Therapeutic Target For Gastric Cancer Research Articles

Identification of the Expression of TIE1 and Its Mediated Immunosuppression in Gastric Cancer.

Background: Recently, various evidence has confirmed that Tyrosine Kinase with Immunoglobulin-like and EGF-like domains 1 (TIE1) promotes tumor growth in many cancers. However, the precise mechanism underlying TIE1's involvement in Gastric Cancer (GC) remains elusive. This research aimed to investigate the biological function of TIE1 in regulating GC progression. Methods: The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), GEPIA2.0, Sangerbox3.0 and TIMER databases were used to analyze the TIE1 expression. Immunohistochemistry (IHC) was used to demonstrate the expression of TIE1. TCGA, GEPIA2.0 and Kaplan-Meier were utilized for survival analysis and to explore the association of TIE1 with clinicopathological features. Protein-Protein Interaction (PPI) networks were constructed using Cytoscape. The potential molecular mechanism of TIE1 was investigated by Gene Ontology (GO), Kyoto Encyclopedia of Gene Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA). We studied the relationships between TIE1 and mutations, immune checkpoints (ICs), tumor mutational burden (TMB), as well as microsatellite instability (MSI) to explore the underlying mechanism of immunity in GC. Results: Compared with normal tissue, TIE1 was significantly overexpressed in GC tissues (p = 0.0072) and was associated with poor survival (P < 0.05). According to GO and KEGG enrichment analyses, TIE1 was enriched in signal pathways related to the occurrence, invasion, and migration of malignant tumors (i.e., PI3K-Akt signaling pathway, Calcium signaling pathway, etc.). Immune infiltration analysis suggested that TIE1 is positively correlated with macrophages M2 and negatively correlated with Mast cells, naive B cells and Follicular helper T cells (TFH), which may be a contributing factor to tumor progression. Furthermore, the research on the tumor microenvironment (TME) and tumor purity also proved that TIE1 may be an oncogene. Mutation analysis showed that the high expression group of TIE1 had a higher frequency of mutations in TP53 and ARID1, while the TMB score was lower. Conclusion: TIE1 might be an oncogene via regulating dysregulated immune infiltration to cause immunosuppression in GC and could be identified as a biomarker for prognosis and a therapeutic target for GC.

Downregulated lncRNA LINC00908 correlates with a poor prognosis and increasing malignancy of gastric cancer.

Long non-coding RNA LINC00908 is a functional biomarker in regulating tumour progression. Its dysregulation in gastric cancer implies its potential functional role. Few studies have noted the functional role of LINC00908 in gastric cancer. The potential of LINC00908 to serve as a biomarker in gastric cancer was evaluated. A total of 113 paired gastric cancer tissues and normal tissues were collected from patients with gastric cancer. LINC00908 levels were evaluated by polymerase chain reaction, and its significance in disease progression and patients' prognosis was assessed. In vitro, the function of LINC00908 in tumour-related cellular processes was evaluated with CCK8 and Transwell assay. Significant downregulation of LINC00908 was observed in gastric cancer and was negatively associated with disease development and overall survival of patients. LINC00908 showed significant inhibitory effects on the proliferation, migration, and invasion of gastric cancer cells. Additionally, miR-627-3p was sponged by LINC00908 and therefore mediated the function of LINC00908 in gastric cancer cells. LINC00908 functioned as a prognostic biomarker and tumour suppressor of gastric cancer, providing a therapeutic target for gastric cancer.

Tumor-Derived Exosomal LINC01480 Upregulates VCAM1 Expression by Acting as a Competitive Endogenous RNA of miR-204-5p to Promote Gastric Cancer Progression.

Exosomes are a type of cell-derived vesicles that range in size from 30 to 100 nm. They are widely present in various organisms and participate in diverse biological processes, playing crucial roles in tumorigenesis and progression. This study aimed to investigate whether LINC01480 in tumor-derived exosomes is involved in the molecular mechanism of gastric cancer by competitively upregulating the VCAM1 expression through binding miR-204-5p. The study analyzed transcriptome data related to gastric cancer from the cancer genome atlas database and constructed a risk-scoring model for epithelial-mesenchymal transition (EMT)-related lncRNAs to identify eight EMT-related lncRNAs associated with prognosis. EMT-related mRNAs positively correlated with LINC01480 were screened in the ExoRBase database. In vitro cell experiments showed that exosomal LINC01480 can promote the proliferation, migration, invasion, and EMT of gastric cancer cells by upregulating VCAM1 expression through competitive binding with miR-204-5p. In vivo experiments on nude mice showed that exosomal LINC01480 promotes the development of gastric cancer. These results suggest that exosomal LINC01480 could be a potential therapeutic target for gastric cancer.

