Search

Gastric cancer is a remarkably heterogeneous tumor. Despite some advances in the diagnosis and treatment of gastric cancer in recent years, the precise treatment and curative outcomes remain unsatisfactory. Poor prognosis continues to pose a major challenge in gastric cancer. Therefore, it is imperative to identify effective targets to improve the treatment and prognosis of gastric cancer patients. It should be noted that glycosylation, a novel form of posttranslational modification, is a process capable of regulating protein function and influencing cellular activities. Currently, numerous studies have shown that glycosylation plays vital roles in the occurrence and progression of gastric cancer. As crucial enzymes that regulate glycan synthesis in glycosylation processes, glycosyltransferases are potential targets for treating GC. Hence, investigating the regulation of glycosyltransferases and the expression of associated proteins in gastric cancer cells is highly important. In this review, the related glycosyltransferases and their related signaling pathways in gastric cancer, as well as the existing inhibitors of glycosyltransferases, provide more possibilities for targeted therapies for gastric cancer., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Lactylation has been recently identified as a new type of posttranslational modification occurring widely on lysine residues of both histone and nonhistone proteins. The acetyltransferase p300 is thought to mediate protein lactylation, yet the cellular concentration of the proposed lactyl-donor, lactyl-coenzyme A, is about 1,000 times lower than that of acetyl-CoA, raising the question of whether p300 is a genuine lactyltransferase. Here, we report that alanyl-tRNA synthetase 1 (AARS1) moonlights as a bona fide lactyltransferase that directly uses lactate and ATP to catalyze protein lactylation. Among the candidate substrates, we focused on the Hippo pathway, which has a well-established role in tumorigenesis. Specifically, AARS1 was found to sense intracellular lactate and translocate into the nucleus to lactylate and activate the YAP-TEAD complex; and AARS1 itself was identified as a Hippo target gene that forms a positive-feedback loop with YAP-TEAD to promote gastric cancer (GC) cell proliferation. Consistently, the expression of AARS1 was found to be upregulated in GC, and elevated AARS1 expression was found to be associated with poor prognosis for patients with GC. Collectively, this work found AARS1 with lactyltransferase activity in vitro and in vivo and revealed how the metabolite lactate is translated into a signal of cell proliferation.

Background: Modified Jianpi Yangzheng decoction (mJPYZ), as an empirical decoction of Traditional Chinese medicine has been shown significantly to prolong the survival of patients with advanced stage gastric cancer. Pyruvate kinase M2 (PKM2), has attracted attention for its important role on cellular aerobic glycolysis, however, few studies focus on PKM2 non-metabolic roles in tumor progression., Purpose: Our study aimed to investigate the potential role of gastric cancer exosomes containing PKM2 in regulating tumor-associated macrophages (TAM) and the mechanism of mJPYZ against gastric cancer., Methods: Colony Formation Assay, flow cytometry and TUNEL staining were employed to estimate the effect of mJPYZ on gastric cancer in tumor-bearing mice and cells. Western blot analyzed apoptosis-related protein expression changes. Network pharmacology and bioinformatics predicted potential exosomes modulation of mJPYZ in gastric cancer. Exosomes were isolated and co-cultured with TAM. Diff-Quik Staining observed the TAM morphological changes when incubating with gastric cancer cells exosomes. Flow cytometry and immunofluorescence were performed to demonstrate whether exosomes PKM2 involved in TAM polarization., Results: mJPYZ induced apoptosis of gastric cancer cells by targeting PKM2 and downregulating PI3K/Akt/mTOR axis in vivo and in vitro. Network pharmacology showed potential exosomes modulation of mJPYZ in gastric cancer. We extracted exosomes and found mJPYZ decreased the abundance of serum exosomes PKM2 in patients with advanced gastric cancer and xenograft tumor model. Additionally, we firstly detected and confirmed that PKM2 is a package protein of exosomes extracted from gastric cancer cells, and mJPYZ could diminish the content of exosomal PKM2 in gastric cancer cells. Importantly, mJPYZ reduced the delivery of exosomal PKM2 from tumor cells to macrophages, and alleviated exosomal PKM2-induced differentiation of M2-TAM in tumor microenvironment, eventually inhibited gastric cancer progression., Conclusion: Gastric cancer exosomes containing PKM2 could lead to M2 macrophages differentiation, thereby promoting gastric cancer progression. Our findings provide a rationale for potential application of mJPYZ in the treatment of gastric cancer via PKM2., (Copyright © 2022 Elsevier GmbH. All rights reserved.)

Background: Kinesin family member 2A (KIF2A) induces gastric cancer (GC) growth and invasion, while its clinical relevance in GC patients is not reported. This study aimed to investigate the linkage of KIF2A with clinicopathological features, prognosis, and chemosensitivity of GC., Methods: A total of 160 surgical GC patients were reviewed, with their tumor and adjacent tissues acquired for immunohistochemical (IHC) assay to measure KIF2A expression, then scored by a semi-quantitative method (IHC score: 0-12). KIF2A siRNA or nonsense-siRNA were transfected into HGC-27 and NCI-N87 cells underwent various concentrations of capecitabine or oxaliplatin treatment followed by chemosensitivity assessment., Results: Kinesin family member 2A expression was elevated in the tumor tissue compared to the adjacent tissue (IHC score: 5.6 ± 3.1 vs. 2.9 ± 1.7, p < 0.001). Besides, tumor KIF2A expression was related to larger tumor size (p = 0.014), higher N stage (p = 0.004) and TNM stage (p = 0.011); however, it was not linked with other clinicopathological features (all p > 0.05). Signally, tumor KIF2A high expression predicted poor overall survival (p = 0.037). After adjustment via multivariate Cox's regression, tumor KIF2A high expression independently linked with worse disease-free survival (p = 0.033). Finally, KIF2A knockdown improved the oxaliplatin chemosensitivity vastly but only slightly affected capecitabine chemosensitivity in HGC-27 and NCI-N87 cells., Conclusion: Kinesin family member 2A reflects larger tumor size, advanced TNM stage, improved chemosensitivity, and predicts unfavorable survival in GC., (© 2022 The Authors. Journal of Clinical Laboratory Analysis published by Wiley Periodicals LLC.)

Gastric adenocarcinoma of the fundic gland type (GAFG) has been recently classified by the World Health Organization (WHO), however, clinicopathologic features of pepsinogen I- or H+/K+-ATPase-positive gastric tumors remain unclear. Therefore, this study evaluates the frequency and clinicopathologic features of those tumors, using a tissue microarray block to identify pepsinogen I- or H+/K+-ATPase-positive tumors from 810 endoscopically resected, early gastric epithelial tumors. The frequency of pepsinogen I-positive lesions was 2.1%, and that of H+/K+-ATPase-positive lesions was 2.0%. Pepsinogen I- or H+/K+-ATPase positivity was not observed in undifferentiated-type tumors, while gastric tumors with morphologic similarity to fundic glands were positive for pepsinogen I- or H+/K+-ATPase. We divided pepsinogen I- or H+/K+-ATPase-positive gastric tumors into group A, with fundic gland-like structure, or group B, without fundic gland-like structure. The frequency of group A was 1.6%: 46.2% were positive only for pepsinogen I and 53.8% for H+/K+-ATPase and pepsinogen I. The frequency of group B was 1.5%: 25% were positive only for pepsinogen I, 8.3% for H+/K+-ATPase and pepsinogen I, and 66.7% only for H+/K+-ATPase. The 2 tumor groups differed in location and endoscopic features. Hematoxylin and eosin staining showed that group B had more exposed tumors to the surface, larger nuclei, and more background atrophy than group A. Immunostaining showed significantly higher positivity rates for MUC5AC, CD10, CDX2, and p53 expression, and a higher Ki-67 labeling score. Our results provide novel insights into the pathology of early gastric tumors with histologic or immunohistochemical evidence of fundic gland differentiation., Competing Interests: Conflicts of Interest and Source of Funding: J.H. received a grant from Toranomon Hospital. N.I. and S.H. received a grant from Okinaka Memorial Institute of Medical Research. For the remaining authors none were declared., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

The oncogenic role of β -1,3-N-acetylglucosaminyltransferase 3 (B3GNT3) in several cancers is well documented. However, the expression, function, and mechanism of B3GNT3 in gastric cancer (GC) remain to be investigated. Here, we extracted RNA using the nanomagnetic bead method and investigated B3GNT3 expression in GC and its mechanism for promoting malignant progression of GC using bioinformatics, quantitative reverse transcription-polymerase chain reaction (qPCR), and western blot (WB). The results showed that the upregulation of B3GNT3 expression was positively related to original T phase, lymph node metastasis, and TNM stage but negatively related to GC prognosis. Meanwhile, the knockdown of the B3GNT3 gene significantly suppressed the growth and infiltration of GC cells. In addition, B3GNT3 promoted the malignant progression of GC cells by upregulating EphA2 transcription and subsequently activating the PI3K/AKT pathway. This work reveals for the first time the upregulation and protumor role of B3GNT3 in GC and highlights the potential clinical applications of B3GNT3/EphA2/AKT signaling in GC diagnosis, treatment, and prognosis prediction.

