Resistant Gastric Cancer Research Articles

Circ_0006089 facilitates gastric cancer progression and oxaliplatin resistance via miR-217/NRP1

BackgroundOxaliplatin (OXA) is a vital tool in the chemotherapy of gastric cancer (GC) patients. Circular RNAs (circRNAs) are a group of non-coding RNAs that have been associated with tumorigenesis. Nevertheless, the function of circRNAs in OXA resistance of GC is unknown. MethodsCirc_0006089/miR-217/NRP1 were elucidated through qRT-PCR in GC OXA-tolerant tissues and cell lines. OXA half-inhibitory concentration (IC50) was quantified by MTT assay. RNA pull-down and luciferase reporter tests were applied to characterize the interaction between circ_0006089 and miR-217, miR-217 and NRP1 in GC cells. ResultsThe findings disclosed that circ_0006089 and NRP1 was heightened whereas miR-217 was dramatically declined in OXA-tolerant GC tissues and cell lines. OXA resistance was reduced and the proliferation, migration and invasion ability of OXA cells were diminished after silencing circ_0006089. In addition, circ_0006089 raised OXA resistance by sponging miR-217. Further studies revealed that miR-217 bound to NRP1 and weakened OXA resistance. In addition, it was found that circ_0006089 accelerated GC progression and OXA resistance by upregulating NRP1 expression via sponging miR-217. ConclusionCirc_0006089 regulated OXA resistance in GC cells through miR-217/NRP1 axis, implying it was a promising biomarker for GC therapy.

Blockade of Src signaling prevented stemness gene expression and proliferation of patient-derived gastric cancer stem cells

ABSTRACT Objectives: Gastric cancer (GC) is one of the most malignant tumors. Mounting studies highlighted gastric cancer stem cells (GCSCs) were responsible for the failure of treatment due to recurrence and drug resistance of advanced GC. However, targeted therapy against GCSC for improving GC prognosis suffered from lack of suitable models and molecular targets in terms of personalized medicine. To address this issue, two patient-derived GC cell lines SD209 and SD292 with cancer stem cells (CSCs) such as phenotype were isolated for establishing targeted therapy aiming at critical metastatic signaling in GC. Materials and Methods: The primary patient-derived GCSCs were established from parts of GC tissues for characterization of stem cells (SCs) phenotype at both cellular and molecular levels. Western blot and Immunohistochemistry (IHC) were performed for identifying the deregulated signaling in GC tissue. Immunofluorescence was used for analyzing proliferating and SC markers in GCSC attached on fibroblast. Acridine orange and propidium iodide analyses were performed for the survival of GCSC in suspensions. Results: In the culture environments of both SD209 and SD292, a lot of mesenchymal fibroblasts spread and crowd together on which a lot of cell clumps, suspected as GCSC, were firmly attached. In the IHC analysis, the GCSC stemness genes CD44 and Ep-CAM increased in tumor tissues of SD209, whereas Nanog-1 and octamer-binding transcription factor 3 (OCT-3) increased in that of SD292. By immunofluorescent analysis of a proliferation marker Ki67, the growth of SD209 and SD292 on mesenchymal fibroblasts was found to be reduced by dasatinib, the inhibitor of the Src kinase whose activity was upregulated in tumor tissues of both GCs. Dasatinib also suppressed the expression of Nanog-1 and OCT-3 in SD292 attached on mesenchymal fibroblasts. Conclusion: This study may provide a base for targeted therapy against GCSCs/GCs progression in future preclinical/clinical settings.

LncRNAs orchestration of gastric cancer - particular emphasis on the etiology, diagnosis, and treatment resistance.