Leveraging synthetic lethality to uncover potential therapeutic target in gastric cancer.

Since trastuzumab was approved in 2012 for the first-line treatment of gastric cancer (GC), no significant advancement in GC targeted therapies has occurred. Synthetic lethality refers to the concept that simultaneous dysfunction of a pair of genes results in a lethal effect on cells, while the loss of an individual gene does not cause this effect. Through exploiting synthetic lethality, novel targeted therapies can be developed for the individualized treatment of GC. In this study, we proposed a computational strategy named Gastric cancer Specific Synthetic Lethality inference (GSSL) to identify synthetic lethal interactions in GC. GSSL analysis was used to infer probable synthetic lethality in GC using four accessible clinical datasets. In addition, prediction results were confirmed by experiments. GSSL analysis identified a total of 34 candidate synthetic lethal pairs, which included 33 unique targets. Among the synthetic lethal gene pairs, TP53-CHEK1 was selected for further experimental validation. Both computational and experimental results indicated that inhibiting CHEK1 could be a potential therapeutic strategy for GC patients with TP53 mutation. Meanwhile, in vitro experimental validation of two novel synthetic lethal pairs TP53-AURKB and ARID1A-EP300 further proved the universality and reliability of GSSL. Collectively, GSSL has been shown to be a reliable and feasible method for comprehensive analysis of inferring synthetic lethal interactions of GC, which may offer novel insight into the precision medicine and individualized treatment of GC.

Glucose transporter 3 (GLUT3) promotes lactylation modifications by regulating lactate dehydrogenase A (LDHA) in gastric cancer

ObjectivesGlucose transporter 3 (GLUT3) plays a major role in glycolysis and glucose metabolism in cancer cells. We aimed to investigate the correlation between GLUT3 and histone lactylation modification in the occurrence and progression of gastric cancer.Materials and methodsWe initially used single-cell sequencing data to determine the expression levels of GLUT3 and lactate dehydrogenase A (LDHA) in primary tumor, tumor-adjacent normal, and metastasis tumor tissues. Immunohistochemistry analysis was conducted to measure GLUT3, LDHA, and L-lactyl levels in gastric normal and cancer tissues. Transwell and scratch assays were performed to evaluate the metastatic and invasive capacity of gastric cancer cell lines. Western blotting was used to measure L-lactyl and histone lactylation levels in gastric cancer cell lines.ResultsSingle-cell sequencing data showed that GLUT3 expression was significantly increased in primary tumor and metastasis tumor tissues. In addition, GLUT3 expression was positively correlated with that of LDHA expression and lactylation-related pathways. Western blotting and immunohistochemistry analyses revealed that GLUT3 was highly expressed in gastric cancer tissues and cell lines. GLUT3 knockdown in gastric cancer cell lines inhibited their metastatic and invasive capacity to various degrees. Additionally, the levels of LDHA, L-lactyl, H3K9, H3K18, and H3K56 significantly decreased after GLUT3 knockdown, indicating that GLUT3 affects lactylation in gastric cancer cells. Moreover, LDHA overexpression in a GLUT3 knockdown cell line reversed the levels of lactylation and EMT-related markers, and the EMT functional phenotype induced by GLUT3 knockdown. The in vivo results were consistent with the in vitro results.ConclusionsThis study suggests the important role of histone lactylation in the occurrence and progression of gastric cancer, and GLUT3 may be a new diagnostic marker and therapeutic target for gastric cancer.

Effects of methylation and imprinting expression of Insulin-like growth factor 2 gene in gastric cancer.

