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[18F]tetrafluoroborate (TFB) has been introduced as the 18F-labeled PET imaging probe for the human sodium iodide symporter (NIS). Noninvasive NIS imaging using [18F]TFB has received much interest in recent years for evaluating various NIS-expressing tumors. Cancers are a global concern with enormous implications; therefore, improving diagnostic methods for accurate detection of cancer is extremely important. Our aim was to investigate the PET imaging capabilities of [18F]TFB in NIS-transfected lung cell line A549 and endogenous NIS-expressing tumor cells, such as thyroid cancer K1 and gastric cancer MKN45, and broaden its application in the medical field. Western blot and flow cytometry were used to assess the NIS expression level. Radioactivity counts of [18F]TFB, in vitro, in the three tumor cells were substantially higher than those in the KI inhibition group in the uptake experiment. In vivo PET imaging clearly delineated the three tumors based on the specific accumulation of [18F]TFB in a mouse model. Ex vivo biodistribution investigation showed high [18F]TFB absorption in the tumor location, which was consistent with the PET imaging results. These results support the use of NIS-transfected lung cell line A549 and NIS-expressing tumor cells MKN45 and K1, to investigate probing capabilities of [18F]TFB. We also demonstrate, for the first time, the feasibility of [18F]TFB in diagnosing stomach cancer. In conclusion, this study illustrates the promising future of [18F]TFB for tumor diagnosis and NIS reporter imaging. [ABSTRACT FROM AUTHOR]

Background: Gastric cancer patients harboring a TP53 mutation exhibit a more aggressive and chemoresistant phenotype. Unfortunately, efforts to identify the vulnerabilities to overcome these aggressive malignancies have made minimal progress in recent years. Therefore, there is an urgent need to explore the novel therapeutic strategies for this subclass. Histone methylation modulators are critical epigenetic targets for cancer therapies that help maintain the malignancies of cancers harboring TP53 mutations and senescence evasion. Triggering senescence is now considered to benefit multiple cancer therapies. Furthermore, senescence-based "one-two punch" therapy was validated in clinical trials. Therefore, we hypothesized that screening epigenetic modulators might help identify a novel vulnerability to trigger senescence in gastric cancer harboring TP53 mutations. Results: We developed a novel efficient approach to identify senescence inducers by sequentially treating cells with drug candidates and senolytic agents. Based on this, we demonstrated that QC6352 (a selective KDM4C inhibitor) efficiently triggered cellular senescence in gastric cancer harboring TP53 mutations. More importantly, the "one-two punch' therapy consisting of QC6352 and SSK1 eliminates tumor cells harboring TP53 mutations. This finding highlights a potential therapeutic strategy for the aggressive subgroup of gastric cancer. Besides, the functions of QC6352 were totally unknown. We demonstrated that QC6352 might possess far more powerful anti-tumor capacities compared to the traditional genotoxic drugs, 5-Fu and Oxaliplatin. Conclusions: This initial investigation to identify a senescence inducer revealed that QC6352 triggers senescence in gastric cancer cells harboring TP53 mutations by regulating the SP1/CDK2 axis through suppressing KDM4C. QC6352 and senolytic agent-SSK1 represent a novel 'one-two punch' therapeutic strategy for the more malignant gastric cancer subtypes. Highlights: Sequentially treating cells with drug candidates and senolytic agents serve as a novel efficient approach to identify senescence inducers QC6352 acts as a novel pro-senescence drug in gastric cancer harboring TP53 mutations The "one-two punch' therapy consisted of QC6352 and SSK1 eliminates tumor cells harboring TP53 mutations [ABSTRACT FROM AUTHOR]