Gastric cancer (GC) remains a major public health challenge worldwide. Long non-coding RNAs (lncRNAs) play important roles in the development, progression, and resistance to the treatment of GC, as shown by recent developments in molecular characterization. Still, an in-depth investigation of the lncRNA landscape in GC is absent. However, The objective of this systematic review is to evaluate our present understanding of the role that lncRNA dysregulation plays in the etiology of GC and treatment resistance, with a focus on the underlying mechanisms and clinical implications. Research that described the functions of lncRNA in angiogenesis, stemness, epigenetics, metastasis, apoptosis, development, and resistance to key treatments was given priority. In GC, it has been discovered that a large number of lncRNAs, including MALAT1, HOTAIR, H19, and ANRIL, are aberrantly expressed and are connected with disease-related outcomes. Through various methods such as chromatin remodeling, signal transduction pathways, and microRNA sponging, they modulate hallmark cancer capabilities. Through the activation of stemness programs, epithelial-mesenchymal transition (EMT), and survival signaling, LncRNAs also control resistance to immunotherapy, chemotherapy, and targeted therapies. By clarifying their molecular roles further, we may be able to identify new treatment targets and ways to overcome resistance. This article aims to explore the interplay between lncRNAs, and GC. Specifically, the focus is on understanding how lncRNAs contribute to the etiology of GC and influence treatment resistance in patients with this disease.

Circ_0001947 encapsulated by small extracellular vesicles promotes gastric cancer progression and anti-PD-1 resistance by modulating CD8+ T cell exhaustion

BackgroundWhile small extracellular vesicles (sEVs)-derived circular RNAs (circRNAs) have been emerged as significant players in cancer, the function and underlying mechanism of sEVs-derived circRNAs in anti-cancer immunity remain unclear.MethodsGastric cancer (GC)-derived circRNAs were identified using RNA-seq data from GEO datasets and quantitative reverse transcription polymerase chain reaction (qRT-PCR), RNA immunoprecipitation, dual-luciferase assay, and bioinformatics analysis were performed to investigate the regulatory axis. Transwell assay, wound healing assay, cell counting kit-8 (CCK-8) assay, and xenograft models were used to evaluate its role in GC progression in vivo and in vitro. The delivery of specific circRNAs into sEVs were verified through electron microscopy, nanoparticle tracking analysis (NTA) and fuorescence in situ hybridization (FISH). Flow cytometric analysis and immunohistochemical staining were conducted to find out how specific circRNAs mediated CD8+ T cell exhaustion and resistant to anti-programmed cell death 1 (PD-1) therapy.ResultsWe identified that circ_0001947, packaged by GC-derived sEVs, was obviously elevated in GC and was associated with poor clinical outcome. High circ0001947 level augmented the proliferation, migration, and invasion of GC cells. Mechanistically, circ0001947 sponged miR−661 and miR−671−5p to promote the expression of CD39, which further facilitated CD8+ T cell exhaustion and immune resistance. Conversely, blocking circ_0001947 attenuated CD8+ T cell exhaustion and increased the response to anti-PD−1 therapy.ConclusionsOur study manifested the therapeutic potential of targeting sEVs-transmitted circ_0001947 to prohibit CD8+ T cell exhaustion and immune resistance in GC.

PILRB potentiates the PI3K/AKT signaling pathway and reprograms cholesterol metabolism to drive gastric tumorigenesis and metastasis

Paired immunoglobin-like type 2 receptor beta (PILRB) mainly plays a crucial role in regulating innate immunity, but whether PILRB is involved in cancer is poorly understood. Here, we report that PILRB potentiates the PI3K/AKT pathway to drive gastric tumorigenesis by binding and stabilizing IRS4, which could hyperactivate the PI3K/AKT pathway. Firstly, the levels of PILRB are upregulated in human gastric cancer (GC) specimens and associated with poor prognosis in patients with GC. In addition, our data show that PILRB promotes cell proliferation, colony formation, cell migration and invasion in GC cells in vitro and in vivo. Mechanistically, PILRB recruits the deubiquitination enzymes OTUB1 to IRS4 and relieves K48-linked ubiquitination of IRS4, protecting IRS4 protein from proteasomal-mediated degradation and subsequent activation of the PI3K/AKT pathway. Importantly, the levels of PILRB are positively correlated with IRS4 in GC specimens. Meanwhile, we also found that PILRB reprogrammed cholesterol metabolism by altering ABCA1 and SCARB1 expression levels, and PILRB-expression confers GC cell resistance to statin treatment. Taken together, our findings illustrate that the oncogenic role of PILRB in gastric tumorigenesis, providing new insights into the regulation of PI3K/AKT signaling in GC and establishing PILRB as a biomarker for simvastatin therapy resistance in GC.

