INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2024
·Vol. 25
·期 5
·2817
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IF 4.9
Gengchen Xie,Bo Lei,Zhijie Yin,Fei Xu,Xinghua Liu
Our previous study has reported that metastasis-associated protein 2 (MTA2) plays essential roles in tumorigenesis and aggressiveness of gastric cancer (GC). However, the underlying molecular mechanisms ofMTA2-mediated GC and its upstream regulation mechanism remain elusive. In this study, we identified a novel circular RNA (circRNA) generated from theMTA2gene (circMTA2) as a crucial regulator in GC progression. CircMTA2was highly expressed in GC tissues and cell lines, and circMTA2promoted the proliferation, invasion, and metastasis of GC cells both in vitro and in vivo. Mechanistically, circMTA2interacted with ubiquitin carboxyl-terminal hydrolase L3 (UCHL3) to restrainMTA2ubiquitination and stabilizeMTA2protein expression, thereby facilitating tumor progression. Moreover, circMTA2was mainly encapsulated and transported by exosomes to promote GC cell progression. Taken together, these findings uncover that circMTA2suppressesMTA2degradation by interacting with UCHL3, thereby promoting GC progression. In conclusion, we identified a cancer-promoting axis (circMTA2/UCHL3/MTA2) in GC progression, which paves the way for us to design and synthesize targeted inhibitors as well as combination therapies.Keywords:CircRNAs;MTA2;gastric cancer;UCHL3;ubiquitination
研究领域:
分子生物学
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肿瘤学
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细胞生物学
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DOI
PubMed
高影响因子
Translational Oncology
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2025
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IF 4.1
Zhe Qin,Fangzhou Ye,Jiayi Wang,Jun Jiang,Xiaohong Zhang,Huanqing Li,Li Feng
Background Cisplatin resistance significantly impedes the treatment of gastric cancer (GC). This work examined the possible therapeutic target status and function of BUB1B in controlling cisplatin resistance. Methods Following the identification of differentially expressed genes (DEGs), protein-protein interaction (PPI) network analysis was conducted using datasets from the Cancer Genome Atlas-stomach adenocarcinoma (TCGA-STAD), GSE51575, and GSE79973. Functional tests assessed the effect of BUB1B overexpression and knockdown on the GC cells. Enrichment analysis and RNA-seq identified pathways linked to BUB1B . Additionally, the function of BUB1B in GC cells resistant to cisplatin in regulating DNA repair was examined, as its relationship with Rad51 inhibitor (B02) in regulating cell cycle, proliferation, and apoptosis. The combined effects of Rad51 suppression and BUB1B overexpression on tumor development in cisplatin-resistant GC cells were further validated in vivo xenograft models. Results Significant overexpression of six critical overlapping genes was seen in GC tissues. The GC cell invasion, migration, and proliferation processes were improved by BUB1B overexpression, whereas BUB1B knockdown prevented these outcomes. Genes involved in DNA repair were downregulated by BUB1B knockdown, according to an RNA-seq study. BUB1B overexpression boosted cell survival via modulating cell cycle proteins, but BUB1B knockdown hampered DNA repair and increased death in cisplatin-resistant GC cells. Overexpression of BUB1B enhanced tumor development in vivo and counteracted the inhibitory effects of B02 on cell growth. Conclusion BUB1B enhances cisplatin resistance in gastric cancer by regulating DNA repair and cell cycle progression, suggesting that targeting BUB1B may be a feasible therapeutic strategy.
