PVR. Inhibition of TIGIT decreased tumor growth, development and reversed tumor phenotype. In conclusion, miR-206 derived from BMSCs induces CD8 expression in gastric cancer through regulating the signaling pathway of TIGIT/PVR, indicating that it might be a novel target for the treatment of gastric cancer.

scholarly journals Gastrin Vaccine Alone and in Combination With an Immune Checkpoint Antibody Inhibits Growth and Metastases of Gastric Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Jill P. Smith ◽  
Hong Cao ◽  
Wenqiang Chen ◽  
Kanwal Mahmood ◽  
Teresa Phillips ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Tumor Growth ◽  
Immune Checkpoint ◽  
Receptor Expression ◽  
Tissue Array ◽  
Cancer Tissue ◽  
Human Gastric Cancer ◽  
Gastric Cancer Cells

Gastric cancer is a leading cause of cancer-related deaths worldwide. Recently, clinical studies have demonstrated that many of those with advanced gastric cancer are responsive to immune checkpoint antibody therapy, although the median survival even with these new agents is less than 12 months for advanced disease. The gastrointestinal peptide gastrin has been shown to stimulate growth of gastric cancer in a paracrine and autocrine fashion through the cholecystokinin-B receptor (CCK-BR), a receptor that is expressed in at least 56.6% of human gastric cancers. In the current investigation, we studied the role of the gastrin-CCK-BR pathway in vitro and in vivo as well as the expression of the CCK-BR in a human gastric cancer tissue array. CCK-BR and PD-L1 receptor expression and gastrin peptide was found in two murine gastric cancer cells (NCC-S1 and YTN-16) by qRT-PCR and immunocytochemistry. Treatment of NCC-S1 cells with gastrin resulted in increased growth. In vivo, the effects of a cancer vaccine that targets gastrin peptide (polyclonal antibody stimulator—PAS) alone or in combination with a Programed Death-1 antibody (PD-1 Ab) was evaluated in immune competent mice (N = 40) bearing YTN-16 gastric tumors. Mice were treated with PBS, PD-1 Ab (50 µg), PAS (250 µg), or the combination of PD-1 Ab with PAS. Tumor growth was significantly slower than controls in PAS-treated mice, and tumor growth was decreased even more in combination-treated mice. There were no metastases in any of the mice treated with PAS either alone or in combination with PD-1 Ab. Tumor proliferation by the Ki67 staining was significantly decreased in mice treated with PAS monotherapy or the combination therapy. PAS monotherapy or combined with PD-1 Ab increased tumor CD8+ T-lymphocytes and decreased the number of immunosuppressive M2-polarized tumor-associated macrophages. CCK-BR expression was identified in samples from a human tissue array by immunohistochemistry confirming the clinical relevance of this study. These results confirm the significance of the gastrin-CCK-BR signaling pathway in gastric cancer and suggest that the addition of a gastrin vaccine, PAS, to therapy with an immune checkpoint antibody may decrease growth and metastases of gastric cancer by altering the tumor microenvironment.

scholarly journals Resveratrol Enhances Inhibition Effects of Cisplatin on Cell Migration and Invasion and Tumor Growth in Breast Cancer MDA-MB-231 Cell Models In Vivo and In Vitro

Molecules ◽  
2021 ◽  
Vol 26 (8) ◽  
pp. 2204
Author(s):  
Meng-Die Yang ◽  
Yang Sun ◽  
Wen-Jun Zhou ◽  
Xiao-Zheng Xie ◽  
Qian-Mei Zhou ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Migration ◽  
Tumor Growth ◽  
Cell Viability ◽  
Synergistic Effects ◽  
Migration And Invasion ◽  
Cell Migration And Invasion ◽  
Tgf Β1