Integrated single-cell and bulk RNA sequencing analyses identify an immunotherapy nonresponse-related fibroblast signature in gastric cancer.

Factors that determine nonresponse to immune checkpoint inhibitor (ICI) remain unclear. The protumor activities of cancer-associated fibroblasts (CAFs) suggest that they are potential therapeutic targets for cancer treatment. There is, however, a lack of CAF-related signature in predicting response to immunotherapy in gastric cancer (GC). Single-cell RNA sequencing (scRNA-seq) and RNA sequencing (RNA-seq) data of GC immunotherapy were downloaded from the Gene Expression Omnibus database. Bulk RNA-seq data were obtained from The Cancer Genome Atlas. The R package 'Seurat' was used for scRNA-seq data processing. Cellular infiltration, receptor-ligand interactions, and evolutionary trajectory analysis were further explored. Differentially expressed genes affecting overall survival were obtained using the limma package. Weighted Gene Correlation Network Analysis was used to identify key modules of immunotherapy nonresponder. Prognostic model was constructed by univariate Cox and least absolute contraction and selection operator analysis using the intersection of activated fibroblast genes (AFGs) with key module genes. The differences in clinicopathological features, immune microenvironment, immunotherapy prediction, and sensitivity to small molecule agents between the high- and low-risk groups were further investigated. Based on scRNA-seq, we finally identified 20 AFGs associations with the prognosis of GC patients. AFGs' high expression levels were correlated with both poor prognosis and tumor progression. Three genes (FRZB, SPARC, and FKBP10) were identified as immunotherapy nonresponse-related fibroblast genes and used to construct the prognostic signature. This signature is an independent significant risk factor affecting the clinical outcomes of GC patients. Remarkably, there were more CD4 memory T cells, resting mast cells, and M2 macrophages infiltrating in the high-risk group, which was characterized by higher tumor immune exclusion. Moreover, patients with higher risk scores were more prone to not respond to immunotherapy but were more sensitive to various small molecule agents, such as memantine. In conclusion, this study constructed a fibroblast-associated ICI nonresponse gene signature, which could predict the response to immunotherapy. This study potentially revealed a novel way to overcome immune resistance in GC.

Targeting LINC00665/miR-199b-5p/SERPINE1 axis to inhibit trastuzumab resistance and tumorigenesis of gastric cancer via PI3K/AKt pathway

Long noncoding RNAs (lncRNAs) serve as critical mediators of tumor progression and drug resistance in cancer. Herein, we identified a lncRNA, LINC00665, associated with trastuzumab resistance and development in gastric cancer (GC). LINC00665 was highly expressed in GC tissues and high expression of LINC00665 was correlated with poor prognosis. LINC00665 knockdown was verified to suppress migration, invasion, and resistance to trastuzumab in GC. Furthermore, we found that LINC00665 participates in the infiltration of naive B cells, mast cells, and T follicular helper (Tfh) cells. Mechanistically, LINC00665 was confirmed to regulate tumorigenesis and trastuzumab resistance by activating PI3K/AKt pathway. LINC00665 sponged miR-199b-5p to interact with SERPINE1 expression, resulting in the increase of phosphorylation of AKt, thus participating in the PI3K/AKt pathway. To summarize, LINC00665 facilitated the tumorigenesis and trastuzumab resistance of GC by sponging miR-199b-5p and promoting SERPINE1 expression, which further activated PI3K/AKt signaling; this finding reveals a new mechanism by which LINC00665 modulates tumor development and drug resistance in GC.