Epstein-Barr virus (EBV)-associated gastric cancer (EBVaGC) is a common malignant tumor associated with EBV infection. Insulin-like growth factor 2 (IGF2) is an imprinted gene and a key protein that regulates growth, especially during normal fetal development. Loss of imprinting (LOI), is a common epigenetic anomaly in a variety of human cancers. However, the promoter methylation, imprinting status and function of IGF2 gene in GC are unclear. To explore the role of IGF2 in the occurrence and development of gastric cancer. The biological function of IGF2 in gastric cancer was investigated by Transwell, wound healing, CCK-8 and flow cytometry assays. IGF2 imprinting status and gene promoter methylation in gastric cancer tissues were detected by PCR-RFLP and BGS. The results showed that the expression of IGF2 was higher in GC tissues than adjacent tissues. IGF2 gene promoter methylation and LOI were significantly higher in EBVaGC tissues than in EBV-negative gastric cancer (EBVnGC) tissues. The high expression of IGF2 in gastric cancer can promote the migration and proliferation of gastric cancer cells. Our data suggest that IGF2 is involved in the occurrence and development of gastric cancer. Targeting IGF2 may be a potential therapeutic target for gastric cancer.

Depicting the Profile of METTL3-Mediated lncRNA m6A Modification Variants and Identified SNHG7 as a Prognostic Indicator of MNNG-Induced Gastric Cancer.

As a representative example of an environmental chemical carcinogen, MNNG exposure is closely associated with the onset of gastric cancer (GC) where N6-methyladenosine (m6A) RNA methylation tends to be the critical epigenetic event. However, the effect of m6A modification on long non-coding RNAs (lncRNAs) in MNNG-induced GC onset is still unclear. To address the above issue, based on the Methylated RNA immunoprecipitation sequencing (MeRIP-seq) data of MNNG-induced malignant cells (MCs) and GC cells, we comprehensively analyzed the MNNG exposure-associated vital lncRNAs. MeRIP-seq analysis identified 1432 lncRNA transcripts in the MC cell, and 3520 lncRNA transcripts were found to be m6A modified in the GC cell, respectively. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed that MNNG exposure could spark cellular localization change, which might be the critical cellular note variation for malignant transformation. We demonstrated that METTL3 is responsible for N6 methylation of lncRNAs and identified SNHG7 as a downstream target of METTL3. More importantly, we observed that SNHG7 was progressively up-regulated during gastric carcinogenesis by MNNG exposure. Finally, we investigated SNHG7 expression in different stages of GC malignancies and found that elevated SNHG7 expression correlated with advanced clinical features and poor prognosis in GC. In conclusion, our study found for the first time that METTL3 regulates the m6A methylation level of lncRNA SNHG7 and its expression in MNNG exposure-induced GC, suggesting that SNHG7 as a predictive biomarker or therapeutic target for GC.

Increased expression of LINC00323 correlates with tumor progression and poor prognosis of gastric cancer.

LINC00323 is a novel lncRNA which has reported to play an important role in the development and recurrence in several cancers. However, the expression and predictive value of LINC00323 in gastric cancer (GC) remain mysterious. LINC00323 expression in GC tissues and adjacent normal tissues was evaluated by quantitative reverse-transcription PCR (qRT-PCR). The relationship between LINC00323 expression and clinicopathological features and patients' survival were analyzed. Univariate and multivariate survival analyses were performed. LINC00323 expression were found to be significantly increased in GC tissues. High expression of LINC00323 exerted a pro-tumor effect in the late stage of GC development. Kaplan-Meier analysis showed that patients with high LINC00323 were associated with poor overall survival (OS) and progression-free survival (PFS). Moreover, the combination of TNM stage and drinking status better identified GC patient outcome than those of TNM stage alone. Our data showed that LINC00323 overexpression might serve as a novel independent prognostic factor for survival of GC patients, suggesting LINC00323 was a potential biomarker and therapeutic target for GC.

