scholarly journals Targeting histone deacetylase-3 blocked epithelial-mesenchymal plasticity and metastatic dissemination in gastric cancer

2022 ◽  
Author(s):  
Sheng-Mao Wu ◽  
Yee-Jee Jan ◽  
Shih-Chuan Tsai ◽  
Hung-Chuan Pan ◽  
Chin-Chang Shen ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Er Stress ◽  
Cancer Cells ◽  
Peritoneal Dissemination ◽  
Migration And Invasion ◽  
Gastric Cancer Cells ◽  
Potential Therapeutic Target ◽  
Metastatic Dissemination ◽  
Over Expression

Abstract Background and purpose Histone deacetylase (HDAC) inhibitors (HDIs) can modulate the epithelial-mesenchymal transition (EMT) progression and inhibit the migration and invasion of cancer cells. Emerging as a novel class of anti-cancer drugs, HDIs are attracted much attention in the field of drug discovery. This study aimed to discern the underlying mechanisms of Honokiol in preventing the metastatic dissemination of gastric cancer cells by inhibiting HDAC3 activity/expression. Experimental approach Clinical pathological analysis was performed to determine the relationship between HDAC3 and tumor progression. The effects of Honokiol on pharmacological characterization, functional, transcriptional activities, organelle structure changes, and molecular signaling were analyzed using binding assays, differential scanning calorimetry, luciferase reporter assay, HDAC3 activity, ER stress response element activity, transmission electron microscopy, immune-blotting, and Wnt/β-catenin activity assays. The in vivo effects of Honokiol on peritoneal dissemination were determined by a mouse model and detected by PET/CT tomography. Key results HDAC3 over-expression was correlated with poor prognosis. Honokiol significantly abolished HDAC3 activity (Y298) via inhibition of NFκBp65/CEBPβ signaling, which could be reversed by the over-expression of plasmids of NFκBp65/CEBPβ. Treatments with 4-phenylbutyric acid (a chemical chaperone) and calpain-2 gene silencing inhibited Honokiol-inhibited NFκBp65/CEBPβ activation. Honokiol increased ER stress markers and inhibited EMT-associated epithelial markers, but decreased Wnt/β-catenin activity. Suppression of HDAC3 by both Honokiol and HDAC3 gene silencing decreased cell migration and invasion in vitro and metastasis in vivo. Conclusions and implications Honokiol acts by suppressing HDAC3-mediated EMT and metastatic signaling. By prohibiting HDAC3, metastatic dissemination of gastric cancer may be blocked. Graphical abstract Conceptual model showing the working hypothesis on the interaction among Honokiol, HDAC3, and ER stress in the peritoneal dissemination of gastric cancer. Honokiol targeting HDAC3 by ER stress cascade and mitigating the peritoneal spread of gastric cancer. Honokiol-induced ER stress–activated calpain activity targeted HDAC3 and blocked Tyr298 phosphorylation, subsequently blocked cooperating with EMT transcription factors and cancer progression. The present study provides evidence to demonstrate that HDAC3 is a positive regulator of EMT and metastatic growth of gastric cancer cells. The findings here imply that overexpressed HDAC3 is a potential therapeutic target for honokiol to reverse EMT and prevent gastric cancer migration, invasion, and metastatic dissemination. • Honokiol significantly abolished HDAC3 activity on catalytic tyrosine 298 residue site. In addition, Honokiol-induced ER stress markedly inhibited HDAC3 expression via inhibition of NFκBp65/CEBPβ signaling. • HDAC3, which is a positive regulator of metastatic gastric cancer cell growth, can be significantly inhibited by Honokiol. • Opportunities for HDAC3 inhibition may be a potential therapeutic target for preventing gastric cancer metastatic dissemination.

scholarly journals Targeting Histone Deacetylase-3 Blocked Epithelial-Mesenchymal Plasticity And Metastatic Dissemination In Gastric Cancer

2021 ◽  
Author(s):  
Sheng-Mao Wu ◽  
Yee-Jee Jan ◽  
Shih-Chuan Tsai ◽  
Hung-Chuan Pan ◽  
Chin-Chang Shen ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Gene Silencing ◽  
Er Stress ◽  
Cancer Cells ◽  
Histone Deacetylase ◽  
Migration And Invasion ◽  
Chemical Chaperone ◽  
Metastatic Dissemination ◽  
Over Expression