The mTOR complex 1 (mTORC1) is an essential metabolic hub that coordinates cellular metabolism with the availability of nutrients, including amino acids. Sestrin2 has been identified as a cytosolic leucine sensor that transmits leucine status signals to mTORC1. In this study, we identify an E3 ubiquitin ligase RING finger protein 167 (RNF167) and a deubiquitinase STAMBPL1 that function in concert to control the polyubiquitination level of Sestrin2 in response to leucine availability. Ubiquitination of Sestrin2 promotes its interaction with GATOR2 and inhibits mTORC1 signaling. Bioinformatic analysis reveals decreased RNF167 expression and increased STAMBPL1 expression in gastric and colorectal tumors. Knockout of STAMBPL1 or correction of the heterozygous STAMBPL1 mutation in a human colon cancer cell line suppresses xenograft tumor growth. Lastly, a cell-permeable peptide that blocks the STAMBPL1-Sestrin2 interaction inhibits mTORC1 and provides a potential option for cancer therapy., Competing Interests: Declaration of interests Y.L., D.W., C.X., W.Y., and Y.G. are named inventors of pending patent applications (202110704816.2 to the Chinese Patent Office) related to the work. The authors declare no competing interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Ubiquitin-specific protease 1 (USP1) has been documented to involved in the occurrence and development of different kinds of malignancies, containing breast cancer, glioma and prostatic cancer. However, the role of USP1 in gastric cancer (GC) is still obscure. In method, gene expression profiling interactive analysis and Kaplan-Meier Plotter databases were applied to analyze the prognostic value of USP1 in human cancers. The expression of USP1 was evaluated by quantitative reverse transcription polymerase chain reaction assay and western blotting. Cell proliferation, migration, and invasion abilities were detected to determin the role of USP1 in the tumorigenesis of GC. As a result, USP1 was upregulated in GC samples relative to its paired normal samples. USP1 was a valuable diagnostic marker for GC, and its overexpression indicated the poor overall survival time of patients with GC. More importantly, USP1 levels were increased in GC cells and its silencing restrained the proliferation, migration, invasion and epithelial-to-mesenchymal transition (EMT) of GC cells. In Conclusion, USP1 was upregulated in GC, and might be a valuable diagnostic and prognostic marker for GC. Moreover, USP1 silencing hindered the proliferation, migration, invasion, and EMT of GC cells, revealing the oncogenic role of USP1 in GC progression., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Circular RNA (circRNA) has been shown to be closely associated with cancer progression, including gastric cancer (GC). However, the function of circ&#95;0004104 in GC progression has not been clarified., Aims: The purpose of this study was to explore the role of circ&#95;0004104 in GC progression., Methods: The expression levels of circ&#95;0004104, miR-539-3p, and ring finger protein 2 (RNF2) were assessed using quantitative real-time polymerase chain reaction. Cell proliferation was measured by 3-(4,5-dimethyl-2 thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide assay, and cell migration and invasion were detected using transwell assay. The levels of glutamine, glutamate, and α-ketoglutarate were determined to evaluate the glutaminolysis of cells, and the protein levels of glutaminolysis-related markers and RNF2 were detected using western blot analysis. Furthermore, Dual-Luciferase Reporter Assay was employed to assess the interaction between miR-539-3p and circ&#95;0004104 or RNF2. Animal experiments were carried out to evaluate the effect of circ&#95;0004104 silencing on GC tumor growth in vivo., Results: Circ&#95;0004104 was upregulated in GC, and its knockdown repressed the proliferation, metastasis, and glutaminolysis of GC cells in vitro and reduced GC tumor growth in vivo. Furthermore, we discovered that circ&#95;0004104 could sponge miR-539-3p and miR-539-3p could target RNF2. The rescue experiments suggested that miR-539-3p inhibitor could reverse the suppressive effect of circ&#95;0004104 silencing on GC progression, and RNF2 overexpression also reversed the inhibition effect of miR-539-3p mimic on GC progression., Conclusion: Circ&#95;0004104 accelerated GC progression via regulating the miR-539-3p/RNF2 axis, indicating that circ&#95;0004104 might be a potential therapeutic target for GC., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature.)

Background & Aims: Metaplasia and dysplasia in the corpus are reportedly derived from de-differentiation of chief cells. However, the cellular origin of metaplasia and cancer remained uncertain. Therefore, we investigated whether pepsinogen C (PGC) transcript-expressing cells represent the cellular origin of metaplasia and cancer using a novel Pgc-specific CreERT2 recombinase mouse model., Methods: We generated a Pgc-mCherry-IRES-CreERT2 (Pgc-CreERT2) knock-in mouse model. Pgc-CreERT2/ + and Rosa-EYFP mice were crossed to generate Pgc-CreERT2/Rosa-EYFP (Pgc-CreERT2/YFP) mice. Gastric tissues were collected, followed by lineage-tracing experiments and histologic and immunofluorescence staining. We further established Pgc-CreERT2;Kras G12D/+ mice and investigated whether PGC transcript-expressing cells are responsible for the precancerous state in gastric glands. To investigate cancer development from PGC transcript-expressing cells with activated Kras, inactivated Apc, and Trp53 signaling pathways, we crossed Pgc-CreERT2/ + mice with conditional Kras G12D , Apc flox , Trp53 flox mice., Results: Expectedly, mCherry mainly labeled chief cells in the Pgc-CreERT2 mice. However, mCherry was also detected throughout the neck cell and isthmal stem/progenitor regions, albeit at lower levels. In the Pgc-CreERT2;Kras G12D/+ mice, PGC transcript-expressing cells with Kras G12D/+ mutation presented pseudopyloric metaplasia. The early induction of proliferation at the isthmus may reflect the ability of isthmal progenitors to react rapidly to Pgc-driven Kras G12D/+ oncogenic mutation. Furthermore, Pgc-CreERT2;Kras G12D/+ ;Apc flox/flox mice presented intramucosal dysplasia/carcinoma and Pgc-CreERT2;Kras G12D/+ ;Apc flox/flox ;Trp53 flox/flox mice presented invasive and metastatic gastric carcinoma., Conclusions: The Pgc-CreERT2 knock-in mouse is an invaluable tool to study the effects of successive oncogenic activation in the mouse corpus. Time-course observations can be made regarding the responses of isthmal and chief cells to oncogenic insults. We can observe stomach-specific tumorigenesis from the beginning to metastatic development., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

To investigate the potential role of GXYLT2 (glucoside xylosyltransferase 2) in gastric cancer (GC), the TCGA (The Cancer Genome Atlas) database and Gene Expression Omnibus (GEO) dataset were used to evaluate GXYLT2 mRNA expression, and the standardized mean difference and diagnostic value were comprehensively assessed. Survival analysis and univariate/multivariate cox regression analysis were performed to evaluate the prognostic value of GXYLT2 in GC patients. The correlation between GXYLT2 and tumor immune cells was identified by using the CIBERSORT algorithm. The results showed that GXYLT2 expression level was significantly increased in GC tissues. GXYLT2 expression was significantly correlated with the grade, stage, and invasion depth of gastric cancer. Overall survival was reduced in the high GXYLT2 expression group. Univariate and multivariate Cox regression analyses showed that GXYLT2 was a reliable prognostic factor. GSEA showed that GXYLT2 might participate in the development of GC through tumor-related pathways. The expression of GXYLT2 was positively correlated with 5 tumor-infiltrating immune cells (resting dendritic cells, m2 macrophages, monocytes, active NK cells and resting mast cells), and was negatively correlated with 6 tumor-infiltrating immune cells (plasma cells, activated memory CD4 T cells, resting NK cells, activated dendritic cells, and activated neutrophils and mast cells). Through cell experiment verification, GXYLT2 expression level in gastric cancer cells was found to be high, which verified the results from the bioinformatics analysis. Furthermore, immunohistochemical staining results also showed that GC tissues had positive GXYLT2 expression. In summary, GXYLT2 might be a potential diagnostic and prognostic biomarker for gastric cancer.

The oncogenic signaling pathway Wnt is often activated in many cancers including gastric cancer. Wnt signaling pathway is considered as a potential target for developing new targeted therapeutics. Kinase inhibitors are the promising class of drugs for many diseases including cancers. Toward identifying the potent inhibitors targeting Wnt signaling pathway, a kinase inhibitor library with 82 inhibitors were screened using Wnt pathway reporter assay in gastric cancer cells. Notably, 34 kinase inhibitors were identified to inhibit Wnt mediated reporter activity to the extent of more than 50%. The corresponding kinase genes, which are known targets of these kinase inhibitors, were investigated for their expression in the available mRNA profiles of gastric tumors. A major group of the kinase genes showed higher expression in intestinal subtype gastric tumors. Another group of kinase genes were found expressed in diffuse type gastric tumors. The kinase genes expressed in intestinal type gastric tumors were found associated with varying survival of gastric cancer patients whereas those expressed in diffuse type tumors were found associated with the poor survival. Thus, the kinase genes specifically expressed in intestinal and diffuse type gastric tumors and the kinase inhibitors to target Wnt signaling pathway in gastric cancer subtypes have been identified., (© 2021 Wiley Periodicals LLC.)