Long Non-Coding RNAs in Drug Resistance of Gastric Cancer: Complex Mechanisms and Potential Clinical Applications.

Gastric cancer (GC) ranks as the third most prevalent malignancy and a leading cause of cancer-related mortality worldwide. However, the majority of patients with GC are diagnosed at an advanced stage, highlighting the urgent need for effective perioperative and postoperative chemotherapy to prevent relapse and metastasis. The current treatment strategies have limited overall efficacy because of intrinsic or acquired drug resistance. Recent evidence suggests that dysregulated long non-coding RNAs (lncRNAs) play a significant role in mediating drug resistance in GC. Therefore, there is an imperative to explore novel molecular mechanisms underlying drug resistance in order to overcome this challenging issue. With advancements in deep transcriptome sequencing technology, lncRNAs-once considered transcriptional noise-have garnered widespread attention as potential regulators of carcinogenesis, including tumor cell proliferation, metastasis, and sensitivity to chemo- or radiotherapy through multiple regulatory mechanisms. In light of these findings, we aim to review the mechanisms by which lncRNAs contribute to drug therapy resistance in GC with the goal of providing new insights and breakthroughs toward overcoming this formidable obstacle.

POLQ inhibition attenuates the stemness and ferroptosis resistance in gastric cancer cells via downregulation of dihydroorotate dehydrogenase

Gastric cancer (GC) contains subpopulations of cancer stem cells (CSCs), which are described as the main contributors in tumor initiation and metastasis. It is necessary to clarify the molecular mechanism underlying CSCs phenotype and develop novel biomarkers and therapeutic targets for gastric cancer. Here, we show that POLQ positively regulates stem cell-like characteristics of gastric cancer cells, knockdown of POLQ suppressed the stemness of GC cells in vitro and in vivo. Further mechanistic studies revealed that POLQ knockdown could downregulate the expression of dihydroorotate dehydrogenase (DHODH). DHODH overexpression rescued the reduced stemness resulted by POLQ knockdown. Furthermore, we found that POLQ expression correlated with resistance to ferroptosis, and POLQ inhibition renders gastric cancer cells more vulnerable to ferroptosis. Further investigation revealed that POLQ regulated DHODH expression via the transcription factors E2F4, thereby regulating ferroptosis resistance and stemness of gastric cancer cells. Given the importance of POLQ in stemness and ferroptosis resistance of GC, we further evaluated the therapeutic potential of POLQ inhibitor novobiocin, the results show that novobiocin attenuates the stemness of GC cells and increased ferroptosis sensitivity. Moreover, the combination of POLQ inhibitor and ferroptosis inducer synergistically suppressed MGC-803 xenograft tumor growth and diminished metastasis. Our results identify a POLQ-mediated stemness and ferroptosis defense mechanism and provide a new therapeutic strategy for gastric cancer.

FAM120A deficiency improves resistance to cisplatin in gastric cancer by promoting ferroptosis

The occurrence of chemoresistance is an inescapable obstacle affecting the clinical efficacy of cisplatin in gastric cancer (GC). Exploring the regulatory mechanism of cisplatin resistance will help to provide potential effective targets for improving the prognosis of gastric cancer patients. Here, we find that FAM120A is upregulated in GC tissues and higher in cisplatin-resistant GC tissues, and its high expression is positively correlated with the poor outcome of GC patients. Functional studies indicate that FAM120A confers chemoresistance to GC cells by inhibiting ferroptosis. Mechanically, METTL3-induced m6A modification and YTHDC1-induced stability of FAM120A mRNA enhance FAM120A expression. FAM120A inhibits ferroptosis by binding SLC7A11 mRNA and enhancing its stability. FAM120A deficiency enhances cisplatin sensitivity by promoting ferroptosis in vivo. These results reveal the function of FAM120A in chemotherapy tolerance and targeting FAM120A is an effective strategy to alleviate cisplatin resistance in GC.