研究领域:
肿瘤学
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分子生物学
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癌症治疗
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DOI
PubMed
高影响因子
Biomaterials Research
·
2025
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IF 9.6
Yunsheng Lu,Yibin Huang,Chenchen Mao,Pengfei Shan,Chenkang Wu,Jiongzhou Zhu,Yujie Lin,Zhongyu Li,Mingdong Lu
Silencing NOP2/Sun RNA methyltransferase family member 2 (NSUN2) effectively inhibits gastric cancer (GC) progression but is limited by RNase degradation, rapid renal clearance, and low uptake. Based on the characteristic high levels of reactive oxygen species (ROS) in the tumor microenvironment, this study designed and synthesized a novel ROS-responsive ferrocene nanoparticle loaded with siNSUN2 (PRPFc@siNSUN2). Under ROS conditions, the nanoparticle disintegrates to release siNSUN2. Characterization by proton nuclear magnetic resonance, transmission electron microscopy, dynamic light scattering, and ultraviolet–visible spectrophotometry revealed that PRPFc@siNSUN2 is spherical, with an average diameter of 88.79 ± 1.14 nm, an encapsulation efficiency of 83.10%, and a drug loading capacity of 13.85%. Moreover, these nanoparticles demonstrated excellent stability and, under hydrogen peroxide conditions, exhibited structural disruption leading to the release of siNSUN2, thereby confirming their high ROS responsiveness. In vitro, PRPFc@siNSUN2 markedly enhanced the inhibition of GC cell proliferation, migration, and invasion, and promoted apoptosis, accompanied by increased intracellular ROS and improved siNSUN2 uptake. In vivo studies further confirmed that PRPFc@siNSUN2 markedly enhanced the therapeutic efficacy of siNSUN2 against GC, while exhibiting low cytotoxicity and good biocompatibility. Overall, our findings indicate that PRPFc@siNSUN2, with its favorable morphology, stability, and ROS-triggered release, substantially improves the anti-GC effects of siNSUN2 by inhibiting GC cell proliferation, migration, and invasion, as well as by promoting apoptosis. These results support NSUN2 as a promising therapeutic target and underscore the potential of PRPFc@siNSUN2 nanoparticles in drug delivery, offering a novel strategy to improve clinical outcomes for GC patients.
研究领域:
肿瘤学
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分子生物学
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药剂学
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产品关联
DOI
PubMed
高影响因子
TISSUE & CELL
·
2021
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IF 2.466
Limao Xu,Chengmin Liu,Zhiyao Ye,Chengfeng Wu,Yuhang Ding,Juan Huang
Long non-coding RNA (lncRNA) LINC00467 plays a proto-oncogenic role in non-small cell lung cancer. However, its effect and modulatory mechanism in gastric cancer (GC) are unknown. Thereby, we elucidated the mechanism of LINC00467 in GC. LINC00467 level in GC tissues was assessed by bioinformatic analysis, and clinicopathological parameters from GC patients were collected. The levels of LINC00467, integrin subunit beta 3 (ITGB3), proliferating cell nuclear antigen (PCNA), cleaved caspase-3 and cleaved poly (ADP-ribose) polymerase 1 (PARP1) in tissue samples or treated GC cells were assessed by quantitative real-time polymerase chain reaction (qRT-PCR), fluorescence in situ hybridization (FISH), or Western blot. The viability, proliferation and apoptosis of GC cells were detected by methyl thiazolyl tetrazolium assay, colony formation assay, and flow cytometry. Levels of LINC00467 and ITGB3 were up-regulated in GC, and highly expressed LINC00467 was positively associated with tumor size, differentiation, N stage, and T stage in GC patients. LINC00467 was enriched in cytoplasm of GC cells, and overexpressed LINC00467 promoted the viability and proliferation as well as levels of ITGB3 and PCNA, while suppressing the apoptosis and levels of cleaved caspase-3 and cleaved PARP1 in GC cells. Besides, the effects of shLINC00467 on inhibiting cell viability, proliferation of GC cells and PCNA level and promoting apoptosis as well as levels of cleaved caspase-3 and cleaved PARP1 were all partially reversed by overexpressed ITGB3. Overexpressed LINC00467 enhanced the viability and proliferation but inhibited apoptosis of GC cells via increasing ITGB3 level.
研究领域:
肿瘤学
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分子生物学
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癌症研究
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DOI
PubMed
高影响因子
NUTRITION AND CANCER-AN INTERNATIONAL JOURNAL
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2025
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IF 2.4
Tong Zhang,Bin Xu
Gastric cancer (GC) is a malignant tumor with high morbidity and mortality rates worldwide. This study aimed to investigate the effects and mechanisms of action of didymin, a dietary flavonoid glycoside, on GC treatment. Human GC cell lines Hs-746T and AGS were used to assess the effects of didymin on cell viability, cell proliferation, and cell cycle. The results showed that didymin decreased the proliferative capacity of GC cells and blocked cell cycle. Didymin decreased wound healing, invasion, and migration capacities of GC cells. Mitochondrial reactive oxygen species (ROS) levels and mitochondrial membrane potentials were reduced in cells treated with didymin. Network pharmacology analysis revealed that the therapeutic effects of didymin on AGS cells were related to the phosphatidylinositol 3-kinase (PI3K)/Akt pathway. In vivo mouse xenograft studies confirmed that didymin treatment decreased tumor cell proliferation, cell cycle protein levels, and Akt phosphorylation. The present study demonstrated that didymin regulates mitochondrial function and the PI3K/Akt pathway to inhibit cell proliferation and induce apoptosis in GC cells in vitro and in vivo. Therefore, didymin is a promising drug for the treatment of GC.