Background: Exosome-mediated transfer of circular RNAs (circRNAs) is related to gastric cancer (GC) development. CircRNA NIMA-related kinase 9 (circNEK9; hsa&#95;circ&#95;0032683) was reported to be up-regulated in GC., Aims: The biological role of circNEK9 and its underlying mechanisms in GC progression were explored., Methods: The levels of RNAs and proteins were determined by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot assay. Cell proliferation was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, colony formation assay, and flow cytometry. Wound healing assay and transwell assays were conducted to analyze cell motility. Intermolecular interaction was verified by dual-luciferase reporter assay and RNA pull-down assay. Animal experiments were used to evaluate the role of circNEK9 in the growth of xenograft tumors in vivo., Results: CircNEK9 was up-regulated in GC tissues and cell lines. CircNEK9 interference suppressed the proliferation and motility of GC cells. CircNEK9 silencing enhanced microRNA-409-3p (miR-409-3p) level through direct interaction. CircNEK9 silencing-mediated influences on the proliferation and metastasis of GC cells were partly overturned by the interference of miR-409-3p. MiR-409-3p directly interacted with microtubule-associated protein 7 (MAP7) messenger RNA (mRNA). MiR-409-3p-induced effects in GC cells were largely counteracted by the overexpression of MAP7. CircNEK9 silencing blocked GC tumor growth in vivo. Exosome-mediated transfer of circNEK9 promoted the motility of recipient GC cells., Conclusions: CircNEK9 accelerated the proliferation, migration, and invasion of GC cells through targeting miR-409-3p/MAP7 axis. Plasma exosomal circNEK9 promoted the migration and invasion of recipient GC cells., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature.)

Gastric cancer (GC) is one of the most common and lethal cancers worldwide. The Nudix hydroxylase (NUDT) genes have been reported to play notable roles in tumor progression. However, the role of NUDT10 in GC has not been reported. In this study, we investigated the expression of NUDT10 in GC and its association with clinicopathological characteristics. Quantitative real-time polymerase chain reaction and analyses of The Cancer Genome Atlas and Human Protein Atlas databases were performed to determine NUDT10 mRNA and protein expression. Receiver operating characteristic curve analysis was used to assess the diagnostic value of NUDT10 in patients with GC. We used Cox regression and the Kaplan-Meier method to assess the correlations between clinicopathological factors and survival outcomes of patients with GC. Gene set enrichment analysis (GSEA) was performed to identify the underlying signaling pathways. NUDT10 mRNA and protein expression was significantly lower in GC tissues compared to normal tissues. Interestingly, higher NUDT10 expression was correlated with advanced tumor stage, deeper local invasion, and worse survival outcomes. Patients with higher NUDT10 expression had a significantly worse prognosis than those with lower NUDT10 expression. Multivariate analysis showed that high NUDT10 expression was an independent predictor of survival outcome. Several pathways, including mismatch repair, nucleotide excision repair, extracellular matrix receptor interaction, and cancer signaling, were identified as enriched pathways in GC through GSEA. To our knowledge, this study is the first to characterize NUDT10 expression in GC. Our study demonstrates that NUDT10 is a promising independent biomarker for GC prognosis.

Background: CircRNAs are a new subset of noncoding RNAs formed by covalent closed loops and play crucial roles in the regulation of cancer gene expression. However, the roles and underlying mechanisms of circRNAs in gastric cancer (GC) remain indistinct. This study aimed to explore the role and mechanism of hsa&#95;circ&#95;0006421 (circPTK2) in GC., Methods: The differential expression of circRNAs between GC tissues and adjacent normal tissues were identified by a circRNA expression profiling. Associations of circPTK2 or miR-134-5p expression with clinicopathological characteristics and prognosis of GC patients were analyzed by chi-square of Fisher's exact tests and Kaplan-Meier analysis. CCK8, colony formation, EdU assays and animal models were performed to assess the effects of circPTK2 on proliferation and invasion of GC cells. CircPTK2-specific probes were used to purify the RNA pulled down from the circPTK2, and enrichment of circPTK2 and miR-134-5p was detected by qRT-PCR. The effects of circPTK2 on miR-134-5p expression and CELF2/PTEN signaling were examined by qRT-PCR and Western blotting analysis., Results: Low expression of circPTK2 and high expression of miR-134-5p were related to the poor survival, and high expression of miR-134-5p was related to the tumor recurrence in GC patients. Overexpressing circPTK2 suppressed the proliferation, colony formation, DNA synthesis and cell invasion as well as xenograft tumor growth and lung metastasis in vitro and in vivo, whereas silencing circPTK2 had the opposite effects. Moreover, circPTK2 was negatively correlated and co-localized with miR-134-5p in the cytoplasm of GC tissue cells. circPTK2 bound to and sponged miR-134-5p in GC cells, and miR-134-5p facilitated cell growth and invasion but attenuated circPTK2 induced tumor suppressive effects and CELF2/PTEN signaling activation in GC cells., Conclusions: circPTK2 functions as a tumor suppressor in GC by sponging miR-134-5p and activating the CELF2/PTEN axis., (Copyright © 2021 Elsevier GmbH. All rights reserved.)

Gastric cancer is one of the most common and deadly types of cancer in the world, and poor prognosis with treatment failure is widely reported in the literature. In this context, kinases have been considered a relevant choice for targeted therapy in gastric cancer. Here, we explore the antiproliferative and antimigratory effects of the AURKA inhibitor and the prognostic and therapeutic value as a biomarker of gastric cancer. A total of 145 kinase inhibitors were screened to evaluate the cytotoxic or cytostatic effects in the gastric cancer cell line. Using the Alamar Blue assay, flow cytometry, quantitative polymerase chain reaction, and observation of caspase 3/7 activity and cell migration, we investigated the antiproliferative, proapoptotic, and antimigratory effects of the AURKA inhibitor. Moreover, AURKA overexpression was evaluated in the gastric cell lines and the gastric tumor tissue. Out of the 145 inhibitors, two presented the highest antiproliferative effect. Both molecules can induce apoptosis by the caspases 3/7 pathway in addition to inhibiting cancer cell migration, mainly the AURKA inhibitor. Moreover, molecular docking analysis revealed that GW779439X interacts in the active site of the AURKA enzyme with similar energy as a well-described inhibitor. Our study identified AURKA overexpression in the gastric cancer cell line and gastric tumor tissue, revealing that its overexpression in patients with cancer is correlated with low survival. Therefore, it is feasible to suggest AURKA as a potential marker of gastric cancer, besides providing robust information for diagnosis and estimated survival of patients. AURKA can be considered a new molecular target used in the prognosis and therapy of gastric cancer., (© 2021 Wiley Periodicals LLC.)

The primary cause of gastric cancer is chronic infection with Helicobacter pylori (H. pylori), particularly the high-risk genotype cagA, and risk modification by human genetic variants. We studied 94 variants in 54 genes for association with gastric cancer, including rs2302615 in ornithine decarboxylase (ODC1), which may affect response to chemoprevention with the ODC inhibitor, eflornithine (difluoromethylornithine; DFMO). Our population-based, case-control study included 1366 individuals (664 gastric cancer cases and 702 controls) from Western Honduras, a high incidence region of Latin America. CagA seropositivity was strongly associated with cancer (OR = 3.6; 95% CI: 2.6, 5.1). The ODC1 variant rs2302615 was associated with gastric cancer (OR = 1.36; p = 0.018) in a model adjusted for age, sex, and CagA serostatus. Two additional single nucleotide polymorphisms (SNPs) in CASP1 (rs530537) and TLR4 (rs1927914) genes were also associated with gastric cancer in univariate models as well as models adjusted for age, sex, and CagA serostatus. The ODC1 SNP association with gastric cancer was stronger in individuals who carried the TT genotype at the associating TLR4 polymorphism, rs1927914 (OR = 1.77; p = 1.85 × 10 -3 ). In conclusion, the ODC1 variant, rs2302615, is associated with gastric cancer and supports chemoprevention trials with DFMO, particularly in individuals homozygous for the T allele at rs1927914., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Heparanase is highly implicated in tumor metastasis due to its capacity to cleave heparan sulfate and, consequently, remodel the extracellular matrix underlying epithelial and endothelial cells. In striking contrast, only little attention was given to its close homolog, heparanase 2 (Hpa2), possibly because it lacks heparan sulfate-degrading activity typical of heparanase. We subjected sections of gastric carcinoma to immunostaining and correlated Hpa2 immunoreactivity with clinical records, including tumor grade, stage and patients' status. We over-expressed Hpa2 in gastric carcinoma cell lines and examined their tumorigenic properties in vitro and in vivo. We also evaluated the expression of Hpa2 by gastric carcinoma cells following inhibition of the proteasome, leading to proteotoxic stress, and the resulting signaling responsible for Hpa2 gene regulation. Here, we report that gastric cancer patients exhibiting high levels of Hpa2 survive longer. Similarly, mice administrated with gastric carcinoma cells engineered to over-express Hpa2 produced smaller tumors and survived longer than mice administrated with control cells. This was associated with increased phosphorylation of AMP-activated protein kinase (AMPK), a kinase that is situated at the center of a tumor suppressor network. We also found that MG132, an inhibitor of the proteasome that results in proteotoxic stress, prominently enhances Hpa2 expression. Notably, Hpa2 induction by MG132 appeared to be mediated by AMPK, and AMPK was found to induce the expression of Hpa2, thus establishing a loop that feeds itself where Hpa2 enhances AMPK phosphorylation that, in turn, induces Hpa2 expression, leading to attenuation of gastric tumorigenesis. These results indicate that high levels of Hpa2 in some tumors are due to stress conditions that tumors often experience due to their high rates of cell proliferation and high metabolic demands. This increase in Hpa2 levels by the stressed tumors appears critically important for patient outcomes., (Copyright © 2021. Published by Elsevier Inc.)