Triple-negative breast cancer (TNBC) is a refractory type of breast cancer that does not yet have clinically effective drugs. The aim of this study is to investigate the synergistic effects and mechanisms of resveratrol combined with cisplatin on human breast cancer MDA-MB-231 (MDA231) cell viability, migration, and invasion in vivo and in vitro. In vitro, MTS assays showed that resveratrol combined with cisplatin inhibits cell viability as a concentration-dependent manner, and produced synergistic effects (CI < 1). Transwell assay showed that the combined treatment inhibits TGF-β1-induced cell migration and invasion. Immunofluorescence assays confirmed that resveratrol upregulated E-cadherin expression and downregulated vimentin expression. Western blot assay demonstrated that resveratrol combined with cisplatin significantly reduced the expression of fibronectin, vimentin, P-AKT, P-PI3K, P-JNK, P-ERK, Sma2, and Smad3 induced by TGF-β1 (p < 0.05), and increased the expression of E-cadherin (p < 0.05), respectively. In vivo, resveratrol enhanced tumor growth inhibition and reduced body weight loss and kidney function impairment by cisplatin in MDA231 xenografts, and significantly reduced the expressions of P-AKT, P-PI3K, Smad2, Smad3, P-JNK, P-ERK, and NF-κB in tumor tissues (p < 0.05). These results indicated that resveratrol combined with cisplatin inhibits the viability of breast cancer MDA231 cells synergistically, and inhibits MDA231 cells invasion and migration through Epithelial-mesenchymal transition (EMT) approach, and resveratrol enhanced anti-tumor effect and reduced side of cisplatin in MDA231 xenografts. The mechanism may be involved in the regulations of PI3K/AKT, JNK, ERK and NF-κB expressions.

A novel design of HA-coated nanoparticles co-encapsulating plasmid METase and 5-Fu shows enhanced application in targeting gastric cancer stem cells

2018 ◽  
Vol 399 (3) ◽  
pp. 293-303 ◽  
Author(s):  
Weifeng Yang ◽  
Houting Zhang ◽  
Lin Xin
Keyword(s):  
Gastric Cancer ◽  
Tumor Growth ◽  
Precipitation Method ◽  
Inhibition Effect ◽  
Coated Nanoparticles ◽  
Transmission Electron ◽  
Targeted Drug ◽  
Gastric Cancer Stem Cells ◽  
Novel Design

AbstractNanoparticles (NPs) are recognized as an attractive vehicles for cancer treatment due to their targeted drug release. Gastric cancer is an important killer disease, and its therapy methods still need improvement. The NPs were prepared using a precipitation method, and were evaluated using transmission electron microscopy (TEM). MTT and Transwell assays were used to determine cell viability and apoptosis.In vivoexperiments were performed to validate the effects of NPs on tumor growth. Methioninase (METase)/5-Fu co-encaspulated NPs showed highest ζ size and lowest ζ potential than other NPs. The migration and tumorsphere formation ability of CD44(+) was stronger than CD44(−). The effects of METase/5-Fu co-encaspulated NPs on inhibition cell growth was stronger than that of 5-Fu encaspulated NPs, while HA coated NPs showed significant target ability than that NPs without HA. METase supplementation promoted the inhibition effect of 5-Fu on thymidylate synthetase (TS), as well as cell apoptosis. Thein vivoexperiments demonstrated that HA coated NPs significantly inhibited tumor growth. It was concluded that HA-coated NPs enhance the target ability, while METase/5-Fu co-encaspulated NPs promote the inhibition effects on tumor growth in gastric cancer.

scholarly journals Hypermethylation of DHRS3 as a Novel Tumor Suppressor Involved in Tumor Growth and Prognosis in Gastric Cancer

2021 ◽  
Vol 9 ◽  
Author(s):  
Sha Sumei ◽  
Kong Xiangyun ◽  
Chen Fenrong ◽  
Sun Xueguang ◽  
Hu Sijun ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Tumor Suppressor ◽  
Tumor Growth ◽  
Human Cancer ◽  
Methylation Status ◽  
Ectopic Expression ◽  
Survival Times

Background/AimsThe role of DHRS3 in human cancer remains unclear. Our study explored the role of DHRS3 in gastric cancer (GC) and its clinicopathological significance and associated mechanisms.MaterialsBisulfite-assisted genomic sequencing PCR and a Mass-Array system were used to evaluate and quantify the methylation levels of the promoter. The expression levels and biological function of DHRS3 was examined by both in vitro and in vivo assays. A two-way hierarchical cluster analysis was used to classify the methylation profiles, and the correlation between the methylation status of the DHRS3 promoter and the clinicopathological characteristics of GC were then assessed.ResultsThe DHRS3 promoter was hypermethylated in GC samples, while the mRNA and protein levels of DHRS3 were significantly downregulated. Ectopic expression of DHRS3 in GC cells inhibited cell proliferation and migration in vitro, decreased tumor growth in vivo. DHRS3 methylation was correlated with histological type and poor differentiation of tumors. GC patients with high degrees of CpG 9.10 methylation had shorter survival times than those with lower methylation.ConclusionDHRS3 was hypermethylated and downregulated in GC patients. Reduced expression of DHRS3 is implicated in gastric carcinogenesis, which suggests DHRS3 is a tumor suppressor.