Background: Peritoneal metastasis (PM) frequently occurs in patients with gastric cancer (GC) and is a major cause of mortality. Risk stratification for PM can optimize decision making in GC treatment. Methods: A total of 25 GC patients (13 with synchronous, 6 with metachronous PM and 6 PM-free) were included in this study. Quantitative proteomics by high-depth tandem mass tags labeling and whole-exome sequencing were conducted in primary GC and PM samples. Proteomic signature and prognostic model were established by machine learning algorithms in PM and PM-free GC, then validated in two external cohorts. Tumor-infiltrating immune cells in GC were analyzed by CIBERSORT. Results: Heterogeneity between paired primary and PM samples was observed at both genomic and proteomic levels. Compared to primary GC, proteome of PM samples was enriched in RNA binding and extracellular exosomes. 641 differently expressed proteins (DEPs) between primary GC of PM group and PM-free group were screened, which were enriched in extracellular exosome and cell adhesion pathways. Subsequently, a ten-protein signature was derived based on DEPs by machine learning. This signature was significantly associated with patient prognosis in internal cohort and two external proteomic datasets of diffuse and mixed type GC. Tumor-infiltrating immune cell analysis showed that the signature was associated with immune microenvironment of GC. Conclusions: We characterized proteomic features that were informative for PM progression of GC. A protein signature associated with immune microenvironment and patient outcome was derived, and it could guide risk stratification and individualized treatment. [ABSTRACT FROM AUTHOR]

Gastric cancer (GC) is a common form of cancer and the leading cause of cancer-related deaths worldwide. Chemotherapy is the primary treatment for patients with unresectable or partially resectable GC. However, its adverse effects and chemoresistance greatly restrict its applicability and efficacy. Although HER2-targeted therapy and immunotherapy have been successfully used for GC treatment, their beneficial population is limited. To expand the range of cancer treatments, drug repurposing has emerged as a promising strategy. In this study, we evaluated the potential of Metformin, an oral anti-hyperglycemic agent, to suppress GC progression both in vivo and in vitro. Functional investigations showed that Metformin significantly inhibits GC proliferation and migration. Furthermore, we discovered that Metformin bound and disrupted STAT1 phosphorylation, inhibiting PRMT1 expression and consequently GC progression. In conclusion, our study not only provides further evidence for the anti-GC role of Metformin but also identifies the direct target mediating the tumor-inhibitory effects of Metformin in GC. [ABSTRACT FROM AUTHOR]

[18F]tetrafluoroborate (TFB) has been introduced as the 18F-labeled PET imaging probe for the human sodium iodide symporter (NIS). Noninvasive NIS imaging using [18F]TFB has received much interest in recent years for evaluating various NIS-expressing tumors. Cancers are a global concern with enormous implications; therefore, improving diagnostic methods for accurate detection of cancer is extremely important. Our aim was to investigate the PET imaging capabilities of [18F]TFB in NIS-transfected lung cell line A549 and endogenous NIS-expressing tumor cells, such as thyroid cancer K1 and gastric cancer MKN45, and broaden its application in the medical field. Western blot and flow cytometry were used to assess the NIS expression level. Radioactivity counts of [18F]TFB, in vitro, in the three tumor cells were substantially higher than those in the KI inhibition group in the uptake experiment. In vivo PET imaging clearly delineated the three tumors based on the specific accumulation of [18F]TFB in a mouse model. Ex vivo biodistribution investigation showed high [18F]TFB absorption in the tumor location, which was consistent with the PET imaging results. These results support the use of NIS-transfected lung cell line A549 and NIS-expressing tumor cells MKN45 and K1, to investigate probing capabilities of [18F]TFB. We also demonstrate, for the first time, the feasibility of [18F]TFB in diagnosing stomach cancer. In conclusion, this study illustrates the promising future of [18F]TFB for tumor diagnosis and NIS reporter imaging. [ABSTRACT FROM AUTHOR]