YTHDF2 promotes gastric cancer progression and enhances chemoradiotherapy resistance.

The role of YTHDF2 in gastric cancer (GC) is controversial. Due to the limitations of technical difficulty and experimental period, research on completely knocking out YTHDF2 is rare. Therefore, further investigations are still needed to clarify the YTHDF2's clinical significance and biological function in GC. To carry out the investigation, an analysis was performed on the expression levels of YTHDF2 in both publicly available databases and samples obtained from patients with gastric cancer. Based on the complete knockout of YTHDF2 using the CRISPR-Cas9 system, in vivo and in vitro experiments were conducted to analyze the effects of YTHDF2 on tumor formation, radiotherapy and chemoradiotherapy resistance in GC. Our investigation revealed an increase in YTHDF2 levels in GC tissues, which was found to be associated with a negative prognosis. Under hypoxic conditions, high expression of YTHDF2 enhanced the invasion of gastric cancer cells, and high expression of YTHDF2 was associated with HIF-1a. YTHDF2 facilitated gastric cancer cell growth in vitro and in vivo. Moreover, the results of the present study demonstrated that YTHDF2 mediated the expression of CyclinD1 and stability of CyclinD1 mRNA. CyclinD1 knockdown inhibited YTHDF2-mediated GC cell proliferation whereas CyclinD1 overexpression ameliorated YTHDF2 knockdown-induced inhibition of GC progression. Furthermore, YTHDF2 also promoted resistance to DDP and CTX chemotherapy, along with radiotherapy treatment for GC cells. The findings suggested that YTHDF2 expression accelerated GC progression through a potential mechanism involving CyclinD1 expression, and enhanced chemoradiotherapy resistance. This indicated that YTHDF2 could be a promising prognostic biomarker and therapeutic target for individuals diagnosed with GC.

Abstract 5583: Helicobacter pylori induces the wee1, promoting immune suppressive in human gastric adenocarcinoma

Abstract Background: Gastric cancer (GC) is the fourth most common cause of cancer-related death worldwide. GC has a dismal 5-year survival rate of about 32%. Helicobacter pylori (H. pylori) infection is the strongest risk factor for gastric carcinogenesis. 75-90% of gastric cancer patients exhibit positive H. pylori serology. WEE1 is a nuclear kinase that regulates cell cycle progression by inhibiting cyclin-dependent kinases. Methods & Results: Analysis of non-cancer normal stomach tissue (n=360) and human GC samples (n=1221) identified that WEE1 mRNA was significantly overexpressed in GC. Using immunohistochemistry (IHC) staining in 41 normal and 44 GC human samples, the data indicated that WEE1 protein was significantly overexpressed in GC. Western blot and immunofluorescence (IF) staining confirmed that H. pylori infection induces WEE1 overexpression in GC cells with an unexpected cytosolic localization of WEE1 in GC cells. Tff1 knockout GC mouse model (Tff1-/-) was infected with mouse-adapted H. pylori strain PMSS1. Western blot and immunohistochemistry data demonstrated that H. pylori infection induced WEE1 expression in Tff1 -/- HGD/cancer mouse gastric tissues compared to control Tff1 -/- mouse stomach. To study how H. pylori infection induces WEE1 in GC, analysis from miRTAR, Target Scan, and miRDB demonstrated that WEE1 is predicted to be targeted by miR-497-5p. Using qRT-PCR analysis, we assessed 30 normal and 30 GC human tissue samples, revealing a pronounced downregulation of miR-497-5p in GC specimens. Western blot analysis confirmed that the restoration of miR-497-5p in GC cells markedly reduced WEE1 protein expression. Interestingly, H. pylori infection further decreased miR-497-5p levels in GC cells, upregulating WEE1 protein expression. Since the miR-497-5P host gene promoter region contains CpG islands, we confirmed that treatment with 5 Azacytidine (demethylating agent) or DNMT1 knockdown induced expression of miR-497-5p with decreased WEE1 level in GC cells. Furthermore, our preliminary results indicate that aberrant WEE1 overexpression in GC demonstrates a significant positive correlation with immune-suppression gene signatures, underscoring its predictive value for unfavorable patient survival outcomes in GC. Using the TFF1 knockout mouse GC model, we found that WEE1 inhibition notably decreases the number and activation of CD4+ and CD8+ T cells in neoplastic gastric tissues. These findings also indicate a crucial relationship between WEE1 and the immunosuppressive microenvironment in GC, establishing WEE1 as a promising therapeutic target to enhance therapeutic efficacy and overcome immunotherapy resistance in GC. Conclusions: Our findings demonstrated a novel mechanism in which H. pylori activates the WEE1 in GC, promoting an immune suppressive microenvironment. WEE1 inhibition with immunotherapy could be a promising therapeutic method for GC patients. Citation Format: Md Obaidul Islam, Krishnapriya Thangaretnam, Heng Lu, Dunfa Peng, Nadeem Sidiq Bhat, Mohammed Soutto, Wael El-Rifai, Zheng Chen. Helicobacter pylori induces the wee1, promoting immune suppressive in human gastric adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5583.

