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 Has-miR-875-5p Inhibits Tumorigenesis by Targeting USF2 via TGF-β Signaling Pathway in Gastric Cancer

2021 ◽  
Author(s):  
Shenshuo Gao ◽  
Zhikai Zhang ◽  
Xubin Wang ◽  
Yan Ma ◽  
Chensheng Li ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Signaling Pathway ◽  
Research Direction ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Gastric Cancer Cells ◽  
New Research

Abstract Background: Gastric cancer (GC) is one of the most common malignancies, and more and more evdiences show that the pathogenesis is regulated by various miRNAs.In this study, we investigated the role of miR-875 in GC. Methods:The expression of miR-875-5p was detected in human GC specimens and cell lines by miRNA RT-PCR. The effect of miR-875-5p on GC proliferation was determined by CCK-8 proliferation assay and EDU assay. Migration and invasion were examined by transwell migration and invasion assay and wound healing assay. The interaction between miR-875-5p and its target gene USF2 was verified by a dual luciferase reporter assay. The effects of miR-875-5p in vivo were studied in xenograft nude mice models.Related proteins were detected by Western blot.Results:The results showed that miR-875-5p inhibited the proliferation, migration and invasion of gastric cancer cells in vitro, and inhibited tumorigenesis in vivo. USF2 proved to be a direct target of miR-875-5p. Knockdown of USF2 partially counteracts the effects of miR-875-5p inhibitors.Overexpression of miR-875-5p can inhibit proliferation, migration, and invasion through the TGF-β signaling pathway by down-regulation of USF2 in GC, providing a new research direction for the diagnosis and targeted therapy of GC.Conclusions: MiR-875-5pcan inhibited the progression of GC by directly targeting USF2 and negatively regulating TGF-β signaling pathway.In the future, miR-875-5p is expected to be used as a potential therapeutic target for GC therapy.

scholarly journals Apelin Over-Expression Promotes Proliferation and Angiogenesis of Gastric Cancer Cells

2021 ◽  
Author(s):  
Li-Jun Tian ◽  
Hong-Zhi Liu ◽  
Qiang Zhang ◽  
Dian-Zhong Geng ◽  
Jing Yang ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cyclin D1 ◽  
Cancer Cells ◽  
Signaling Pathway ◽  
Cox Regression ◽  
Gastric Cancer Cells ◽  
Over Expression ◽  
Normal Tissues

Abstract Background: Apelin is a recently identified endogenous ligand associated with proliferation and angiogenesis of several cancers. However, only few studies have reported on the functions and the role of apelin in gastric cancer (GC). Therefore, in the present study, we investigated the association and the mechanisms underlying Apelin expression and proliferation of GC cells both in vitro and in vivo.Methods: We enrolled 178 postoperative care GC patients to investigate clinicopathological and immunohistochemical factors associated with Apelin expression. The relationship between Survival of patients and apelin expression was evaluated using Kaplan-Meier method and Cox regression analyses. The expression of apelin mRNA and its proteins in GC tissues and cell lines were analyzed using quantitative real-time reverse transcription-polymerase chain reaction (RT-PCR), western blot and ELISA. The role and mechanisms underlying regulation of Apelin expression in human GC cells were evaluated through several in vitro and in vivo experiments. Results: Apelin was over expressed in human GC cells, relative to adjacent normal tissues. The over expression of apelin was associated with vessel invasion (P <0.01), lymph node metastasis (P <0.01), late-staged tumor (T) (P <0.05), worse pathological type (P <0.05), nerve invasion (P <0.05). In addition, expression of apelin strongly and positively correlated with that of vascular endothelial growth factor (VEGF). Over-expression of apelin promoted proliferation and invasion of MGC-803 cell via the ERK/Cyclin D1/MMP-9 signaling pathway. Apelin over-expression also promoted angiogenesis of GC cells, accelerating growth of subcutaneous xenograft of the cancer cells in vivo.Conclusions: Over-expression of apelin promotes proliferation and metastasis of GC cells via the ERK/Cyclin D1/MMP-9 signaling pathway and is associated with adverse events of the cancer. Consequently, apelin is a potential therapeutic target for human GC.