Introduction: Despite multimodality treatment for curatively-treated gastroesophageal adenocarcinoma (GEA), prognosis remains dismal. The benefit of adding trastuzumab to chemotherapy for advanced Human Epidermal Growth Factor 2 (HER2) positive GEA has been established in the ToGA trial. However, it remains unclear if HER2 inhibition might also be beneficial in the curative setting. Therefore, we conducted a systematic review to investigate the role of HER2 inhibitors for the curative treatment of GEA., Methods: A systematic literature search was performed in PubMed, EMBASE, CENTRAL, and clinicaltrials.gov to identify clinical trials investigating HER2 inhibition for the curative treatment of GEA. Study quality was assessed using the GRADE methodology., Results: From the 1825 studies retrieved, 17 were included (seven published articles; three published conference abstracts; seven ongoing studies). From the published studies, eight studies investigated single-agent HER2 inhibition. Four studies had a nonrandomized design, and two were randomized controlled trials. Two published studies were assessed as high-quality. The addition of single-agent HER2 inhibition to chemo(radio)therapy showed a pathological complete response rate (pCR) of 22.2% (range, 9.6-25%) and dual HER2 inhibition of 34.5% (34-35%). Two-year disease-free survival (DFS) was 51.0% (40-71%) with single-agent and 70.0% (70-70%) with dual HER2 therapy., Discussion: Dual-agent HER2 inhibition showed promising pCR rates and DFS. Given the limited additional toxicity of the addition of HER2 targeting agents and the potential benefit of dual-targeting, further investigation is required in a phase III randomized clinical trial. Next steps include combining checkpoint inhibitors and HER2 blockade given the suggested synergism, as well as investigating new anti-HER2 agents., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Glycosylation is a common posttranslational modification of proteins, which plays a role in the malignant transformation, growth, progression, chemoresistance, and immune response of tumors. Disulfide isomerase family A3 (PDIA3) specifically acts on newly synthesized glycoproteins to promote the correct folding of sugar chains. Studies have shown that PDIA3 participates in multidrug-resistant gastric cancer (MDR-GC). In this study, we performed western blot analysis and immunohistochemistry to identify PDIA3 expression. Cell proliferation was assessed by CCK-8 assay. Transwell assays were used to detect the migration and invasion abilities of cells. Immunoprecipitation coupled to mass spectrometry (IP-MS) analysis was employed to identify PDIA3-interacting proteins and the associated pathways in MDR-GC cells. Glycoprotein interactions and translocation were detected by immunofluorescence assay. The results showed that PDIA3 knockdown significantly inhibited the proliferation, invasion, and migration abilities of MDR-GC cells. Kyoto Encyclopedia of Genes and Genomes analysis of the IP-MS results showed that PDIA3 was closely associated with focal adhesion pathways in MDR-GC cells. Additionally, important components of focal adhesion pathways, including fibronectin-1 (FN1) and integrin α5 (ITGA5), were identified as pivotal PDIA3-binding glycoproteins. Knockdown of PDIA3 altered the cellular locations of FN1 and ITGA5, leading to abnormal accumulation. In conclusion, our results suggest that knockdown of PDIA3 inhibited the malignant behaviors of MDR-GC cells and influenced the translocation of FN1 and ITGA5., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Gastric carcinoma has serious morbidity and mortality, which seriously threats human health. The studies on gastrointestinal cell biology have shown that the ubiquitination modification that occurs after protein translation plays an essential role in the pathogenesis of gastric carcinoma. Protein ubiquitination is catalyzed by E3 ubiquitin ligase and can regulate various substrate proteins in different cellular pathways. Cullin-RING E3 ligase (CRLs) is a representative of the E3 ubiquitin ligase family, which requires cullin (CUL) neddylation modification for activation to regulate homeostasis of ~20% of cellular proteins. The substrate molecules regulated by CRLs are often involved in many cell progressions such as cell cycle progression, cell apoptosis, DNA damage and repair. Given that CRLs play an important role in modulation of biological activities, so targeting a certain CULs member neddylation may be an attractive strategy for selectively controlling the cellular proteins levels to achieve the goal of cancer treatment. In this review, we will discuss the roles of CULs and Ring protein in gastric carcinoma and summarize the current neddylation modulators for gastric carcinoma treatment., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Molecular targeted therapy of cancer has always been the focus of clinicians. Among those therapeutic targets, the human epidermal growth factor receptor-2 (HER-2) signaling pathway is one of the most popular targets for translational research in cancer. However, unlike prospect in breast cancer, HER-2 inhibitor trastuzumab is the only molecular targeted drug approved by US Food and Drug Administration (FDA) for the first-line treatment of HER-2 positive advanced gastric cancer. On this basis, a variety of novel HER2- targeted drugs for gastric cancer are under development, and related clinical researches are in full swing, including small molecular kinase inhibitors (e.g., afatinib, neratinib, pyrotinib), antibody-drug conjugates (e.g., DS-8201a, RC48-ADC) and other novel therapies (e.g., ZW25, CAR-T, BVAC-B). In this study, we will summarize the recent advances in anti-HER-2 agents, potential mechanisms of resistance to HER2-targeted therapy in HER2-positive gastric cancer. We will also discuss the future prospects of potential strategies to overcome anti-HER-2 resistance and development of novel anti-HER-2 approaches for the treatment of HER2-positive gastric cancer patients., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Ubiquitination, a crucial post-translational modification, controls substrate degradation and can be reversed by deubiquitinases (DUBs). An increasing number of studies are showing that DUBs regulate the malignant behavior and chemotherapy resistance of gastric cancer (GC) by stabilizing various proteins. However, the expression level and biological function of the DUB, proteasome 26S subunit, non-ATPase 7 (PSMD7), in GC remains unknown. Herein, we report for the first time that PSMD7 is frequently overexpressed in GC tissues. Elevated levels of PSMD7 were also detected in GC cell lines. Notably, the upregulation of PSMD7 closely correlated with malignant clinical parameters and reduced the survival of GC patients. Functionally, we found that PSMD7 knockdown consistently suppressed the proliferation, migration, and invasion of AGS and SGC-7901 cells. Ectopic expression of PSMD7 facilitated GC cell proliferation and mobility. Based on protein-protein interaction prediction, RAD23 homolog B (RAD23B) protein was identified as a candidate substrate of PSMD7. PSMD7 positively regulated the abundance of RAD23B and xeroderma pigmentosum, complementation group C (XPC) protein in GC cells. The interaction between PSMD7 and RAD23B was confirmed using protein immunoprecipitation. PSMD7 knockdown enhanced the ubiquitination and degradation of RAD23B protein in GC cells. PSMD7 promoted cell viability, apoptosis resistance, and DNA damage repair in GC cells upon cisplatin (DDP) treatment. Moreover, PSMD7 silencing inhibited tumor growth and enhanced the sensitivity of GC cells to DDP treatment in mice. In summary, PSMD7 was highly expressed in GC and contributed to the malignant behavior and DDP resistance of tumor cells by stabilizing RAD23B., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Immune-checkpoint inhibitors (ICIs) play a key role in the treatment of advanced stage colorectal cancer (CRC) patients featuring a deficient DNA mismatch repair (dMMR) system or a high microsatellite instability (MSI-H) profile. However, beyond the established role in CRC patients, ICIs have highly proven efficacy in other solid tumors featuring MSI-H/dMMR status represented by endometrial, gastric, ovarian, prostatic, and pancreatic carcinomas (EC, GC, OC, PrC, and PaC). Our aim was to compare the concordance rates among the Idylla™ MSI test, TapeStation 4200, and immunohistochemical (IHC) analysis in assessing MSI-H/dMMR status in EC, GC, OC, PrC, and PaC patients. The Sanger sequencing-based Titano MSI test was used in discordant cases. One hundred and eighty-five cases ( n = 40 PrC, n = 39 GC, n = 38 OC, n = 35 PaC, and n = 33 EC) were retrospectively selected. MMR protein expression was evaluated by IHC. After DNA quality and quantity evaluations, the Idylla TM and TapeStation 4200 platforms were adopted for the evaluation of MSI status. Remarkably, compared to IHC, the Idylla™ platform achieved a global concordance rate of 94.5% (154/163) for the microsatellite stable (MSS)/proficient MMR (pMMR) cases and 77.3% (17/22) for the MSI-H/dMMR cases. Similarly, a global concordance rate of 91.4% (149/163) and 68.2% (15/22) for MSS/pMMR and MSI-H/dMMR cases was also identified between IHC and the TapeStation 4200 microfluidic system. In addition, a global concordance of 93.1% (148/159) and 69.2% (18/26) for MSS/pMMR and MSI-H/dMMR cases was observed between the Idylla™ and TapeStation 4200 platforms. Discordant cases were analyzed using the Titano MSI kit. Overall, our data pinpointed a central role for molecular techniques in the diagnostic evaluation of dMMR/MSI-H status not only in CRC patients but also in other types of solid tumors.