YY1: a key regulator inhibits gastric cancer ferroptosis and mediating apatinib-resistance

ObjectiveGastric cancer (GC) stands as a prevalent and deadly global malignancy. Despite its role as a preoperative neoadjuvant therapy, Apatinib’s effectiveness is curtailed among GC patients exhibiting elevated YY1 expression. YY1’s connection to adverse prognosis, drug resistance, and GC metastasis is established, yet the precise underlying mechanisms remain elusive. This study aims to unravel potential pathogenic pathways attributed to YY1.DesignUtilizing bioinformatics analysis, we conducted differentially expressed genes, functional annotation, and pathway enrichment analyses, and further validation through cellular and animal experiments.ResultsHigher YY1 expression correlated with diminished postoperative progression-free survival (PFS) and disease-specific survival (DSS) rates in TCGA analysis, identifying YY1 as an independent DSS indicator in gastric cancer (GC) patients. Notably, YY1 exhibited significantly elevated expression in tumor tissues compared to adjacent normal tissues. Bioinformatics analysis revealed noteworthy differentially expressed genes (DEGs), transcriptional targets, factors, and co-expressed genes associated with YY1. LASSO Cox analysis unveiled Transferrin as a prospective pivotal protein regulated by YY1, with heightened expression linked to adverse DSS and PFS outcomes. YY1’s role in governing the p53 signaling pathway and ferroptosis in GC cells was further elucidated. Moreover, YY1 overexpression dampened immune cell infiltration within GC tumors. Additionally, YY1 overexpression hindered GC cell ferroptosis and mediated Apatinib resistance via the p53 pathway. Remarkably, IFN-a demonstrated efficacy in reversing Apatinib resistance and immune suppression in GC tissues.ConclusionsOur findings underscore the pivotal role of YY1 in driving GC progression and influencing prognosis, thus pinpointing it as a promising therapeutic target to enhance patient outcomes.

ITGBL1 promotes anoikis resistance and metastasis in human gastric cancer via the AKT/FBLN2 axis.