Abstract Background and purpose: Histone deacetylase (HDAC) inhibitors (HDIs) were shown to modulate the epithelial-mesenchymal transition (EMT) progression and inhibit the migration and invasion of cancer cells. Emerging as a novel class of anti-cancer drugs, HDIs have attracted much attention in the field of drug discovery. This study aimed to the underlying mechanisms of Honokiol in preventing the metastatic dissemination of gastric cancer cells by inhibiting HDAC3 activity/expression.Experimental Approach: Clinical pathological analysis was performed to determine the relationship between HDAC3 and tumor progression. The effects of Honokiol on pharmacological characterization, functional, transcriptional activities, organelle structure changes, and molecular signalings were analyzed using binding assays, Differential Scanning Calorimetry, luciferase reporter assay, HDAC3 activity, ER stress response element activity, transmission electron microscopy, immune-blotting and Wnt/b-catenin activity assays. The in vivo effects of Honokiol on peritoneal dissemination were determined by a mouse model and detected by the PET/CT tomography.Key Results: HDAC3 over-expression was correlated with poor prognosis. Honokiol significantly abolished HDAC3 activity (Y298) via inhibition of NFκBp65/CEBPb signaling, which was reversed by the over-expression of plasmids of NFκBp65/CEBPb. Honokiol-inhibited NFκBp65/CEBPb activation could be reversed by 4-phenylbutyric acid (a chemical chaperone) and calpain-2 gene silencing. Honokiol increased ER stress markers and inhibited EMT-associated epithelial markers, but decreased Wnt/β-catenin activity. Suppression of HDAC3 by both Honokiol and HDAC3 gene silencing decreased cell migration and invasion in vitro and metastasis in vivo. Conclusions and Implications: Honokiol acts by suppressing HDAC3-mediated EMT and metastatic signaling. By prohibiting HDAC3, metastatic dissemination of gastric cancer may be blocked.

scholarly journals CircPSMC3 suppresses the proliferation and metastasis of gastric cancer by acting as a competitive endogenous RNA through sponging miR-296-5p

2019 ◽  
Vol 18 (1) ◽  
Author(s):  
Dawei Rong ◽  
Chen Lu ◽  
Betty Zhang ◽  
Kai Fu ◽  
Shuli Zhao ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cancer Cells ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Circular Rnas ◽  
Gastric Cancer Cells ◽  
Over Expression ◽  
Tensin Homolog

Abstract Background Circular RNAs (circRNAs) are a class of non-coding RNAs with a loop structure, but its functions remain largely unknown. Growing evidence has revealed that circRNAs play a striking role as functional RNAs in the progression of malignant disease. However, the precise role of circRNAs in gastric cancer (GC) remains unclear. Methods CircRNAs were determined by human circRNA array analysis and quantitative reverse transcription polymerase reaction. Luciferase reporter, RNA pull down, and fluorescence in situ hybridization assays were employed to test the interaction between circPSMC3 and miR-296-5p. Ectopic over-expression and siRNA-mediated knockdown of circPSMC3, proliferation, migration and invasion in vitro, and in vivo experiment of metastasis were used to evaluate the function of circPSMC3. Results CircPSMC3 rather than liner PSMC3 mRNA was down-regulated in GC tissues, corresponding plasmas from GC patients as well as GC cell lines compared to normal controls. Lower circPSMC3 expression in GC patients was correlated with higher TNM stage and shorter overall survival. Over-expression of circPSMC3 and miR-296-5p inhibitor could inhibit the tumorigenesis of gastric cancer cells in vivo and vitro whereas co-transfection of circPSMC3 and miRNA-296-5p could counteract this effect. Importantly, we demonstrated that circPSMC3 could act as a sponge of miR-296-5p to regulate the expression of Phosphatase and Tensin Homolog (PTEN), and further suppress the tumorigenesis of gastric cancer cells. Conclusion Our study reveals that circPSMC3 can serve as a novel potential circulating biomarker for detection of GC. CircPSMC3 participates in progression of gastric cancer by sponging miRNA-296-5p with PTEN, providing a new insight into the treatment of gastric cancer.

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.

Downregulation of CCKBR Expression Inhibits the Proliferation of Gastric Cancer Cells, Revealing a Potential Target for Immunotoxin Therapy

2022 ◽  
Vol 22 ◽  
Author(s):  
Meng Li ◽  
Jiang Chang ◽  
Honglin Ren ◽  
Defeng Song ◽  
Jian Guo ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cancer Cells ◽  
Cell Counting ◽  
Migration And Invasion ◽  
Gastric Cancer Cells ◽  
Aberrant Expression ◽  
Promising Target ◽  
The Impact