As the endogenous ligand for the GH secretagogue receptor (GHSR), Ghrelin is aberrant expressed in multiple malignant carcinoma, and involved in regulating a number of progression of cancer, especially in metastasis and proliferation. However, the precise role of Ghrelin in tumorigenesis of gastric cancer (GC) is still poorly understood. In this study, we extensively investigated the roles and mechanisms of Ghrelin in human gastric cancer. Ghrelin levels in cancer tissues and cell lines were analyzed by immunohistochemistry, qRT-PCR, and Western blot. Functional studies were performed after Ghrelin overexpressed or knockdown in AGS cell line. Cell proliferation was evaluated in by MTT and clone formation assays. The wound healing and Transwell system were used to assess the cell migration and invasive ability of GC cells. Cell apoptosis was detected by flow cytometry, and metabolic assays were performed to reveal the function of Warburg effect in the process. Ghrelin was lowly expressed in gastric cancer tissues and cell lines. Overexpression of Ghrelin inhibited gastric cancer cell proliferation, migration, invasion, and promoted apoptosis by activating the AMPK pathway, while D-[lys3]-GHRP-6 (a GHSR agonist) treatment relieved the effect, promoting tumorigenesis. Ghrelin knockdown increased the glucose uptake and lactic acid release, suggesting that Ghrelin elicited an anti-Warburg effect via AMPK pathway to inhibit gastric tumorigenesis. Ghrelin inhibits cell proliferation, migration, and invasion by eliciting an anti-Warburg effect via AMPK signaling pathway in gastric cancer cells.

Asparagine endopeptidase (AEP), also called legumain, is currently the only known cysteine protease that specifically cleaves peptide bonds in asparaginyl residue in the mammalian genome. Since 2003, AEP has been reported to be widely expressed in a variety of carcinomas and is considered a potential therapeutic target. In the following years, researchers intensively investigated the substrates of AEP and the mechanism of AEP in partial tumors. With the identification of substrate proteins such as P53, integrin αvβ3, MMP-2, and MMP-9, the biochemical mechanism of AEP in carcinomas is also more precise. This review will clarify the probable mechanisms of AEP in the progression of breast carcinoma, glioblastoma, gastric carcinoma, and epithelial ovarian carcinoma. This review will also discuss the feasibility of targeted therapy with AEP inhibitor (AEPI) in these carcinomas.

Genetic and epigenetic alterations have been under concentrated investigations for many years in order to unearth the molecules regulating human cancer pathogenesis. However, the identification of a wide range of dysregulated genes and their protein products has raised a question regarding how the results of this large collection of alterations could converge into a formation of one malignancy. The answer may be found in the signaling cascades that regulate the survival and metabolism of the cells. Aberrancies of each participant molecule of such cascades may well result in augmented viability and unlimited proliferation of cancer cells. Among various signaling pathways, the phosphatidylinositol-3-kinase (PI3K) axis has been shown to be activated in about one-third of human cancers. One of the malignancies that is mostly affected by this axis is gastric cancer (GC), one of the most fatal cancers worldwide. In the present review, we aimed to illustrate the significance of the PI3K/Akt/mTOR axis in the pathogenesis of GC and also provided a wide perspective about the application of the inhibitors of this axis in the therapeutic strategies of this malignancy., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Disintegrin and metalloproteinase 28 (ADAM28) is a member of the disintegrin and metalloprotease domain (ADAM) family. It is associated with the growth and metastasis of various malignancies in vivo, but its role in gastric cancer remains unclear. The purpose of this study was to investigate the effect of ADAM28 derived from gastric cancer and endothelium on gastric cancer cells and its related mechanisms. In this study, Western blot analysis and q-PCR results showed that ADAM28 was up-regulated in gastric cancer cell lines. The TCGA database showed that patients with high ADAM28 expression had significantly shorter overall survival than those with low ADAM28 expression. By MTT analysis, wound healing assay, and flow cytometry, we found that overexpression/knockdown of ADAM28 expression in gastric cancer cells can regulate cell proliferation, apoptosis and migration in vitro. In addition, overexpression/knockdown of ADAM28 in human umbilical vein endothelial cells (HUVECs) in the upper ventricle can regulate the apoptosis of lower ventricular gastric cancer cells in the co-culture system. Furthermore, ELISA demonstrated that knockdown of ADAM28 from endothelial cells increased the expression of von Willebrand Factor (vWF) in the supernatant. We found that ADAM28 both from gastric cancer cells and HUVECs eliminated vWF-induced apoptosis of gastric cancer cells by cleaving vWF, and the addition of the vWF knockdown plasmid eliminated the increase of integrin β3, p-TP53 and c-Casp3 caused by ADAM28 knockdown. In conclusion, ADAM28 from endothelium and gastric cancer may cleave vWF to eliminate vWF-induced apoptosis of gastric cancer cells and play an pro-metastasis effect., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Extrapulmonary neuroendocrine carcinoma (EPNEC) is a lethal disease with a poor prognosis. Platinum-based chemotherapy is used as the standard first-line treatment for unresectable EPNEC. Several retrospective studies have reported the results of the utilization of temozolomide (TMZ) as a drug for the second-line treatment for EPNEC. Patients with unresectable EPNEC that were resistant to platinum-based combination chemotherapy were recruited for a prospective phase II study of TMZ monotherapy. A 200 mg/m 2 dose of TMZ was given from day 1 to day 5, every 4 weeks. Response rate (RR) was evaluated as the primary end-point. The presence of O 6 -methylguanine DNA methyltransferase (MGMT) in EPNEC patients was also evaluated as exploratory research. Thirteen patients were enrolled in this study. Primary lesions were pancreas (n = 3), stomach (n = 3), duodenum (n = 1), colon (n = 1), gallbladder (n = 1), liver (n = 1), uterus (n = 1), bladder (n = 1), and primary unknown (n = 1). Each case was defined as pathological poorly differentiated neuroendocrine carcinoma from surgically resected and/or biopsied specimens. The median Ki-67 labeling index was 60% (range, 22%-90%). The RR was 15.4%, progression-free survival was 1.8 months (95% confidence interval [CI], 1.0-2.7), overall survival (OS) was 7.8 months (95% CI, 6.0-9.5), and OS from first-line treatment was 19.2 months (95% CI, 15.1-23.3). No grade 3 or 4 hematological toxicity had occurred and there was one case of grade 3 nausea. One case presented MGMT deficiency and this case showed partial response. Temozolomide monotherapy is a feasible, modestly effective, and safe treatment for patients with unresectable EPNEC following platinum-based chemotherapy, especially those with MGMT deficiency., (© 2021 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Gastric cancer (GC), known for high morbidity and mortality, is poorly prognosed with traditional chemotherapy and biological agents. Current studies have found that over-activation of AKT is a common molecular characteristic in GC. Although the development of this targeted inhibitor has entered clinical phases, limited success is reported because of its compensatory signaling pathways. Here, we found that GC cell lines with high phosphorylation of AKT show different sensitivity to AKT inhibitors (AKTis), but a reduction of p-GSK3β related sensitivity of AKTis in GC cells. Besides, we revealed that Ceritinib exerted a strongly synergistic antitumor effect with AKT inhibitors both in vitro and in vivo. Obviously, Ceritinib improved the sensitivity of Capivasertib (AZD5363, AKTs) and Afuresertib (GSK2110183, AKTis) in gastric cancer cells, as illustrated by a significant reduction in the GC cell proliferation and enhanced apoptosis. The drug combination showed tumor regression in BALB/c (nu/nu) mouse MKN45 (Gastric cancer), tumor model. Also, the combination strategy indicated significantly low p-AKT levels due to AKTis compensation and reduced the levels of p-GSK3β in both GC cell lines and GC patient-derived cells. These findings may provide a novel combination strategy for gastric cancer treatment., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Gastric cancer (GC) is one of the most common malignant tumors in China and the third leading cause of cancer-related death. Parkin has been shown to be a tumor suppressor in a variety of malignancies, including GC. However, the mechanism of Parkin in GC remains unclear. In this study, the low expression of Parkin in GC cells and patient tumor tissues was observed, and Parkin inhibited proliferation and migration of GC cells. Additionally, doxorubicin (DOX) upregulated the expression of Parkin and promoted its anticancer effect. Forkhead box O3 (FOXO3a) is a crucial transcription factor that involves in the regulation of cancer cell proliferation, apoptosis, and metabolism. Here, we found that FOXO3a inhibits cell proliferation, migration, and promotes apoptosis in GC by regulating Parkin expression at the transcriptional level. In addition, Parkin inhibited cell proliferation, migration, and promoted apoptosis by inhibiting ATP-binding box protein E1 (ABCE1) expression. In summary, our results demonstrated a new regulatory axis of FOXO3a-Parkin-ABCE1 that modulated GC cell proliferation, migration, and apoptosis, and it can serve as a potential therapeutic target in GC., (© 2020 Wiley Periodicals LLC.)