The resistance to anoikis plays a critical role in the metastatic progression of various types of malignancies, including gastric cancer (GC). Nevertheless, the precise mechanism behind anoikis resistance is not fully understood. Here, our primary focus was to examine the function and underlying molecular mechanism of Integrin beta-like 1 (ITGBL1) in the modulation of anoikis resistance and metastasis in GC. The findings of our investigation have demonstrated that the overexpression of ITGBL1 significantly augmented the resistance of GC cells to anoikis and promoted their metastatic potential, while knockdown of ITGBL1 had a suppressive effect on both cellular processes invitro and invivo. Mechanistically, we proved that ITGBL1 has a role in enhancing the resistance of GC cells to anoikis and promoting metastasis through the AKT/Fibulin-2 (FBLN2) axis. The inhibition of AKT/FBLN2 signalling was able to reverse the impact of ITGBL1 on the resistance of GC cells to anoikis and their metastatic capability. Moreover, the expression levels of ITGBL1 were found to be significantly elevated in the cancerous tissues of patients diagnosed with GC, and there was a strong correlation observed between high expression levels of ITGBL1 and worse prognosis among individuals diagnosed with GC. Significantly, it was revealed that within our cohort of GC patients, individuals exhibiting elevated ITGBL1 expression and diminished FBLN2 expression experienced the worst prognosis. In conclusion, the findings of our study indicate that ITGBL1 may serve as a possible modulator of resistance to anoikis and the metastatic process in GC.

HIPK3 maintains sensitivity to platinum drugs and prevents disease progression in gastric cancer

In the realm of cancer therapeutics and resistance, kinases play a crucial role, particularly in gastric cancer (GC). Our study focused on platinum-based chemotherapy resistance in GC, revealing a significant reduction in homeodomain-interacting protein kinase 3 (HIPK3) expression in platinum-resistant tumors through meticulous analysis of transcriptome datasets. In vitro and in vivo experiments demonstrated that HIPK3 knockdown enhanced tumor proliferation and metastasis, while upregulation had the opposite effect. We identified the myocyte enhancer factor 2C (MEF2C) as a transcriptional regulator of HIPK3 and uncovered HIPK3's role in downregulating the morphogenesis regulator microtubule-associated protein (MAP7) through ubiquitination. Phosphoproteome profiling revealed HIPK3's inhibitory effects on mTOR and Wnt pathways crucial in cell proliferation and movement. A combined treatment strategy involving oxaliplatin, rapamycin, and IWR1-1-endo effectively overcame platinum resistance induced by reduced HIPK3 expression. Monitoring HIPK3 levels could serve as a GC malignancy and platinum resistance indicator, with our proposed treatment strategy offering novel avenues for reversing resistance in gastric cancer.

Gastric cancer mesenchymal stem cells promote tumor glycolysis and chemoresistance by regulating B7H3 in gastric cancer cells.

Despite surgical treatment combined with multidrug therapy having made some progress, chemotherapy resistance is the main cause of recurrence and death of gastric cancer (GC).Gastric cancer mesenchymal stem cells (GCMSCs)have been reported to be correlated with the limited efficacy of chemotherapy in GC, but the mechanism of GCMSCs regulating GC resistance needs to be further studied. The gene set enrichment analysis (GSEA)was performed to explore the glycolysis-related pathways heterogeneity across different cell subpopulations. Glucose uptake and lactate production assays were used to evaluate the importance of B7H3 expression in GCMSCs-treated GCcells. The therapeutic efficacy of oxaliplatin (OXA)and paclitaxel (PTX)was determined using CCK-8and colony formation assays. Signaling pathways altered by GCMSCs-CMwere revealed by immunoblotting. The expression of TNF-αin GCMSCs and bone marrow mesenchymal stem cells (BMMSCs)was detected by western blot analysis and qPCR. Our results showed that the OXA and PTX resistance of GC cells were significantly enhanced in the GCMSCs-CMtreated GC cells. Acquired OXA and PTX resistance was characterized by increased cell viability for OXA and PTX, the formation of cell colonies, and decreased levels of cell apoptosis, which were accompanied by reduced levels of cleaved caspase-3 and Bax expression, and increased levels of Bcl-2, HK2, MDR1, and B7H3 expression. Blocking TNF-αin GCMSCs-CM,B7H3 knockdown or the use of 2-DG,a key enzyme inhibitor of glycolysis in GC cells suppressed the OXA and PTX resistance of GC cells that had been treated with GCMSCs-CM. This study shows that GCMSCs-CMderived TNF-α could upregulate the expression of B7H3 of GC cells to promote tumor chemoresistance. Our results provide a new basis for the treatment of GC.