Clinicopathologic features and prognostic value of claudin 18.2 overexpression in patients with resectable gastric cancer

Claudin 18.2 has emerged as a promising therapeutic target in gastric cancer based on phase 3 studies. However, clinicopathologic features associated with claudin 18.2 overexpression have not been comprehensively studied specifically for patients with resectable gastric cancer. This retrospective study included 299 patients with stage I–III resectable gastric cancer who underwent curative surgical resection. Possible associations between claudin 18.2 overexpression (moderate-to-strong expression in ≥ 75% by the 43-14A clone) and clinicopathologic features and survival outcomes were analyzed. There were 90 (30.1%), 96 (32.1%), and 113 (37.8%) patients with stage I, II, and III disease, respectively. Claudin 18.2 overexpression was noted in 139 out of 299 patients (46.5%). Claudin 18.2 overexpression was associated with a younger age, a lower invasion depth limited to the mucosa/submucosa, and less frequent lymphovascular invasion. Claudin 18.2 overexpression was also associated with Borrmann type 4 among patients with advanced gastric cancer and the diffuse histological type. Claudin 18.2 overexpression was not an independent factor for survival outcomes. In conclusion, claudin 18.2 was overexpressed in almost half of resectable gastric cancer patients. Claudin 18.2 overexpression was associated with some clinicopathological characteristics, but was not an independent prognostic factor in a localized setting.

Super-enhancer-associated EEPD1 facilitates EMT-mediated metastasis by regulating the PI3K/AKT/mTOR pathway in gastric cancer

This study focused on exploring the mechanism of the EMT mediated by endonuclease/exonuclease/phosphatase family domain-containing 1 (EEPD1) in gastric cancer metastasis. Through bioinformatics analysis, EEPD1 was found to be a target gene of super enhancers (SEs) in gastric cancer tissues. EEPD1 exhibited higher expression levels in tumor tissues and was associated with poor prognosis. In vitro and in vivo studies have demonstrated that silencing EEPD1 significantly suppressed the proliferation, metastasis, and invasion of gastric cancer cells. Furthermore, EEPD1 knockdown was involved in the regulation of the EMT and suppressed expression of AKT, a downstream component of the PI3K pathway, leading to a reduction in the phosphorylation levels of AKT and its downstream molecule, mTOR. These results showed the potential of EEPD1 as a prognostic indicator and therapeutic target in gastric cancer.

Integrated analysis of single-cell and bulk RNA-sequencing data reveals the prognostic value and molecular function of THSD7A in gastric cancer.

The biological role and prognostic value of thrombospondin domain-containing 7A (THSD7A) in gastric cancer remain unclear. Our purpose was to determine the molecular mechanisms underlying the functioning of THSD7A and its prognostic value in gastric cancer. Gastric cancer-associated single cell and bulk RNA sequencing data obtained from two databases, were analyzed. We used bulk RNA sequencing to examine the differential expression of THSD7A in gastric cancer and normal gastric tissues and explored the relationship between THSD7A expression and clinicopathological characteristics. Kaplan-Meier survival and Cox analyses revealed the prognostic value of THSD7A. Gene set enrichment and immune infiltration analyses were used to determine the cancer-promoting mechanisms of THSD7A and its effect on the immune microenvironment. We explored the relationship between THSD7A expression and sensitivity of anti-tumor drugs and immune checkpoint levels. Biological functions of THSD7A were validated at single-cell and in vitro levels. THSD7A expression was significantly increased in gastric cancer samples. High THSD7A expression was associated with poor clinical phenotypes and prognoses. Cox analysis showed that THSD7A was an independent risk factor for patients with gastric cancer. Enrichment analysis suggested that epithelial-mesenchymal transition and inflammatory responses may be potential pro-cancer mechanisms of THSD7A. Upregulation of THSD7A promoted infiltration by M2 macrophages and regulatory T cells. High THSD7A expression suppressed the sensitivity of patients with gastric cancer to drugs, such as 5-fluorouracil, bleomycin, and cisplatin, and upregulated immune checkpoints, such as HAVCR2, PDCD1LG2, TIGIT, and CTLA4. At the single cell level, THSD7A was an endothelial cell-associated gene and endothelial cells overexpressing THSD7A showed unique pro-oncogenic effects. In vitro experiments confirmed that THSD7A was overexpressed in gastric cancer samples and cells, and that knocking out THSD7A significantly inhibited gastric cancer cell proliferation and invasion. THSD7A overexpression may be a unique prognostic marker and therapeutic target in gastric cancer. Therefore, our study provides a new perspective on the precise treatment of gastric cancer.