Background: Gastric cancer (GC) is one of the leading causes of cancer deaths with high heterogeneity. There is currently a paucity of clinically applicable molecular classification system to guide precise medicine. Methods: A total of 70 Chinese patients with GC were included in this study and whole-exome sequencing was performed. Unsupervised clustering was undertaken to identify genomic subgroups, based on mutational signature, copy number variation, neoantigen, clonality, and essential genomic alterations. Subgroups were characterized by clinicopathological factors, molecular features, and prognosis. Results: We identified 32 significantly mutated genes (SMGs), including TP53, ARID1A, PIK3CA, CDH1, and RHOA. Of these, PREX2, PIEZO1, and FSIP2 have not been previously reported in GC. Using a novel genome-based classification method that integrated multidimensional genomic features, we categorized GC into four subtypes with distinct clinical phenotypes and prognosis. Subtype 1, which was predominantly Lauren intestinal type, harbored recurrent TP53 mutation and ERBB2 amplification, high tumor mutation burden (TMB)/tumor neoantigen burden (TNB), and intratumoral heterogeneity, with a liver metastasis tendency. Subtype 2 tended to occur at an elder age, accompanying with frequent TP53 and SYNE1 mutations, high TMB/TNB, and was associated with poor prognosis. Subtype 3 and subtype 4 included patients with mainly diffuse/mixed type tumors, high frequency of peritoneal metastasis, and genomical stability, whereas subtype 4 was associated with a favorable prognosis. Conclusions: By integrating multidimensional genomic characteristics, we proposed a novel genomic classification system of GC associated with clinical phenotypes and provided a new insight to facilitate genome-guided risk stratification and disease management. [ABSTRACT FROM AUTHOR]

Gastric cancer (GC) is one of the most prevalent digestive malignancies. A great number of patients at first visit or post curative resections are diagnosed with widespread metastasis within the peritoneal cavity. Overwhelming evidence has demonstrated that exosomes, a variety of biologically functional extracellular vesicles comprising active factors, mediate the progression and metastasis of GC. Although the regulatory mechanisms of exosomes remain fairly elusive, they are responsible for intercellular communication between tumor cells and normal stroma, cancer-related fibroblasts, immune cells within the primary tumor and metastatic niche. In this review, we provide new insight into the molecular signatures of GC-associated exosomes in reprogramming the tumor microenvironment and the subsequent promotion of peritoneal metastasis—including infiltration of the gastric wall, implantation of tumor cells onto the pre-metastatic peritoneum, and remodeling of the pre-metastatic niche. Based on this review, we hope to draw a more general conclusion for the functions of exosomes in the progression and peritoneal metastasis of GC and highlight the future perspective on strategies targeting exosomes in prognostic biomarkers and therapy for peritoneal metastasis. [ABSTRACT FROM AUTHOR]

Alpha-fetoprotein producing gastric carcinoma (AFPGC) is a rare and aggressive subtype of gastric cancer. However, little is known about the genomic features of this disease. We perform whole-exome sequencing analysis of AFPGC, and identify 34 significantly mutated genes. Somatic copy number alterations analysis reveals several significant focal amplifications (e.g. 19q12, 17q12) and focal deletions (e.g. 1p36.11, 9p21.3), and some of these negatively affect the patient prognosis. Comparative analyses reveal that AFPGC has distinct genomic features from gastric cancer of The Cancer Genome Atlas as well as four molecular subtypes. Several frequently altered genes with potential as therapeutic targets are identified in AFPGC. Further analysis reveals that AFPGC with amplification of CCNE1 at 19q12 and/or ERBB2 at 17q12 show poorer survival and more aggressive. Subsequently, based on our established patient-derived xenograft models for AFPGC, translational research is performed and the therapeutic value of targeting CCNE1 and ERBB2 is validated. In this work, we provide an understanding of genomic characteristics of AFPGC and propose a platform to explore and validate the genome-guided personalized treatment for this disease. Alpha-fetoprotein producing gastric carcinomas (AFPGC) are rare and aggressive. Here, the authors profile AFPGC tumours using whole exome sequencing, and find amplifications in CCNE1 and ERBB2 that are associated with poor outcomes but are potential therapeutic targets, as shown in patient-derived xenografts. [ABSTRACT FROM AUTHOR]