scholarly journals BCAT1 Activates PI3K/AKT/mTOR Pathway and Contributes to the Angiogenesis and Tumorigenicity of Gastric Cancer

2021 ◽  
Vol 9 ◽  
Author(s):  
Xiong Shu ◽  
Pan-Pan Zhan ◽  
Li-Xin Sun ◽  
Long Yu ◽  
Jun Liu ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Tumor Growth ◽  
Western Blotting ◽  
Mtor Pathway ◽  
Clinical Samples ◽  
Xenograft Models ◽  
Cell Phenotypes

BackgroundFocusing on antiangiogenesis may provide promising choices for treatment of gastric cancer (GC). This study aimed to investigate the mechanistic role of BCAT1 in the pathogenesis of GC, particularly in angiogenesis.MethodsBioinformatics and clinical samples analysis were used to investigate the expression and potential mechanism of BCAT1 in GC. BGC823 cells with BCAT1 overexpression or silencing were induced by lentiviral transduction. Cell phenotypes and angiogenesis were evaluated. The relevant proteins were quantized by Western blotting, immunohistochemistry, or immunofluorescence. Xenograft models were constructed to confirm the role of BCAT1 in vivo.ResultsBCAT1 was overexpressed in GC patients and associated with lower survival. BCAT1 expression was correlated with proliferation-, invasion-, or angiogenesis-related markers expression and pathways. Silencing BCAT1 expression suppressed cell viability, colony formation, cycle progression, invasion, and angiogenesis of BGC823 cells, as well as the tumor growth of xenograft models, whereas overexpressing BCAT1 had the opposite results both in vitro and in vivo. Bioinformatics analysis and Western blotting demonstrated that BCAT1 activated the PI3K/AKT/mTOR pathway. The addition of LY294002 reversed the tumor growth induced by BCAT1 overexpression, further verifying this mechanism.ConclusionBCAT1 might act as an oncogene by facilitating proliferation, invasion, and angiogenesis through activation of the PI3K/AKT/mTOR pathway. This finding could aid the optimization of antiangiogenesis strategies.

scholarly journals The effects of recombinant human GH on promoting tumor growth depend on the expression of GH receptor in vivo

2011 ◽  
Vol 211 (3) ◽  
pp. 249-256 ◽  
Author(s):  
Yan Lin ◽  
Suyi Li ◽  
Peng Cao ◽  
Lu Cheng ◽  
Ming Quan ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Tumor Growth ◽  
Safety Concern ◽  
Severe Malnutrition ◽  
High Dose ◽  
Gastric Adenoma ◽  
Malignant Diseases ◽  
Gh Receptor ◽  
Tumor Bearing

Cancer-related malnutrition is a mortal threat to gastric carcinoma patients. However, conventional nutrition treatment is not effective for recovery. Recombinant human GH (rhGH) is widely accepted clinically to treat severe malnutrition caused by non-malignant diseases, but not approved to treat malignant diseases due to the safety concern. To explore the safety of rhGH on gastric cancer, we assessed the effect of rhGH on two tumor-bearing mice modelsin vivoestablished by human gastric adenoma cell lines of SGC-7901 and MKN-45. VEGF expression in tumor tissues was detected using immunohistochemistry. The expression of GH receptor (Ghr),Jak-2,Stat3,Vegf, Hif-1α, Fgf, andMmp-2was measured by RT-PCR and protein expression of STAT3, phosphorylated STAT3, VEGF, HIF-1α, and MMP-2 was measured by western blotting. The immunocytochemistry results showed that the GHR expression of SGC-7901 was strongly positive (GHR+++), while GHR expression of MKN-45 was regarded as negative (GHR−). After 14 days of rhGH treatment in SGC-7901 (GHR+++) tumor-bearing mice, we found that the tumor growth was significantly increased, and the expressions of downstream factors and VEGF were increased. However, in MKN-45 (GHR−) tumor-bearing mice, tumor growth was not significantly increased by rhGH, but tumor-free body weight was increased especially in high-dose rhGH-treated group (P<0.05). These findings suggest that the level of GHR expression is a key target that influences the effectiveness of rhGH on promoting the growth of gastric cancer and angiogenesis. rhGH may promote the activation of tumor angiogenesis factors through the Jak-2–STAT3 pathway.