Demonstration of the efficacy of compound CFAK-C4 targeting FAK-VEGFR3 protein-protein interaction in gastric cancer.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e22143-e22143
Author(s):  
Elena V. Kurenova ◽  
Sartaj Singh Sanghera ◽  
Jianqun Liao ◽  
Michael Yemma ◽  
William G. Cance
Keyword(s):  
Gastric Cancer ◽  
Tumor Growth ◽  
Tumor Progression ◽  
Colony Formation ◽  
Tumor Regression ◽  
Cancer Therapeutics ◽  
Scaffolding Protein ◽  
Dependent Manner ◽  
Gastric Cancer Cells

e22143 Background: While the emerging data strongly suggest that FAK is an excellent target for developmental therapeutics of cancer, kinase inhibitors of FAK have shown crossreactivity with other protein kinases and toxicity in preclinical and clinical studies. It is known that FAK acts pleiotropically, as a kinase and as a scaffolding protein, and our goal is to explore targeting the scaffolding function of FAK to inhibit protein-protein interactions important for tumor progression. Previously, we have shown that FAK physically interacts with VEGFR3 and we identified small molecule inhibitor CFAK-C4 that targets this site of interaction. Both of these kinases are overexpressed in gastric cancers and were found to be independent poor prognostic factors. The prognosis of patients with gastric cancer remains unfavorable and molecular based treatments are necessary for a potential breakthrough in the therapy of this disease. We hypothesize that FAK-VEGFR3 interaction provides essential survival signals for gastric tumor growth and that simultaneous inhibition of these signals will inhibit tumor progression. Methods: Effects of CFAK-C4 on gastric cancer cell lines AGS and NCI-N87 were examined by MTT assay (viability), colony formation assay and Western blotting (phosphorylation, apoptosis). Subcutaneous mouse model was used to demonstrate effect of CFAK-C4 in vivo. Results: CFAK-C4 specifically blocked phosphorylation of VEGFR3 and FAK, directly inhibited cell viability (p<0.05), increased cell detachment and inhibited colony formation in a dose-dependent manner (range 1-100µM). CFAK-C4 (50mg/kg, IP) effectively caused tumor regression in vivo, when administered alone and its effects were synergistic (p<0.05) with chemotherapy. In vivo effects of C4 were confirmed by a decrease in tumor FAK and VEGFR3 phosphorylation, and disruption of their complexes. Conclusions: In this study we have shown that CFAK-C4 inhibits FAK-VEGFR3 signaling in gastric cancer cells and affects tumor growth. This result demonstrates that targeting the scaffolding function of FAK is a unique approach of highly-specific molecular-targeted therapy and can be used to develop oral-based cancer therapeutics.

scholarly journals YTHDF2 Inhibits Gastric Cancer Cell Growth by Regulating FOXC2 Signaling Pathway

2021 ◽  
Vol 11 ◽  
Author(s):  
Xudong Shen ◽  
Kui Zhao ◽  
Liming Xu ◽  
Guilian Cheng ◽  
Jianhong Zhu ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cancer Patient ◽  
Signaling Pathway ◽  
Inhibitory Effect ◽  
Signal Pathways ◽  
Gastric Cancer Cells ◽  
Cancer Cell Growth ◽  
Patient Prognosis

BackgroundGastric cancer (GC) is one of the most common malignancies in the world, and the fourth most frequent malignancy worldwide. YTHDF2 (YTH domain family 2, YTHDF2) binds to mRNA containing m6A, thereby regulating the localization and stability of the bound mRNA. YTHDF2 was shown to be associated with some cancer patient prognosis. However, the effect of YTHDF2 on gastric cancer and the molecular mechanism of this effect have not been documented.MethodsTo conduct this research, YTHDF2 expression levels in public databases and gastric cancer patient samples were analyzed. The effects of YTHDF2 on the growth of gastric cancer cells were detected in vivo and in vitro. RNA-seq was used to analyze the signal pathways regulated by YTHDF2, and experiments were carried out for verification.ResultsIn our study, we found that YTHDF2 has lower expression in GC tissues and GC cells, and inhibits the growth of GC cells. In addition, the analysis of clinical data found that the expression level of YTHDF2 is closely related to the stage of GC and the survival of patients with GC. RNA sequencing results showed that overexpression of YTHDF2 significantly reduced protein expression in the FOXC2 (Forkhead box protein C2, FOXC2) signaling pathway. Finally, we found that knockout of FOXC2 reversed the inhibitory effect of YTHDF2 on GC cells.ConclusionIn summary, YTHDF2 inhibits the growth of GC cells by negatively regulating FOXC2 and may serve as a prognostic marker in GC.

scholarly journals Ethaselen synergizes with oxaliplatin in tumor growth inhibition by inducing ROS production and inhibiting TrxR1 activity in gastric cancer

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Haiyong Zhang ◽  
Jing Wu ◽  
Jinqiu Yuan ◽  
Huafu Li ◽  
Yawei Zhang ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Tumor Growth ◽  
Growth Inhibition ◽  
Cancer Cells ◽  
Nude Mice ◽  
Combined Treatment ◽  
Thioredoxin Reductase ◽  
Tumor Growth Inhibition ◽  
Gastric Cancer Cells