研究领域:
肿瘤学
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分子生物学
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药理学
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产品关联
DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
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2025
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IF 5.6
Yueyang Guo,Zhuang Hu,Linyue Bai,Yanjun Tang,Jingyi Hu,Qianqian Zhang,Jiali Liu,Siqi Feng
Gastric cancer, a leading cause of cancer-related mortality, has a median survival of just 15 months in advanced stages and currently lacks effective treatment options. Neddylation blockade is a promising therapeutic strategy, yet its clinical application faces challenge with the emergence of drug resistance. Currently, the underlying mechanisms behind the drug resistance are not fully understood. Our study uncovers the link between MLN4924-induced metabolic reprogramming and its antitumor efficacy in gastric cancer cells. We first demonstrated that MLN4924, a neddylation blocker, has multiple effects on gastric cancer cell growth, notably inducing mitochondrial damage. Untargeted metabolomic analysis revealed that MLN4924 enhances glucose utilization in gastric cancer cells in a concentration-dependent manner. Mechanistically, MLN4924 reduces the neddylation of cullin2, thereby inhibiting the degradation of HIF-1α. This leads to the accumulation of HIF-1α, which upregulates GLUT1 levels and facilitates increased glucose uptake. This metabolic adaptation allows gastric cancer cells to maintain their energy supply despite mitochondrial impairment. Based on the increased glucose dependency following neddylation inhibition by MLN4924, we propose a co-targeting strategy with GLUT1 inhibition, which significantly improves therapeutic efficacy in vitro and in vivo models without safety risks. This dual-targeting approach represents a potent new strategy for gastric cancer treatment.
研究领域:
肿瘤学
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代谢组学
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药理学
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产品关联
DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2025
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IF 8.3
XiaoMing Zhou,ChenXi Zhang,Wen Shen,RuiFei Zhuang,ShenLin Liu,JinDi Liu
Background Curzerene, a bioactive compound from Curcuma zedoaria, exhibits anticancer effects, but its role in gastric precancerous lesions remains poorly understood. This study investigates the potential of Curzerene in inhibiting gastric precancerous lesions progression by regulating the long non-coding RNA (LncRNA) AFAP1-AS1 and the Hippo/YAP signaling pathway. Methods In vitro, a gastric precancerous cell model (MC cells) was established by treating GES-1 cells with MNNG. The effects of Curzerene on cell proliferation, migration, and EMT were assessed using CCK-8, scratch assays, RT-PCR, and Western blot. In vivo, a gastric precancerous mouse model was induced by MNU, and the therapeutic effects of Curzerene (14 mg/kg and 28 mg/kg) were evaluated through histological and molecular analysis. Results Curzerene treatment significantly inhibited MC cell proliferation, migration, and EMT, downregulating LncRNA AFAP1-AS1 and YAP while upregulating E-cadherin and downregulating N-cadherin. In vivo, Curzerene alleviated gastric mucosal damage, reduced cancer markers (P53 and CD133), and improved histopathology. Transcriptomic analysis identified the Hippo/YAP pathway as a key mediator of Curzerene’s effects. YAP activation reversed Curzerene’s inhibitory effects on EMT, confirming the involvement of this pathway. Conclusion Curzerene effectively inhibits gastric precancerous lesion progression by targeting the YAP signaling and the following LncRNA AFAP1-AS1 to suppress EMT. These findings suggest Curzerene’s novel potential as a promising therapeutic agent for early intervention and prevention of gastric cancer.