Background Increased CCKBR expression density or frequency has been reported in many neoplasms. Objective We aimed to investigate whether CCKBR drives the growth of gastric cancer (GC) and its potential as a therapeutic target of immunotoxins. Methods A lentiviral interference system was used to generate CCKBR-knockdown gastric cancer cells. Cell Counting Kit-8 and clonogenic assays were used to evaluate cell proliferation. Wound-healing and cell invasion assays were performed to evaluate cell mobility. Cell cycle was analyzed by flow cytometry. Tumor growth in vivo was investigated using a heterologous tumor transplantation model in nude mice. In addition, we generated the immunotoxin FQ17P and evaluated the combining capacity and tumor cytotoxicity of FQ17P in vitro. Results Stable downregulation of CCKBR expression resulted in reduced proliferation, migration and invasion of BGC-823 and SGC-7901 cells. The impact of CCKBR on gastric cancer cells was further verified through CCKBR overexpression studies. Downregulation of CCKBR expression also inhibited the growth of gastric tumors in vivo. Furthermore, FQ17P killed CCKBR-overexpressing GC cells by specifically binding to CCKBR on the tumor cell surface. Conclusion The CCKBR protein drives the growth, migration, and invasion of gastric cancer cells, and it might be a promising target for immunotoxin therapy based on its aberrant expression, functional binding interactions with gastrin, and subsequent internalization.

scholarly journals MiR-144-3p inhibits gastric cancer progression and stemness via directly targeting GLI2 involved in hedgehog pathway

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Yixun Lu ◽  
Benlong Zhang ◽  
Baohua Wang ◽  
Di Wu ◽  
Chuang Wang ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Flow Cytometry ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Gastric Cancer Cells ◽  
Cancer Tissues ◽  
Gastric Cancer Progression

Abstract Background Gastric cancer (GC) is the fifth most commonly diagnosed cancer worldwide. Due to the dismal prognosis, identifying novel therapeutic targets in GC is urgently needed. Evidences have shown that miRNAs played critical roles in the regulation of tumor initiation and progression. GLI family zinc finger 2 (GLI2) has been reported to be up-regulated and facilitate cancer progression in multiple malignancies. In this study, we focused on identifying GLI2-targeted miRNAs and clarifying the underlying mechanism in GC. Methods Paired fresh gastric cancer tissues were collected from gastrectomy patients. GLI2 and miRNAs expression were detected in gastric cancer tissues and cell lines. Bioinformatics analysis was used to predict GLI2-targeted miRNAs and dual-luciferase reporter assay was applied for target verification. CCK-8, clone formation, transwell and flow cytometry were carried out to determine the proliferation, migration, invasion and cell cycle of gastric cancer cells. Tumorsphere formation assay and flow cytometry were performed to detail the stemness of gastric cancer stem cells (GCSCs). Xenograft models in nude mice were established to investigate the role of the miR-144-3p in vivo. Results GLI2 was frequently upregulated in GC and indicated a poor survival. Meanwhile, miR-144-3p was downregulated and negatively correlated with GLI2 in GC. GLI2 was a direct target gene of miR-144-3p. MiR-144-3p overexpression inhibited proliferation, migration and invasion of gastric cancer cells. Enhanced miR-144-3p expression inhibited tumorsphere formation and CD44 expression of GCSCs. Restoration of GLI2 expression partly reversed the suppressive effect of miR-144-3p. Xenograft assay showed that miR-144-3p could inhibit the tumorigenesis of GC in vivo. Conclusions MiR-144-3p was downregulated and served as an essential tumor suppressor in GC. Mechanistically, miR-144-3p inhibited gastric cancer progression and stemness by, at least in part, regulating GLI2 expression.

scholarly journals Yiqi Huayu Jiedu Decoction Inhibits the Invasion and Metastasis of Gastric Cancer Cells through TGF-β/Smad Pathway

2017 ◽  
Vol 2017 ◽  
pp. 1-8 ◽  
Author(s):  
Ting-Ting Wu ◽  
Jun Lu ◽  
Pei-Qiu Zheng ◽  
Shen-Lin Liu ◽  
Jian Wu ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cancer Cells ◽  
In Vivo Studies ◽  
Migration And Invasion ◽  
Invasion And Metastasis ◽  
Gastric Cancer Cells ◽  
Smad Pathway ◽  
Immunohistochemical Assay