Background/aim: Peroxiredoxin V (Prx V) plays crucial roles in cellular apoptosis and proliferation in various cancer cells by regulating the cellular reactive oxygen species (ROS) levels., Materials and Methods: Here, we examined the possible regulatory effects of Prx V on doxorubicin (DOX)-induced cellular apoptosis and its mechanisms in the human gastric adenocarcinoma cell line (AGS cells)., Results: Our findings suggest that Prx V knockdown may significantly increase the DOX-induced apoptosis by aggravating intracellular ROS accumulation. We also found that DOX-induced mitochondrial ROS levels and membrane permeability were significantly higher in short hairpin Prx V cells than in mock cells, and these phenomena were dramatically reversed by ROS scavenger treatment. Prx V knockdown also significantly upregulated the cleaved caspase 9, 3, and B-cell lymphoma 2 (Bcl2)-associated agonist of cell death/Bcl2 protein expression levels, suggesting that Prx V knockdown activates mitochondria-dependent apoptotic signaling pathways., Conclusion: Taken together, this study suggests that Prx V may be a strong molecular target for gastric cancer (GC) chemotherapy, and further elucidates the role of Prx V in oxidative stress-induced cell apoptosis., (Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Cholinesterase (CHE) is a routine serum biomarker in gastric cancer (GC). However, little research has been done on its clinical value in advanced GC. In addition, it is not clear whether it can be used as biomarker for the response and prognosis of advanced GC patients. Methods: Between Jan. 2013 and Dec. 2016, a total of 150 patients with advanced GC treated with first-line chemotherapy were admitted to Changzhou Tumor Hospital Affiliated to Soochow University. We retrospectively identified serum CHE level on the day before chemotherapy and at the end of chemotherapy and abstracted clinicopathologic features and treatment outcomes. Univariate and multivariate survival analyses were performed to assess the relationship between serum CHE levels and progression-free survival (PFS) and overall survival (OS). Results: A total of 150 advanced GC patients were included and divided into serum level ≥5,000 IU/L and serum level <5,000 IU/L. CHE level lower than 5,000 IU/L was associated with poorer PFS (HR, 1.60; 95% CI, 1.141-2.243; p = 0.006), poorer OS (HR, 1.76; 95% CI, 1.228-2.515; p = 0.002) and trend of poorer response (HR, 0.56; 95% CI, 0.272-1.129; p = 0.104). In univariate and multivariate logistic regression analysis, only liver metastasis and PS score were significantly associated with objective response ( p < 0.05). The medium PFS was 8.0 months in patients with post-treatment CHE increased vs. 3.8 months in patients with CHE decreased after chemotherapy (HR, 1.82; 95% CI 1.28-2.57; p = 0.0002). The medium OS was 13.1 months in patients with increased post-treatment CHE vs. 8.1 months in patients with decreased post-treatment CHE (HR, 1.87; 95% CI 1.29-2.71; p = 0.0002). Conclusion: Advanced GC with CHE levels below 5,000 IU/L was significantly associated with poor PFS and OS. The results suggested that CHE analysis before chemotherapy was a promising prognostic marker for advanced GC., Competing Interests: JZ is employees of Shanghai 3D Medicines Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Bi, Zhang, Zeng, Chen, Ye, Yang and Ling.)

Matrix metalloproteinases (MMPs), key molecules of cancer invasion and metastasis, degrade the extracellular matrix and cell-cell adhesion molecules. MMP-10 plays a crucial role in Helicobacter pylori -induced cell-invasion. The mitogen-activated protein kinase (MAPK) signaling pathway, which activates activator protein-1 (AP-1), is known to mediate MMP expression. Infection with H. pylori , a Gram-negative bacterium, is associated with gastric cancer development. A toxic factor induced by H. pylori infection is reactive oxygen species (ROS), which activate MAPK signaling in gastric epithelial cells. Peroxisome proliferator-activated receptor γ (PPAR-γ) mediates the expression of antioxidant enzymes including catalase. β-Carotene, a red-orange pigment, exerts antioxidant and anti-inflammatory properties. We aimed to investigate whether β-carotene inhibits H. pylori -induced MMP expression and cell invasion in gastric epithelial AGS (gastric adenocarcinoma) cells. We found that H. pylori induced MMP-10 expression and increased cell invasion via the activation of MAPKs and AP-1 in gastric epithelial cells. Specific inhibitors of MAPKs suppressed H. pylori -induced MMP-10 expression, suggesting that H. pylori induces MMP-10 expression through MAPKs. β-Carotene inhibited the H. pylori -induced activation of MAPKs and AP-1, expression of MMP-10, and cell invasion. Additionally, it promoted the expression of PPAR-γ and catalase, which reduced ROS levels in H. pylori -infected cells. In conclusion, β-carotene exerts an inhibitory effect on MAPK-mediated MMP-10 expression and cell invasion by increasing PPAR-γ-mediated catalase expression and reducing ROS levels in H. pylori -infected gastric epithelial cells.

Undifferentiated carcinoma of the esophagus and gastroesophageal junction is a recently recognized entity in the fifth edition of the World Health Organization Classification of Digestive Tumors and is diagnostically challenging, particularly on small biopsies. SMARCA4 and SMARCA2 are chromatin remodeling genes with key roles in oncogenesis. We retrieved 14 cases of SMARCA4/SMARCA2-deficient undifferentiated carcinoma of the gastroesophageal junction and esophagus from the authors' institutions. The tumors showed similar histologic findings: the sheet-like proliferation of tumor cells characterized by discohesion, large nuclei, and prominent macronucleoli with many tumor cells exhibiting a rhabdoid appearance. In 8 cases, adjacent specialized intestinal metaplasia was noted and 3 cases exhibited adjacent high-grade dysplasia. Immunohistochemically, tumors variably expressed keratins and disclosed loss of expression of SMARCA4 in 12 and SMARCA2 in 7 cases. In 2 cases SMARCA2 alone was lost without SMARCA4 loss. A mutant p53 immunohistochemical pattern was seen in 4 of 4 cases, 3 of which showed diffuse, strong nuclear expression, and 1 case displayed a complete loss of nuclear expression of p53, including invasive carcinoma and associated dysplasia, when present. Limited clinical follow-up was available, but 3 patients died of disease within 0.6, 2, and 7 months of diagnosis. We present the first series of undifferentiated carcinoma of the esophagus and gastroesophageal junction with this characteristic morphology associated with loss of SMARCA4 and/or SMARCA2 expression. This tumor type likely arises from dedifferentiation of a lower grade carcinoma in some cases, and Barrett esophagus and appears to be associated with an aggressive clinical course., Competing Interests: Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Although a certain proportion of intramucosal carcinomas (IMCs) of the stomach does metastasize, the majority of patients are currently treated with endoscopic resection without lymph node dissection, and this potentially veils any existing metastasis and may put some patients in danger. In this regard, biological markers from the resected IMC that can predict metastasis are warranted. Here, we discovered unique miRNA expression profiles that consist of 21 distinct miRNAs that are specifically upregulated (miR-628-5p, miR-1587, miR-3175, miR-3620-5p, miR-4459, miR-4505, miR-4507, miR-4720-5p, miR-4742-5p, and miR-6779-5p) or downregulated (miR-106b-3p, miR-125a-5p, miR-151b, miR-181d-5p, miR-486-5p, miR-500a-3p, miR-502-3p, miR-1231, miR-3609, and miR-6831-5p) in metastatic (M)-IMC compared to nonmetastatic (N)-IMC, or nonneoplastic gastric mucosa. Intriguingly, most of these selected miRNAs showed stepwise increased or decreased expression from nonneoplastic tissue to N-IMC to M-IMC. This suggests that common oncogenic mechanisms are gradually intensified during the metastatic process. Using a machine-learning algorithm, we demonstrated that such miRNA signatures could distinguish M-IMC from N-IMC. Gene ontology and pathway analysis revealed that TGF-β signaling was enriched from upregulated miRNAs, whereas E2F targets, apoptosis-related, hypoxia-related, and PI3K/AKT/mTOR signaling pathways, were enriched from downregulated miRNAs. Immunohistochemical staining of samples from multiple institutions indicated that PI3K/AKT/mTOR pathway components, MAPK1, phospho-p44/42 MAPK, and pS6 were highly expressed and the expression of SMAD7, a TGF-β pathway component, was decreased in M-IMC, which could aid in distinguishing M-IMC from N-IMC. The miRNA signature discovered in this study is a valuable biological marker for identifying metastatic potential of IMCs, and provides novel insights regarding the metastatic progression of IMC.