研究领域:
肿瘤学
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分子生物学
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药理学
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产品关联
DOI
PubMed
高影响因子
Frontiers in Oncology
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2025
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IF 3.3
Shuming Chen,Xiaoxi Han,Yangyang Lu,Shasha Wang,Yuanyuan Fang,Chuanyu Leng,Xueying Sun,Xin Li,Wensheng Qiu,Weiwei Qi
Background The process of human aging is accompanied by an increased susceptibility to various cancers, including gastric cancer. This heightened susceptibility is linked to the shared molecular characteristics between aging and tumorigenesis. Autophagy is considered a critical mediator connecting aging and cancer, exerting a dynamic regulatory effect in conjunction with cellular senescence during tumor progression. In this study, a combined analysis of autophagy- and senescence-related genes was employed to comprehensively capture tumor heterogeneity. Methods The gene expression profiles and clinical data for GC samples were acquired from TCGA and GEO databases. Differentially expressed autophagy- and senescence-related genes (DEASRGs) were identified between tumor and normal tissues. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were carried out to provide insights into biological significance. A prognostic signature was established using univariate Cox and LASSO regression analyses. Furthermore, consensus clustering analyses and nomograms were employed for survival prediction. TME and drug sensitivity analyses were conducted to compare differences between the groups. To predict immunotherapy efficacy, the correlations between risk score and immune checkpoints, MSI, TMB, and TIDE scores were investigated. Results A fourteen-gene prognostic signature with superior accuracy was constructed. GC patients were stratified into three distinct clusters, each exhibiting significant variations in their prognosis and immune microenvironments. Drug sensitivity analysis revealed that the low-risk group demonstrated greater responsiveness to several commonly used chemotherapeutic agents for gastric cancer, including oxaliplatin. TME analysis further indicated that the high-risk group exhibited increased immune cell infiltration, upregulated expression of ICs, and a higher stromal score, suggesting a greater capacity for immune evasion. In contrast, the low-risk group was characterized by a higher proportion of microsatellite instability-high (MSI-H) cases, an elevated TIDE score, and a greater TMB, indicating a higher likelihood of benefiting from immunotherapy. In addition, Single-cell sequencing demonstrated that TXNIP was expressed in epithelial cells. Cellular experiments preliminarily verified that TXNIP could promote the proliferation and migration of gastric cancer cells. Conclusion This study presents a robust predictive model for GC prognosis using autophagy- and senescence-related genes, demonstrating its ability to predict immune infiltration, immunotherapy effectiveness, and guide personalized treatment.
研究领域:
肿瘤学
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分子生物学
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生物信息学
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产品关联
DOI
PubMed
高影响因子
COMBINATORIAL CHEMISTRY & HIGH THROUGHPUT SCREENING
·
2024
·Vol. 27
·期 13
·1919-1929
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IF 1.6
Zhang Fei,Chu Mingliang,Liu Jiemin,Zhao Qi,Zhu Yanqiu,Wu Xuefang
Aim: The study aimed to study the potential roles and mechanisms of shikonin in gastric cancer by network pharmacology and biological experiments. Methods: The key genes and targets of shikonin in gastric cancer were predicted by network pharmacology and molecular docking study.
The effect of shikonin on the proliferation, migration, and invasion of gastric cancer cells was detected by the CCK8 method, and wound healing and transwell assays. The expression levels of c-Myc and Yap-1 were detected via western blotting in gastric cancer cells after shikonin intervention.
Results: The results of network pharmacology revealed the key target genes of shikonin on gastric cancer cells to be c-Myc, Yap-1, AKT1, etc. GO and KEGG analysis showed regulation of cell migration, proliferation, adhesion, and other biological processes, including the PI3K-Akt signaling
pathway, HIF-1 signaling pathway, necroptosis, and other cancer pathways. Molecular docking showed shikonin to be most closely combined with protooncogenes c-Myc and Yap-1. In vitro experiments showed that the proliferation rate, migration, and invasion ability of the gastric cancer cell group
decreased significantly after shikonin intervention for 24h. The expression levels of c-Myc and Yap-1 in gastric cancer cells were found to be significantly decreased after shikonin intervention. Conclusion: This study showed protooncogenes c-Myc and Yap-1 to be the core target genes
of shikonin on gastric cancer cells. Shikonin may suppress gastric cancer cells by inhibiting the protooncogenes c-Myc and Yap-1. This suggests that shikonin may be a good candidate for the treatment of gastric cancer.