Background: Gastric cancer (GC) is the fifth most frequently diagnosed malignancy, and the third leading cause of tumor-related mortalities worldwide. Due to a high heterogeneity in GC, its treatment and prognosis are challenging, necessitating urgent identification of novel prognostic predictors for GC patients. Methods: We downloaded RNA sequence data, from the Cancer Genome Atlas and microarray data from Gene Expression Omnibus database, then identified common differentially-expressed genes (DEGs) between GC and normal gastric tissues across four datasets. We then used a combination of protein-protein interaction (PPI) network and weighted gene co-expression network analysis (WGCNA) to identify key genes with prognostic value in GC. Thereafter, we used quantitative real time polymerase chain reaction (qRT-PCR) to validate expression of the identified key genes in the Zhejiang University (ZJU) cohort. Finally, we evaluated the relationships between gene expression and immune factors, including immune cells and biomarkers of immunotherapy. Results: Among 426 common DEGs screened, 333 and 93 were upregulated and downregulated, respectively. PPI network and WGCNA successfully identified the top 30 hub genes, among which PTPRC, TYROBP, CCR1, CYBB, LCP2 , and C1QB were common. Furthermore, TYROBP and C1QB were negatively associated with prognosis of GC patients, implying that they were key GC predictors. Interestingly, TYROBP and C1QB were positively correlated with predictive biomarkers for GC immunotherapy, including PD-L1 expression, CD8+ T cells infiltration, and EBV status. Conclusions: TYROBP and C1QB were identified as two novel key genes with prognostic value in GC by network analysis. [ABSTRACT FROM AUTHOR]

The present study aimed to identify genes associated with gastric cancer survival and improve risk stratification for patients with gastric cancer. Transcriptomic and clinicopathological data from 443 gastric cancer samples were retrieved from The Cancer Genome Atlas database. The DESeq R package was applied to screen for differentially expressed genes between Tumor-Node-Metastasis (TNM) stage (I vs. IV) and histological grade (G3 vs. G1 and G2). A total of seven genes were common to both comparisons; spondin 1 (SPON1); thrombospondin 4 (THBS4); Sushi, Von Willebrand factor type A, EGF and pentraxin domain containing 1 (SVEP1); prickle planar cell polarity protein 1 (PRICKLE1); ATP binding cassette subfamily A member 8 (ABCA8); Slit guidance ligand 2 (SLIT2); and EGF containing fibulin extracellular matrix protein 1 (EFEMP1), were selected as candidate survival-associated genes for further analysis. The prognostic value of these genes was assessed according to a literature review and Kaplan-Meier survival analysis. In addition, a multivariate Cox regression analysis revealed PRICKLE1 expression to be an independent prognostic factor for patients with gastric cancer. Furthermore, a predictive nomogram was generated using PRICKLE1 expression, patient age and TNM stage to assess overall survival (OS) rate at 1, 3 and 5 years, with an internal concordance index of 0.65. External validation was conducted in an independent cohort of 59 patients with gastric cancer, and high consistency between the predicted and observed results for OS was exhibited. Overall, the current findings suggest that PRICKLE1 expression may serve as an independent prognostic factor that can be integrated with age and TNM stage in a nomogram able to predict OS rate in patients with gastric cancer. [ABSTRACT FROM AUTHOR]

Gastric cancer (GC) is a frequently occurring malignancy with high mortality rates. However, the underlying mechanism of GC progression is not very clear. The aim of this study is to reveal the inherent molecular mechanism and develop potential therapeutic targets for advanced GC. The microfibril-associated glycoprotein 1 (MAGP1), identified as a potential oncogene, was found upregulated in GC tissues and high MAGP1 expression was associated with aggressive clinicopathological features. Furthermore, the multivariate Cox regression analysis showed that high MAGP1 expression was an independent predictor of poor prognosis (HR = 2.37, 1.07–5.24; P = 0.033). Mechanistically, MAGP1 promoted the migration and invasiveness of GC cells. In addition, the genes co-expressed with MAGP1 were primarily enriched in focal adhesion and PI3K-Akt pathways. MAGP1 overexpression enhanced the phosphorylation of FAK, AKT, and mTOR, whereas its knockdown also inactivated these factors. Furthermore, the AKT inhibitor suppressed the phosphorylation of AKT, FAK, and mTOR in recMAGP1-treated AGS cells, as well as their migration and invasion capacities. Finally, correlation analysis indicated that MAGP1 is involved in AKT signaling in GC, and is clinically relevant. Taken together, MAGP1 is a promising prognostic marker and potential therapeutic target for advanced GC. [ABSTRACT FROM AUTHOR]