Ethno-Pharmacological Relevance: A natural ursolic compound, 2β,3β,23-trihydroxy-urs-12-ene-28-olic acid (TUA) was isolated from the root of Actinidiafulvicoma Hance. (A.fulvicoma Radix), which is used as a traditional hebal medicine to cure innominate inflammation of unknown origin of the digestive tract in the She nationality., Aim of the Study: The aim of present study was to investigate the effects of TUA on gastric cancer and to clarify the potential mechanisms in human gastric cancer cell line BGC823 cells in vitro and in vivo., Materials and Methods: Cell proliferation, apoptosis, cell cycle, autophagy were all measured by MTS assay, flow cytometry following exposure to TUA. The mRNA expressions of PI3K, AKT, mTOR, P70S6K, Survivin and the protein expressions of p-PI3K, p-AKT, p-mTOR, p-P70S6K, Survivin were determined by qRT-PCR and Western blotting analysis, respectively. In vivo antitumor activity of TUA was assessed in a xenograft model., Results: In vitro studies showed that TUA significantly suppressed the viability of BGC823 cells in a concentration- and time-dependent manner but not GES-1 non-tumorigenic human gastric epithelial cells. TUA also significantly increased the apoptosis rate and the sub G2 population by cell cycle analysis in a concentration dependent manner. Exposure to TUA decreased PI3K, AKT, mTOR, P70S6K, Survivin mRNA, inhibited the phosphorylation of major receptors involved in autophagy and apoptosis, such as PI3K, AKT, mTOR and P70S6K, while reduced the expression of Survivin in BGC cells. In vivo studies showed that TUA decreased tumor volume and tumor weight and also down regulated the autophagy-related proteins expression., Conclusions: TUA occupies underlying antitumor effects, the potential mechanisms may involve the suppression of mTOR/Survivin pathways connected to autophagy and the activation of apoptotic pathways in gastric cancer cells., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has the ability to selectively trigger cancer cell apoptosis and can be used as a target for tumor therapy. However, gastric cancer cells are usually insensitive to TRAIL so reducing this drug resistance may improve the treatment of gastric cancer. In this study, we used Cell Counting Kit-8 (CCK-8) and 5-ethynyl-2'-deoxyuridine (EdU) experiments to determine the effects of 5-fluorouracil (5-FU) and TRAIL on the proliferation of gastric cancer cells. An Annexin V/propidium iodide (PI) staining experiment was used to detect apoptosis, and Western blotting was used to analyze the expression levels of apoptosis-related proteins and mitogen-activated protein kinase (MAPK) pathway proteins. The antitumor effects of 5-FU and TRAIL were verified in vivo using a nude mouse tumorigenesis experiment, and a TUNEL assay was performed to evaluate apoptosis in tumor tissue from the nude mice. We found the combination of 5-FU and TRAIL had a greater inhibitory effect on the proliferation of gastric cancer cells than 5-FU or TRAIL alone both in vivo and in vitro. 5-FU enhanced TRAIL-induced gastric cancer cell apoptosis by inactivating the MAPK pathway. Overall, our analysis firstly provided new insights into the role of 5-FU in increasing sensitivity to TRAIL. 5-FU can be used as a sensitizer for TRAIL, and its administration is a potential strategy for the treatment of gastric cancer., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Helicobacter pylori (H. pylori) is listed as a class I carcinogen in human gastric cancer; however, the underlying mechanisms are poorly understood. In this study, we identified Protogenin (PRTG) was upregulated in both gastric cancer tissues and H. pylori-infected tissues by analyzing dysregulated genes in TCGA and GEO databases. Importantly, upregulated PRTG predicted poor prognosis of gastric cancer patients and integrative analysis revealed that PRTG served as an oncogenic protein in gastric cancer and was required for H. pylori-mediated tumorigenic activities in in vitro cellular and in vivo tumor-bearing mouse models. Mechanistically, H. pylori infection enhanced PRTG expression by promoting transcriptional factor ZEB1 stabilization and recruitment to the PRTG promoter, and which then activated the sub-following cGMP/PKG signaling pathway in bioinformatic and cellular studies. Cellular studies further confirmed that PRTG depended on activating cGMP/PKG axis to promote proliferation, metastasis, and chemoresistance of gastric cancer cells. The PKG inhibitor KT5823 played synergistic anti-tumor effects with cisplatin and paclitaxel to gastric cancer cells in in vitro cellular and in vivo tumor-bearing mouse models. Taken together, our findings suggested that H. pylori infection depends on ZEB1 to induce PRTG upregulation, and which leading to the development and progression of gastric cancer through activating cGMP/PKG signaling pathway. Blocking PRTG/cGMP/PKG axis, therefore, presents a promising novel therapeutic strategy for gastric cancer.

Although gastric cancer (GC) is one of the most common cancers with high incidence and mortality rates, its pathogenesis is still not elucidated. GC carcinogenesis is complicated and involved in the activation of oncoproteins and inactivation of tumor suppressors. The ubiquitin-proteasome system (UPS) is crucial for protein degradation and regulation of physiological and pathological processes. E3 ubiquitin ligases are pivotal enzymes in UPS, containing various subfamily proteins. Previous studies report that some E3 ligases, including SKP2, CUL1, and MDM2, act as oncoproteins in GC carcinogenesis. On the other hand, FBXW7, FBXL5, FBXO31, RNF43, and RNF180 exert as tumor suppressors in GC carcinogenesis. Moreover, E3 ligases modulate cell growth, cell apoptosis, and cell cycle; thus, it is complicated to confer cisplatin resistance/sensitivity in GC cells. The intrinsic and acquired cisplatin resistance limits its clinical application against GC. In this review, we explore oncogenic and tumor suppressive roles of E3 ligases in GC carcinogenesis and focus on the effects of E3 ligases on cisplatin resistance in GC cells, which will provide novel therapeutic targets for GC therapy, especially for cisplatin-resistant patients.

N 6 -methyladenosine (m 6 A) is one of the most abundant messenger RNAs modification. Increasing evidence illustrates its critical role on gastric cancer. Here, present research focuses on the potential function of m 6 A methyltransferase Wilms' tumour 1-associated protein (WTAP) in gastric cancer tumorigenesis. Firstly, m 6 A immunoprecipitation sequencing analysis (MeRIP-Seq) analysis demonstrated the m 6 A profile in gastric cancer cells. Both WTAP and the m 6 A expression were up-regulated in gastric cancer tissue and cells. The high-expression of WTAP was closely correlated with poor prognosis of gastric cancer patients. Functional experiments illustrated that WTAP promoted the proliferation and glycolytic capacity (glucose uptake, lactate production and extracellular acidification rate) in vitro, and the knockdown of WTAP suppressed the tumor growth in vivo. Mechanistically, HK2 was identified to be the target of WTAP using MeRIP-Seq and MeRIP-qPCR. WTAP enhanced the stability of HK2 mRNA through binding with the 3'-UTR m 6 A site. In conclusion, our results demonstrate the oncogenic role of WTAP and its m 6 A-mediated regulation on gastric cancer Warburg effect, providing a novel approach and therapeutic target in gastric cancer., (Copyright © 2020 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: β-Arrestins have been found to regulate cell proliferation, invasion and migration; transmit anti-apoptotic survival signals; and affect other characteristics of tumours. However, their role in gastric cancer (GC) is not clear. We investigated the role and mechanism of β-arrestins in the regulation of GC., Methods: We first examined β-arrestins mRNA levels in 17 pairs of GC tissues by qRT-PCR. We also used immunohistochemistry to further examine the expression of β-arrestins in 60 paraffin-embedded primary GC tissues and 20 normal gastric tissues. Then, the function of β-arrestin1 was investigated in vitro and in vivo., Results: β-Arrestin1 was upregulated in GC tissue and was associated with tumour stage, lymph node metastasis, invasion depth and patient sex. High expression of β-arrestin1 expression predicted poor prognosis in GC. β-Arrestin1 promoted GC cell proliferation, migration and invasion, and it suppressed E-cadherin expression and upregulated Vimentin expression via AKT/ERK signalling pathway. The in vivo metastasis assays showed that knockdown of β-arrestin1 reduced lung metastasis and inhibited EMT., Conclusion: The upregulation of β-arrestin1 predicts poor prognosis and promotes metastasis and epithelial-mesenchymal transition in GC through AKT/ERK signalling pathway. This study may provide therapeutic advances for the treatment and early diagnosis of patients with metastatic GC., (Copyright © 2020 The Authors. Published by Elsevier GmbH.. All rights reserved.)