ASAP1 promotes tumor progression and angiogenesis and independently predicts poor prognosis and lymph node metastasis of gastric cancer

2019 ◽  
Author(s):  
Hongyu Gao ◽  
Ling Qin ◽  
Huawen Shi ◽  
Hongfeng Zhang ◽  
Chunfeng Li ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Lymph Node ◽  
Lymph Node Metastasis ◽  
Tumor Growth ◽  
Tumor Progression ◽  
Epithelial Mesenchymal Transition ◽  
The Cancer Genome Atlas ◽  
Mesenchymal Transition ◽  
Node Metastasis ◽  
Tumor Cell Motility

Abstract Background: Although ArfGAP with SH3 Domain, Ankyrin Repeat and PH Domain 1(ASAP1) is involved in the development of various malignancies, its clinical significance and mechanism in gastric cancer (GC) remains unclear.Methods: The effects of ASAP1 on tumor progression, angiogenesis, and epithelial-mesenchymal transition were evaluated in vitro. The effects of ASAP1 on tumor growth and angiogenesis were also explored in vivo. The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases were used to gather ASAP1 expression data.Results: It showed that ASAP1 expression strongly correlated with the TNM stage (P < 0.0001) and lymph node metastasis (P < 0.0001). Multivariate analyses indicated that ASAP1 overexpression (P < 0.0001) was an independent predictor for overall survival in patients with GC. Moreover, the results revealed that ASAP1 overexpression was independently related to lymph node metastasis (P = 0.0001). ASAP1 knockdown inhibited tumor cell motility, migration, invasion, and angiogenesis, which was accompanied with the downregulation of metastatic and angiogenic biomarkers. Furthermore, ASAP1 inhibition resulted in the simultaneous downregulation of mesenchymal markers and upregulation of epithelial markers. In addition, ASAP1 promoted tumor growth and angiogenesis in the xenograft mice model. The combined datasets (TCGA and GEO) suggested that ASAP1 was associated with malignant behavior of tumor and tumor invasion, metastasis, and angiogenesis.Conclusion: To our knowledge, our study is the first to reveal that ASAP1 promotes tumor progression and angiogenesis, and indicates a prognostic potential in GCs.

scholarly journals Berberine Improves Chemo-Sensitivity to Cisplatin by Enhancing Cell Apoptosis and Repressing PI3K/AKT/mTOR Signaling Pathway in Gastric Cancer

2020 ◽  
Vol 11 ◽  
Author(s):  
Yingying Kou ◽  
Bending Tong ◽  
Weiqing Wu ◽  
Xiangqing Liao ◽  
Min Zhao
Keyword(s):  
Gastric Cancer ◽  
Drug Resistance ◽  
Multidrug Resistance ◽  
Cell Viability ◽  
Cancer Cells ◽  
Cell Apoptosis ◽  
Mtor Signaling ◽  
Multi Drug Resistance ◽  
Gastric Cancer Cells

Gastric cancer is one of the most common malignancies ranks as the second leading cause of cancer-related mortality in the world. Cisplatin (DDP) is commonly used for gastric cancer treatment, whereas recurrence and metastasis are common because of intrinsic and acquired DDP-resistance. The aim of this study is to examine the effects of berberine on the DDP-resistance in gastric cancer and explore the underling mechanisms. In this study, we established the DDP-resistant gastric cancer cells, where the IC50 values of DDP in the BGC-823/DDP and SGC-7901/DDP were significantly higher than that in the corresponding parental cells. Berberine could concentration-dependently inhibited the cell viability of BGC-823 and SGC-7901 cells; while the inhibitory effects of berberine on the cell viability were largely attenuated in the DDP-resistant cells. Berberine pre-treatment significantly sensitized BGC-823/DDP and SGC-7901/DDP cells to DDP. Furthermore, berberine treatment concentration-dependently down-regulated the multidrug resistance-associated protein 1 and multi-drug resistance-1 protein levels in the BGC-823/DDP and SGC7901/DDP cells. Interestingly, the cell apoptosis of BGC-823/DDP and SGC-7901/DDP cells was significantly enhanced by co-treatment with berberine and DDP. The results from animals also showed that berberine treatment sensitized SGC-7901/DDP cells to DDP in vivo. Mechanistically, berberine significantly suppressed the PI3K/AKT/mTOR in the BGC-823/DDP and SGC-7901/DDP cells treated with DDP. In conclusion, we observed that berberine sensitizes gastric cancer cells to DDP. Further mechanistic findings suggested that berberine-mediated DDP-sensitivity may be associated with reduced expression of drug transporters (multi-drug resistance-1 and multidrug resistance-associated protein 1), enhanced apoptosis and repressed PI3K/AKT/mTOR signaling.

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