研究领域:
肿瘤学
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药理学
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分子生物学
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DOI
PubMed
高影响因子
BMC CANCER
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2018
·Vol. 18
·期 1
·1-11
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IF 3.288
Liu Hai-Ning,Wu Hao,Tseng Yu-Jen,Chen Yan-Jie,Zhang Dan-Ying,Zhu Lin,Dong Ling,Shen Xi-Zhong,Liu Tao-Tao
Background Many novel diagnostic biomarkers have been developed for gastric cancer (GC) recently. We chose two methods with high diagnostic value, the detection of serum microRNAs and metabolomics based on gas chromatography/mass spectrometry (GC/MS), and aimed to establish appropriate models.Methods We reviewed the diagnostic accuracies of all microRNAs identified by previous diagnostic tests. Then appropriate microRNAs and their combinations were validated the diagnostic value. We included 80 patients with GC and 82 healthy controls (HCs) and detected the expression of the microRNAs. GC/MS analysis was conducted, and we used three multivariate statistical analyses to establish diagnostic models. The concentrations of carcinoembryonic antigen (CEA) and carbohydrate antigen 19–9 (CA19–9) were detected for comparison with the novel models.Results Sixty-seven published studies and 70 microRNAs were finally included in the systematic review. MiR-18a, miR-19a, miR-21, miR-92a, miR-199a and miR-421 were chosen to further validate their diagnostic efficiencies. Five of those microRNAs in GC patients had significantly different expression. The combination of miR-19a and miR-92a had the highest area under the curve (AUC) at 0.850 with a sensitivity of 91.3% and a specificity of 61.0%. The GC/MS analysis performed an excellent diagnostic value and the AUC reached 1.0.Conclusion There is a good potential for microRNAs and GC/MS analysis as new diagnostic methods in view of their high diagnostic value compared with traditional biomarkers.
研究领域:
肿瘤学
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分子生物学
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医学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
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2025
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IF 11.5
Xinxin Xie,Jinxia Zhang,Lihong Sun,Shuyu Xu,Shiti Sha Ma,Haonan Wang,Xiaoda Li,Qiong Xiang,Ligang Cui,Xiaolong Liang
Hypoxia is a common feature of malignant tumors, which can accelerate tumor growth and reduce the sensitivity of chemotherapy and sonodynamic therapy by activating the hypoxia-inducible factor (HIF) signaling pathway. In HER2-positive gastric cancer, HER2 overexpression enhances HIF-1α synthesis, exacerbating hypoxia and impairing sonodynamic therapy. It also reduces trastuzumab-mediated antibody-dependent cytotoxicity, significantly compromising therapeutic outcomes. Herein, pyropheophorbide-conjugated lipid (pyropheophorbide-lipid, PL) and trastuzumab were fabricated into targeted nanoparticles (TP NPs) for loading perfluorobromooctane (PFOB) carrying oxygen (TPPO NPs), thus enabling oxygen self-supplied sonodynamic and antibody therapies. In vitro experiments showed that antibody targeting significantly increased the cellular uptake of sonosensitizers, and the controlled release of oxygen was dependent on ultrasound parameters, greatly enhancing the killing effects of SDT and antibody therapy. In vivo animal experiments showed that TPPO NPs-mediated enhanced permeation and retention (EPR) effects, along with antibody targeting, improved the enrichment of sonosensitizers in tumors. Notably, ultrasound-triggered topical delivery of oxygen significantly alleviated tumor hypoxia and further improved the efficacy of SDT and antibody therapy. Given the good biosafety profile of TPPO NPs, this system holds great promise for future clinical applications in gastric cancer.
研究领域:
肿瘤学
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药剂学
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生物医学工程
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产品关联
DOI
PubMed
高影响因子
PROSTAGLANDINS & OTHER LIPID MEDIATORS
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2025
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IF 2.5
Jindao Wang,Minghui Zhou,Qiuli Zhou,Guangyang Sun,Yu Zhang,Feng Tao,Minfeng Ye
Background Gastric cancer (GC) is the third leading culprit of cancer-related deaths around the world. Beta-sitosterol (BS) is an important phytosterol that has been proven to have anti-proliferative effects on GC and other tumors. However, mechanisms and targets of BS in cancer are rarely explored. Methods In this investigation, the targets of BS in the treatment of GC were analyzed by network pharmacology. Molecular docking and cellular thermal shift assay were introduced to validate the binding relationship between BS and PTGS1. The impacts of BS on GC cell viability, half maximal inhibitory concentration, proliferation ability, apoptosis level, and angiogenesis ability were detected by using Cell Counting Kit-8, clone formation assay, flow cytometry, and angiogenesis experiment, respectively. In addition, the expression levels of angiogenic factors (VEGF, FGF, PAI-1) were detected by using western blot. Results In this project, through cell experiments, PTGS1 was identified as a protein that directly binds to BS. In vitro cell experiments revealed that BS promoted apoptosis and inhibited GC cell proliferation and angiogenesis. Importantly, treatment with BS attenuated the promoting influence of PTGS1 overexpression on GC cell proliferation and angiogenesis. Conclusion This investigation highlighted PTGS1 as the target of BS in GC cells. BS can regulate PTGS1 to inhibit GC cell proliferation and angiogenesis, providing new evidence for the potential use of BS as a therapeutic agent for GC.
研究领域:
肿瘤学
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药理学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
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