SNORD3A acts as a potential prognostic and therapeutic biomarker in gastric cancer

BackgroundAlthough SNORD3A has been implicated in cancer progression, its specific roles and underlying mechanisms in gastric cancer (GC) remain poorly understood. We analysed SNORD3A expression using TCGA data and evaluated patient survival via Kaplan‒Meier curves. Additionally, we conducted GO-KEGG enrichment analysis to identify relevant biological processes and signaling pathways, while ssGSEA was used to assess the correlation between SNORD3A and cancer immune infiltrates. Furthermore, we explored the relationship between SNORD3A and immunotherapy response through TIDE. We verified SNORD3A expression using real-time qPCR and assessed cell proliferation, migration, and invasion via CCK8 and Transwell migration and invasion assays. ResultsOur results revealed that SNORD3A was significantly upregulated in GC, with high expression correlating with poor survival. SNORD3A and related genes were primarily enriched in the insulin/insulin-related growth factor signaling pathway. We also observed negative associations between SNORD3A expression and several immune cells, including activated dendritic cells, CD56bright natural killer cells, central memory CD8 T cells, effector memory CD8 T cells, effector memory CD4 T cells, eosinophils, immature dendritic cells, macrophages, mast cells, MDSCs, memory B cells, monocytes, neutrophil cells, plasmacytoid dendritic cells, regulatory T cells, and T follicular helper cells. High SNORD3A expression also correlated with a poorer response to immunotherapy. Finally, inhibition of SNORD3A suppressed cell proliferation, migration, and invasion. ConclusionsOur findings suggest that SNORD3A plays a catalytic role in the proliferation, migration and invasiveness of GC and may have potential as a diagnostic biomarker and therapeutic target for GC.How to cite: Wang Q, Li Y, Niu X, et al. SNORD3A acts as a potential prognostic and therapeutic biomarker in gastric cancer. Electron J Biotechnol 2023; 67. https://doi.org/10.1016/j.ejbt.2023.08.004.

IGF2BP2-meidated m6A modification of CSF2 reprograms MSC to promote gastric cancer progression

The interaction between tumor cells and stromal cells within the tumor microenvironment plays a critical role in cancer progression. Mesenchymal stem cells (MSCs) are important tumor stromal cells that exhibit pro-oncogenic activities when reprogrammed by the tumor. However, the precise mechanisms underlying MSC reprogramming in gastric cancer remain not well understood. QRT-PCR, western blot, and immunohistochemistry were used to examine gene and protein expression levels. In vitro and in vivo experiments were conducted to assess the biological functions of gastric cancer cells. RNA-sequencing, RNA immunoprecipitation (RIP), and meRIP assays were performed to investigate underlying molecular mechanisms. We found a significant increase in the expression and N6-methyladenosine (m6A) modification levels of colony-stimulating factor 2 (CSF2) in gastric cancer MSCs. CSF2 gene overexpression induced the reprogramming of normal MSCs into cancer-promoting MSCs, thereby enhancing the proliferation, migration, and drug resistance of gastric cancer cells through the secretion of various pro-inflammatory factors. Additionally, we demonstrated that the m6A reader IGF2BP2 bound to and stabilized CSF2 mRNA in gastric cancer MSCs. Notably, overexpression of IGF2BP2 mimicked the effect of CSF2 on MSCs, promoting gastric cancer progression. Finally, we unveiled that CSF2 induced the ubiquitination of Notch1 to reprogram MSCs. Our study highlights a critical role of IGF2BP2-mediated m6A modification of CSF2 in reprogramming MSCs, which presents a promising therapeutic target for gastric cancer.

Jian Yun Qing Hua Decoction inhibits malignant behaviors of gastric carcinoma cells via COL12A1 mediated ferroptosis signal pathway