T-17, a bioactive spirostanol saponin extracted from Tupistra chinensis Baker, was previously reported with anti-inflammatory and cytotoxic activities. However, the mechanism underlying of its anti-proliferation activity remains to be elucidated. In this study, we investigated the anti-gastric cancer cell growth activity of T-17 in terms of cell viability, colony formation, cell cycle, induction of apoptosis/autophagy, and JNK pathway. T-17 showed dose-dependent cytotoxicity in SGC-7901 and AGS cell lines, it induced caspase-mediated apoptosis as well as G0/G1 phase arrest and modulation of cyclinE2 and p21 expression. In addition, T-17 promoted the cancer cell autophagy as evidenced with increased expression of Beclin-1 and decreased p62 in western blot and formation of GFP-LC3 puncta. Furthermore, T-17-induced autophagy decreased gastric cancer cell apoptosis as assessed by pharmacological autophagy inhibitors and ATG5 siRNA usage. Importantly, the activation of JNK pathway was simultaneously involved in T-17-induced apoptosis and autophagy. Taken together, the results suggest that T-17 is a promising cytotoxic agent for therapeutic treatment of human gastric adenocarcinoma, which provides a good foundation for further research and development of Tupistra chinensis Baker., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: Since the essential involvement of microRNAs (miRNAs) in the development and progression of GC, the study was for the exploration of the value of microRNA-7 (miR-7) in the evaluation of neoadjuvant chemotherapy for gastric cancer (GC) and its effects on apoptosis, proliferation and angiogenesis of GC., Methods: miR-7 expression in serum of GC patients before and after neoadjuvant chemotherapy were detected to explore its role in neoadjuvant chemotherapy of GC. The GC cells were transfected with miR-7 mimics/inhibitors, or siRNA-Raf-1 to figure out their roles in proliferation, migration, invasion, cycle distribution and apoptosis. Tumor xenograft was conducted to test tumor growth. Microvessel density (MVD) in tumors was tested by immunohistochemical staining., Results: miR-7 expression in serum of GC patients was lower than that of healthy controls while it was elevated after neoadjuvant chemotherapy. Moreover, higher miR-7 expression was exhibited in chemotherapy-effective patients rather than chemotherapy-ineffective patients ( P < 0.01). miR-7 expression in serum was connected with tumor size, degree of differentiation, TNM stage and lymphatic metastasis.miR-7 was decreased and Raf-1 was elevated in GC cells (both P < 0.05). Elevated miR-7 or declined Raf-1 inhibited GC cell migration, proliferation and invasion, cell cycle entry, xenografted tumor growth and MVD and stimulated apoptosis (all P < 0.05). Down-regulated Raf-1 reversed the impacts of miR-7 knockdown on GC cells (all P < 0.05)., Conclusion: Our study highlights that elevated miR-27a indicates the good efficacy of neoadjuvant chemotherapy in GC and miR-7 targets Raf-1 to suppress tumor development and angiogenesis of GC cells.

Gastric cancer (GC) is one of the most deadly malignancies at global scale, and is particularly common in eastern Asia. MicroRNA-5683 (miR-5683) was confirmed to be downregulated in GC by analyzing data from the Cancer Genome Atlas. We packaged miR-5683-mimics and miR-5683-inhibitors into lentivirus vectors and transfected them into GC cells. MiR-5683 expression and possible target genes were detected by employing quantitative real-time polymerase chain reaction. In vitro, cell proliferation and apoptosis were analyzed using CCK-8, colony formation assay, and flow cytometric assay. We verified the direct interaction between miR-5683 and the possible downstream target gene pyruvate dehydrogenase kinase 4 (PDK4) through luciferase reporter assay. The role of miR-5683 in vivo was explored by injecting stably transfected GC cells subcutaneously into nude mice. Here we show that miR-5683 was downregulated in GC and the decreased level of miR-5683 enhances GC cell proliferation and impairs apoptosis. Tumor oncogene PDK4, which is associated with GC overall survival and disease-free survival, has been identified as the target gene of miR-5683. Besides, we demonstrate that the inhibition of miR-5683 promotes glycolysis by upregulating the PDK4 expression, thus leading to GC progression. Our study determines that miR-5683 represses GC glycolysis and progression through targeting PDK4. MiR-5683 overexpression may thus become a new treatment strategy for GC., (© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Acylglycerol kinase (AGK) uses adenosine triphosphate (ATP) and acylglycerol to generate adenosine diphosphate (ADP) and acyl-sn-glycerol 3-phosphate in cells. Recent evidence has demonstrated that dysregulated AGK expression is associated with the development of various human cancers. This study investigated the effects of AGK on gastric cancer cell proliferation and carcinogenesis and explored the underlying molecular events. AGK expression was up-regulated in gastric cancer and was associated with poor prognosis in gastric cancer patients. AGK overexpression increased gastric cancer proliferation, invasion capacity and the expression of the epithelial-mesenchymal transition markers in vitro. Conversely, the knockdown of AGK expression reduced gastric cancer cell proliferation in vitro and in nude mouse tumour cell xenografts. Importantly, AGK expression was associated with the YAP1 expression in gastric cancer cells and tissues. YAP1 expression also transcriptionally induced AGK expression through the binding of TEAD to the AGK gene promoter. However, AGK expression inhibited the activation of the Hippo pathway proteins and induced YAP1 nuclear localization to enhance the transcription activity of YAP1/TEADs. In conclusion, the study demonstrates that AGK is not only a novel target of the Hippo-YAP1 pathway, but that it also positively regulates YAP1 expression, thus forming a YAP1-AGK-positive feedback loop., (© 2020 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

DNA topoisomerases essentially remove topological strains generated during DNA replication, transcription, DNA repair, and other cytogenetic processes. However, distinct expression level and prognostic significance of individual topoisomerase isoforms in gastric cancer (GC) remain largely unexplored. In this study, we utilized Oncomine and Kaplan-Meier plotter database to detect the mRNA expression level of individual topoisomerase isoforms as well as assess their prognostic significance in GC patients. With the exception of TOP3B and TOP2B, levels of all topoisomerase isoforms were found to be elevated in GC patients when compared to the normal tissues. Elevated expression of TOP1 and TOP1MT was relevant to longer overall survival (OS) in GC and gastric intestinal type adenocarcinoma (GITA) patients, but not in diffuse gastric adenocarcinoma (DFA) patients. Increased expression of TOP2A and TOP2B was related to better OS in GC, as well as in GITA and DFA patients. In contrast, increased expression TOP3A and TOP3B was associated with shorter OS in GC, as well as in GITA and DFA patients. We also applied the Tumor IMmune Estimation Resource (TIMER) tool to assess the correlations between distinct topoisomerase isoforms and the infiltrating immune cell landscape. Furthermore, we found that down-regulating the expression of TOP3A by shRNA significantly inhibited the proliferation and colony formation in GC cells compared to control shRNA treated cells. Thus our study lays the framework for utilizing topoisomerases in better understanding the complexity and heterogeneity of GC and for developing strategies for novel customized therapy in GC patients., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Introduction: Gastric cancer is third leading cause of cancer-related deaths worldwide and remarkably threatens human health and life. BAIAP2L2 is an epithelial-specific BAR domain protein that considered to be closely related to cell migration. In this study, we explored the specific role of BAIAP2L2 in human gastric cancer., Methods: BAIAP2L2 expression was analyzed via online database and immunohistochemistry. The proliferation was detected using CCK8 and colony formation assay. The migration and invasion was confirmed by transwell assay, and the apoptosis of gastric cancer cells was detected by flow cytometry., Results: BAIAP2L2 was highly expressed in tumour tissues and its expression significantly correlated with tumor diameter, T stage, pTNM stage and lymph node metastasis, respectively. Compared with GES-1 cells, SGC7901, MKN28, MKN45, AGS and BGC-823 tumor cells were all presented a high-expression of BAIAP2L2. The in vitro results showed that knockdown of BAIAP2L2 inhibited the proliferation, migration and invasion, and induced the apoptosis of gastric cancer cell. Further, knockdown of BAIAP2L2 inhibited the expression of the related proteins of AKT/mTOR and Wnt3a/β-catenin signaling pathways., Conclusion: BAIAP2L2 is upregulated in gastric cancer, and knockdown of BAIAP2L2 inhibited the proliferation and metastasis through the inactivation of AKT/mTOR and Wnt3a/β-catenin signaling pathways., (Copyright © 2020 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

LSD1 (histone lysine specific demethylase 1) takes part in the physiological process of cell differentiation, EMT (epithelial-mesenchymal transition) and immune response. In this study, we found LSD1 expression in metastatic gastric cancer tissues was significantly higher than that in normal tissues. Furthermore, LSD1 deletion was found to suppress gastric cancer migration by decreasing intracellular miR-142-5p, which further led to the upregulation of migration suppressor CD9, a newly identified target of miR-142-5p. While LSD1 was reported as a demethylase of H3K4me1/2, H3K9me1/2 and several non-histone proteins, this is a new evidence for LSD1 as a functional regulator of miRNA. On the other hand, our data suggested that promoting the secretion of miR-142-5p using small extracellular vesicles as vehicles is a new mechanism for LSD1 abrogation to down-regulate intracellular miR-142-5p. Taken together, this study uncovered a new mechanism for LSD1 that can contribute to gastric cancer migration by facilitating miR-142-5p to target CD9., (Copyright © 2020 Elsevier Ltd. All rights reserved.)