Abstract Background The miR-129-5p has been reported to be aberrant expression and exert vital roles in tumor progression of various malignancies. However, the effects on EMT in gastric cancer and its precise molecular mechanism in gastric cancer remain unclear. Methods and materials RT-qPCR was performed to evaluate the expression level of miR-129-5p and HMGB1 in cell lines. Cell proliferation was detected via CCK-8. The epithelial mesenchymal transition (EMT) related proteins and the expression of HMGB1 were detected by western blot analysis. Luciferase assays were used to validate binding seeds between miR-129-5p and HMGB1. Results miR-129-5p was downregulated in gastric cancer cells compared with GES-1. At the same time EMT was promoted in gastric cancer cells compared to GES-1. Overexpression of miR-129-5p inhibited EMT and proliferation. MiR-129-5p negatively and directly targeted HMGB1. HMGB1 was upregulated in gastric cancer cells and HMGB1 knocked-down inhibited EMT and cell proliferation. Conclusion Taken together, upregulation of miR-129-5p associated with gastric cancer proliferation and EMT, and serves as a potential diagnostic and therapeutic target via miR-129-5p/HMGB1 pathway in gastric cancer. [ABSTRACT FROM AUTHOR]

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Gastric cancer stem cells (GCSCs) are strongly associated with the refractory characteristics of gastric cancer, including drug resistance, recurrence, and metastasis. The prognosis for advanced gastric cancer patients treated with multimodal therapy after surgery remains discouraging. GCSCs hold promise as therapeutic targets for GC patients. We obtained 26 sets of stem cell-related genes from the StemChecker database. The Consensus clustering algorithm was employed to discern three distinct stemness subtypes. Prognostic outcomes, components of the tumor microenvironment (TME), and responses to therapies were compared among these subtypes. Following this, a stemness-risk model was formulated using weighted gene correlation network analysis (WGCNA), alongside Cox regression and random survival forest analyses. The C2 subtype predominantly showed enrichment in negative prognostic CSC gene sets and demonstrated an immunosuppressive TME. This specific subtype exhibited minimal responsiveness to immunotherapies and demonstrated reduced sensitivity to drugs. Four pivotal genes were integrated into the construction of the stemness model. Gastric cancer patients with higher stemness-risk scores demonstrated poorer prognoses, a greater presence of immunosuppressive components in TME, and lower rates of treatment response. Subset analysis indicated that only the low-stemness risk subtype derives benefit from 5-fluorouracil-based adjuvant chemotherapy. The model's effectiveness in immunotherapeutic prediction was further validated in the PRJEB25780 cohort. Our study categorized gastric cancer patients into three stemness subtypes, each demonstrating distinct prognoses, components of TME infiltration, and varying sensitivity or resistance to standard chemotherapy or targeted therapy. We propose that the stemness risk model may help the development of well-grounded treatment recommendations and prognostic assessments. • The expression levels of M2 polarization regulators were significantly elevated in the high-risk stemness group. • In the high stemness-risk group, there was no significant difference in RFS rates between patients with or without adjuvant chemotherapy. • we conducted (2^10-1) iterations to select gene combinations based on the lowest log-rank p-value. • Transfection with FERMT2-siRNA led to a decrease in the expression levels of various stemness-related markers. [ABSTRACT FROM AUTHOR]