BackgroundJian Yun Qing Hua Decoction (JYQHD), a traditional Chinese medicine decoction, which has been applied in the treatment of gastric cancer (GC). We attempt to confirm the anti-gastric cancer effect of JYQHD and explore the mechanism of JYQHD.MethodsAcute toxicity test was used to understand the toxicity of JYQHD. We studied the expression and prognostic outcome of COL12A1 within GC tissues through the network databases. Using several web-based databases, we analyzed the major components and targets of JYQHD, as well as known therapeutic targets in gastric cancer. The Venn diagram was utilized to obtain the overlapped genes. Lentiviral vector, shRNAs and plasmids, were used to transfect GC cells. Cell counting kit-8 (CCK8), sphere formation, malondialdehyde (MDA), glutathione (GSH), reactive oxygen species (ROS), Fe2+, transmission electron microscopy (TEM), quantitative Real-Time Polymerase Chain Reaction (qRT-PCR), Western-Blot (WB), and immunohistochemical (IHC) assays were employed to investigate the role and mechanism of COL12A1 and JYQHD in GC.ResultsThe results showed that JYQHD was non-toxic and safe. JYQHD inhibited growth and sphere formation ability through inducing the ferroptosis of GC cells, and suppressed the GC cells induced subcutaneous xenograft tumor growth. COL12A1 was highly expressed in gastric cancer tissues, indicating poor prognosis. COL12A1 specifically enhanced GC cell progression and stemness via suppressing ferroptosis. JYQHD down-regulated COL12A1 in order to suppress the stemness of GC cells via inducing ferroptosis.ConclusionCOL12A1 inhibited ferroptosis and enhanced stemness in GC cells. JYQHD inhibited the development of GC cells by inhibiting cancer cell stemness via the ferroptosis pathway mediated by COL12A1.

ELOA promotes tumor growth and metastasis by activating RBP1 in gastric cancer.

Elongin A (ELOA), our previous work revealed, serves as a novel tumor suppressor in colorectal cancer. However, the function and mechanism of ELOA in other cancer types, including gastric cancer (GC), remain to be elucidated. The expression of ELOA was measured by quantitative reverse transcription-polymerase chain reaction and western blot. The effects of ELOA on GC growth and metastasis were assessed through a series of in-vitro and in-vivo assays. Furthermore, the potential mechanism of ELOA was revealed by RNA sequencing, dual luciferase reporter assay, chromatin immunoprecipitation, and rescue experiments in GC. We uncovered increased expression of ELOA in GC tissues compared with paired normal tissues via bioinformatic analyses and our sample detection. Enhanced ELOA expression in GC tissues was obviously correlated with poor tumor differentiation, lymph node metastasis, advanced tumor stage, and a poor prognosis. A series of functional experiments showed that ELOA promoted the proliferation and metastasis of GC. Mechanistically, we revealed that the decreased levels of miR-490-3p caused the upregulation of ELOA in GC. Both RNA-seq and ChIP assays revealed that ELOA transcriptionally activated retinol-binding protein 1 (RBP1) by binding to its promotor. Furthermore, specific knockdown of RBP1 reduced the tumor-promoting ability of ELOA in GC cells. In summary, our findings demonstrate that ELOA exerts oncogenic properties by activating RBP1 expression, providing the basis for a promising therapeutic target in GC.

LncRNA THUMPD3-AS1 promotes invasion and EMT in gastric cancer by regulating the miR-1297/BCAT1 pathway

Long noncoding RNA (lncRNA) plays crucial roles in the development of gastric cancer (GC); however, studies of their mechanisms of action are needed to determine their clinical value. The aim of this study is to explore the effects and mechanisms of THUMPD3-AS1 in GC. Elevated levels of THUMPD3-AS1 were observed in GC and demonstrated a significant positive correlation with poor prognosis. Functionally, THUMPD3-AS1 promoted GC cell proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) and induced tumor growth invivo. THUMPD3-AS1 exerts its regulatory function on BCAT1 through competitive binding with miR-1297. Further investigations confirmed that both THUMPD3-AS1 and miR-1297 interact with BCAT1. These findings suggest that THUMPD3-AS1 promotes GC invasion and EMT by regulating the miR-1297/BCAT1 pathway, indicating that THUMPD3-AS1 may serve as a biomarker and therapeutic target for GC.

M5C-methylated lncRNA NR_033928 promotes gastric cancer proliferation by stabilizing GLS mRNA to promote glutamine metabolism reprogramming.

Abnormal 5-methylcytosine (m5C) methylation has been proved to be closely related to gastric carcinogenesis, progression, and prognosis. Dysregulated long noncoding RNAs (lncRNAs) participate in a variety of biological processes in cancer. However, to date, m5C-methylated lncRNAs are rarely researched in gastric cancer (GC). Here, we found that RNA cytosine-C(5)-methyltransferase (NSUN2) was upregulated in GC and high NSUN2 expression was associated with poor prognosis. NR_033928 was identified as an NSUN2-methylated and upregulated lncRNA in GC. Functionally, NR_033928 upregulated the expression of glutaminase (GLS) by interacting with IGF2BP3/HUR complex to promote GLS mRNA stability. Increased glutamine metabolite, α-KG, upregulated NR_033928 expression by enhancing its promoter 5-hydroxymethylcytosine (hm5C) demethylation. In conclusion, our results revealed that NSUN2-methylated NR_033928 promoted GC progression and might be a potential prognostic and therapeutic target for GC.