Abstract Background Oxaliplatin is one of the most commonly used chemotherapeutic agent for the treatment of various cancers, including gastric cancer. It has, however, a narrow therapeutic index due to its toxicity and the occurrence of drug resistance. Hence, it is of great significance to develop novel therapies to potentiate the anti-tumor effect and reduce the toxicity of oxaliplatin. In our previous study, we demonstrated that ethaselen (BBSKE), an inhibitor of thioredoxin reductase, effectively inhibited the growth of gastric cancer cells and promoted apoptosis in vitro. In the present study, we investigated whether BBSKE can potentiate the anti-tumor effect of oxaliplatin in gastric cancer in vivo and vitro. Methods Cellular apoptosis and ROS levels were analyzed by flow cytometry. Thioredoxin reductase 1 (TrxR1) activity in gastric cancer cells, organoid and tumor tissues was determined by using the endpoint insulin reduction assay. Western blot was used to analyze the expressions of the indicated proteins. Nude mice xenograft models were used to test the effects of BBSKE and oxaliplatin combinations on gastric cancer cell growth in vivo. In addition, we also used the combined treatment of BBSKE and oxaliplatin in three cases of gastric cancer Patient-Derived organoid (GC-PDO) to detect the anti-tumor effect. Results We found that BBSKE significantly enhanced oxaliplatin-induced growth inhibition in gastric cancer cells by inhibiting TrxR1 activity. Because of the inhibition of TrxR1 activity, BBSKE synergized with oxaliplatin to enhance the production of ROS and activate p38 and JNK signaling pathways which eventually induced apoptosis of gastric cancer cells. In vivo, we also found that BBSKE synergized with oxaliplatin to suppress the gastric cancer tumor growth in xenograft nude mice model, accompanied by the reduced TrxR1 activity. Remarkably, we found that BBSKE attenuated body weight loss evoked by oxaliplatin treatment. We also used three cases of GC-PDO and found that the combined treatment of BBSKE and oxaliplatin dramatically inhibited the growth and viability of GC-PDO with increased ROS level, decreased TrxR1 activity and enhanced apoptosis. Conclusions This study elucidates the underlying mechanisms of synergistic effect of BBSKE and oxaliplatin, and suggests that the combined treatment has potential value in gastric cancer therapy.

Effects of ASA404, a vascular disrupting agent, on tumor growth of gastric cancer in an experimental model.

2011 ◽  
Vol 29 (4_suppl) ◽  
pp. 48-48 ◽  
Author(s):  
S. A. Lang ◽  
C. Moser ◽  
E. M. Jung ◽  
K. Pfister ◽  
E. K. Geissler ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Tumor Growth ◽  
Experimental Model ◽  
Vascular System ◽  
Tumor Vasculature ◽  
Gastric Cancer Cells ◽  
Vascular Disrupting Agent ◽  
Vascular Disrupting

48 Background: A functional vascular system is essential for growth of solid malignancies including gastric cancer. For establishment and maintenance of such a vascular system endothelial cells (ECs) and pericytes (e.g. vascular smooth muscle cells, VSMC) are required. We hypothesized that targeting tumor vasculature with the vascular disrupting agent (VDA) ASA404 (Novartis Oncology) reduces tumor growth in a model of gastric cancer. Methods: Gastric cancer (GC) cell lines, ECs and VSMCs were used for experiments. Effects of ASA404 on growth of GC, EC and VSMC were assessed by MTT assays. Impact of ASA404 (20 mg/kg on day 1, 5, 9) in combination with paclitaxel (10 mg/kg on day 1 and 7) on tumor growth was assessed in a subcutaneous tumor model. Treatment was started when tumors reached a size of approximately 200 mm3. Tumors were measured and harvested on day 23 for IHC analyses. Effect of ASA404 on blood perfusion of tumors during therapy was monitored by contrast-enhanced ultrasound (CEUS). Results: In vitro ASA404 impaired growth of ECs and VSMCs upon stimulation with condition media from gastric cancer cells. No direct effect on tumor cells was observed. In vivo, treatment with ASA404 led to marked decrease of tumor perfusion and an increase of necrosis as determined by CEUS. Furthermore, combination of ASA404 with paclitaxel showed significant reduction of tumor growth compared to controls (p < 0.05). In addition, tumor vascularisation and tumor cell proliferation were significantly reduced as determined by CD31-positive vessel area and BrdU-positive cells (p < 0.05). Conclusions: Combination of the VDA ASA404 with paclitaxel impairs tumor growth and perfusion of gastric cancer in an experimental model. Hence, targeting tumor vasculature with ASA404 appears to be a promising strategy for therapy of gastric cancer. No significant financial relationships to disclose.

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.

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