Background.Yiqi Huayu Jiedu Decoction (YHJD) can obviously improve the quality of life of those patients with gastric cancer and prolong their survival.Methods. In vitro experiments, we observe YHJD’s effect on the cells’ proliferation by MTT assay. Cell adhesion assay, wound-healing assay, and Transwell invasion assay serve to detect its influence on cells’ adhesion, migration, and invasion, respectively. Inhibitor (10 μM/L of SB431542) and activator (10 ng/mL of TGF-β) of TGF-β/Smad pathway were used to estimate whether YHJD’s impact on the biological behavior of gastric cancer cells was related to TGF-β/Smad pathway. In in vivo studies, YHJD was administered to the nude mice transplanted with gastric cancer to observe its effect on the tumor. Western blotting and immunohistochemical assay were used to test relevant cytokines of TGF-β/Smad pathway and epithelial-mesenchymal transition (EMT) in MGC-803 cells and the tumor bearing nude mice.Results.YHJD inhibited proliferation, adhesion, migration, and invasion of MGC-803 gastric cancer cells in vitro. In in vivo studies, YHJD reduced the volume of the transplanted tumors. It also enhanced the expression of E-cadherin and decreased the levels of N-cadherin, TGF-β, Snail, and Slug in both MGC-803 cells and the transplanted tumor by western blot assay. The immunohistochemical assay revealed that YHJD raised E-cadherin in the tumors of the mice; on the contrary, the expression of N-cadherin, Twist, vimentin, TGF-βR I, p-Smad2, p-Smad3, Snail, and Slug reduced.Conclusion. YHJD can effectively inhibit the invasion and metastasis of gastric cancer cells. The mechanism may be related to TGF-β/Smad pathway.

scholarly journals Knockdown of PD-L1 in Human Gastric Cancer Cells Inhibits Tumor Progression and Improves the Cytotoxic Sensitivity to CIK Therapy

2017 ◽  
Vol 41 (3) ◽  
pp. 907-920 ◽  
Author(s):  
Jing Li ◽  
Lujun Chen ◽  
Yuqi Xiong ◽  
Xiao Zheng ◽  
Quanqin Xie ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cell Cycle ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Human Gastric Cancer ◽  
Gastric Cancer Cells ◽  
Over Expression ◽  
Gastric Cancer Cell Lines ◽  
Cancer Tissues

Background/Abstract: PD-L1 has been an important target of cancer immunotherapy. We have showed that in human gastric cancer tissues, over-expression of PD-L1 was significantly associated with cancer progression and patients’ postoperative prognoses. However, as of now, how PD-L1 regulates the biological function of gastric cancer cells still remains elusive. Methods: We constructed the stable PD-L1 knockdown expression gastric cancer cell lines by using RNAi method, and further investigated the changes of biological functions including cell viability, migration, invasion, cell cycle, apoptosis, tumorigenicity in vivo, and the cytotoxic sensitivity to CIK therapy, in contrast to the control cells. Results: In the current study, we demonstrated that the knockdown of PD-L1 expression in human gastric cancer cells could significantly suppress the cell proliferation, migration, invasion, apoptosis, cell cycle, tumorigenicity in vivo and the cytotoxic sensitivity to CIK therapy. Conclusion: Our results indicate that PD-L1 contributes towards transformation and progression of human gastric cancer cells, and its intervention could prove to be an important therapeutic strategy against gastric cancer.

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

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.

scholarly journals Efficacy of a Hypotonic Treatment for Peritoneal Dissemination from Gastric Cancer Cells: AnIn VivoEvaluation

2014 ◽  
Vol 2014 ◽  
pp. 1-8 ◽  
Author(s):  
Atsushi Shiozaki ◽  
Daisuke Ichikawa ◽  
Kenichi Takemoto ◽  
Yoshito Nako ◽  
Shingo Nakashima ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cancer Cells ◽  
Nude Mice ◽  
Peritoneal Dissemination ◽  
Abdominal Cavity ◽  
Gastric Cancer Cells ◽  
Abdominal Organs ◽  
Hypotonic Treatment

The aim of the present study was to determine the efficacy of a hypotonic treatment for peritoneal dissemination from gastric cancer cells using anin vivomodel. We firstly evaluated the toxicity of a peritoneal injection of distilled water (DW) (2 mL for 3 days) in mice. Macroscopic and microscopic examinations revealed that the peritoneal injection of DW did not severely damage the abdominal organs of these mice. MKN45 gastric cancer cells preincubated with NaCl buffer or DW for 20 minutesin vitrowere then intraperitoneally injected into nude mice, and the development of dissemination nodules was analyzed. The total number, weight, and volume of the dissemination nodules were significantly decreased by the DW preincubation. We then determined whether the peritoneal injection of DW inhibited the establishment of peritoneal dissemination. After a peritoneal injection of MKN45 cells into nude mice, NaCl buffer or DW was injected into the abdominal cavity for 3 days. The total volume of dissemination nodules was significantly lower in DW-injected mice than in NaCl-injected mice. In conclusion, we demonstrated the safeness of a peritoneal injection of DW. Furthermore, the development of dissemination nodules from gastric cancer cells was prevented by a preincubation with or peritoneal injection of DW.

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