TSPAN8 regulates EGFR/AKT pathway to enhance metastasis in gastric cancer.

Tetraspanin 8 (TSPAN8), a transmembrane glycoprotein, is implicated in various pathological conditions including human malignancies. However, the roles and underlying mechanisms of TSPAN8 in promoting gastric cancer(GC)progression are yet to be fully understood. Our study found that TSPAN8 expression was significantly elevated in GC tissues. We also observed a positive correlation between high TSPAN8 expression and various clinicopathological characteristics of GC, including tumor differentiation, invasion depth, lymph node metastasis, and clinical stage. Moreover, the elevated TSPAN8 expression was indicative of poor prognosis. Functionally, we observed that knockdown of TSPAN8 significantly attenuated while overexpression of TSPAN8 promoted GC cell migration and invasion. In vivo experiments, knockdown of TSPAN8 suppressed lung metastasis in nude mice. We further explored the underlying mechanisms of TSPAN8 and found that it regulated EGFR expression in GC cells by accelerating phosphorylation of EGFR and AKT. Our study reveals that TSPAN8 plays a significant role in promoting tumor metastasis by activating the EGFR/AKT pathway, indicating that it may serve as a promising therapeutic target of gastric cancer.

The role of gastric microecological dysbiosis in gastric carcinogenesis.

Gastric cancer (GC) is the leading cause of cancer-related death worldwide, and reducing its mortality has become an urgent public health issue. Gastric microecological dysbiosis (including bacteria, fungi, viruses, acid suppressants, antibiotics, and surgery) can lead to gastric immune dysfunction or result in a decrease in dominant bacteria and an increase in the number and virulence of pathogenic microorganisms, which in turn promotes development of GC. This review analyzes the relationship between gastric microecological dysbiosis and GC, elucidates dynamic alterations of the microbiota in Correa's cascade, and identifies certain specific microorganisms as potential biomarkers of GC to aid in early screening and diagnosis. In addition, this paper presents the potential of gastric microbiota transplantation as a therapeutic target for gastric cancer, providing a new direction for future research in this field.

SKAP1 Is a Novel Biomarker and Therapeutic Target for Gastric Cancer: Evidence from Expression, Functional, and Bioinformatic Analyses.

Gastric cancer (GC) is the third leading cause of cancer-related death worldwide. Due to the lack of early symptoms, GC is often diagnosed at an advanced stage when treatment options are limited. There is an urgent need to identify biomarkers for early detection, prognosis evaluation, and targeted treatment of GC. Studies have shown that Src kinase-associated phosphoprotein 1 (SKAP1) promotes cell proliferation and invasion and is associated with poor prognosis in colorectal cancer, malignant fibrous histiocytoma, and breast cancer. However, the role and mechanism of SKAP1 in GC are unclear. Here, analyses of multiple databases and experiments revealed that SKAP1 expression was higher in GC than in adjacent normal tissues. The Cancer Genome Atlas data showed that high SKAP1 expression was associated with poor GC prognosis. SKAP1 expression was higher in GC than in normal gastric epithelial cells. SKAP1 silencing reduced the proliferation, migration and invasion of the GC cell lines MKN45 and HGC27. Rescue experiments suggest that SKAP1 may promote GC progression by activating JAK1/PI3K/AKT signaling and regulating GC cell proliferation, invasion, migration, and other functions. Bioinformatics analysis revealed that SKAP1 was associated with immune cell infiltration and checkpoint expression in GC. High SKAP1 expression was associated with poorer immunotherapy outcomes, suggesting its potential as a predictive biomarker of GC immunotherapy efficacy. In summary, SKAP1 is overexpressed in GC, where it promotes cell proliferation, invasion and migration and is associated with poor prognosis and poor immunotherapy outcomes. SKAP1 may represent a biomarker and therapeutic target in GC and regulates cellular functions through JAK1/PI3K/AKT signaling.