The ZuoJinWan formula inhibits glycolysis of cisplatin resistant gastric cancer cells via p53 acetylation

IntroductionGastric cancer is one of the common malignancies worldwide, and drug resistance is a major factor contributing to the difficulty of treatment in gastric cancer. Zuojinwan (ZJW) has been found to exhibit a certain inhibitory effect on tumor cells. However, the molecular mechanisms of ZJW reversing drug resistance in gastric cancer are still unclear. MethodHuman gastric cancer cisplatin-resistant cells SGC-7901/DDP and BGC-823/DDP were divided into control groups, DDP groups (10 μg/mL), 2-DG (5 mM) groups, and ZJW (50 μg/mL) combined with DDP (10 μg/mL) groups. After 48 h of culture, cell proliferation inhibition rate, glucose uptake rate, ATP, and lactate production were detected. Following lentiviral transfection to overexpress GLUT1 and HDAC1, western blot analysis was employed to examine the expression of HDAC1, P53, Ace-p53, and glucose metabolism-related proteins such as GLUT1, LDHA, HK II in the cells. ResultsThe combination of ZJW and DDP significantly inhibits the proliferation and glycolysis of cisplatin resistant gastric cancer cells. Compared with the DDP group, the combination of ZJW and DDP exhibited a higher inhibition rate (P < 0.01), accompanied by a reduction in the expression of HDAC1 and P53 proteins. ConclusionsZuojinwan can enhance the proliferation inhibition rate of SGC-7901/DDP and BGC-823/DDP cells, attenuate glycolysis, and reduce chemotherapy resistance. Its mechanism may be associated with the inhibition of HDAC1/P53 axis activity.

SIVA-1 interaction with PCBP1 serves as a predictive biomarker for cisplatin sensitivity in gastric cancer and its inhibitory effect on tumor growth in vivo.

Background: SIVA-1 has been reported to play a key role in cell apoptosis and gastric cancer (GC) chemoresistance in vitro. Nevertheless, the clinical significance of SIVA-1 in GC chemotherapy remains unclear. Methods and results: Immunohistochemistry and histoculture drug response assays were used to determine SIVA-1 expression and the inhibition rate (IR) of agents to GC and to further analyze the relationship between these two phenomena. Additionally, cisplatin (DDP)-resistant GC cells were used to elucidate the role and mechanism of SIVA-1 in vivo. The results demonstrated that SIVA-1 expression was positively correlated with the IR of DDP to GC but not with those of 5-fluorouracil (5-FU) or adriamycin (ADM). Furthermore, SIVA-1 overexpression with DDP treatment synergistically inhibited tumor growth in vivo by increasing PCBP1 and decreasing Bcl-2 and Bcl-xL expression. Conclusions: Our study demonstrated that SIVA-1 may serve as an indicator of the GC sensitivity to DDP, and the mechanism of SIVA-1 in GC resistance to DDP was preliminarily revealed.

Unraveling the Role of GPX4 Pathway in Ferroptosis and its Implications for Gastric Cancer Management

Gastric Cancer (GC) presents a significant global health concern due to its high incidence and mortality rates. Despite advancements in medical treatments, drug resistance poses a major challenge in managing GC. Ferroptosis, a form of programmed cell death driven by iron-dependent lipid peroxidation, has emerged as a key contributor to treatment resistance in GC. The pivotal role of GPX4, a regulator of ferroptosis, has garnered considerable attention in cancer research. GPX4 synthesis and expression are subject to regulation at multiple levels, including transcription, translation, and posttranslational modifications. Ongoing development of pharmacological therapeutics targeting GPX4 aims to induce ferroptosis in cancer cells. This review provides an overview of the GPX4 pathway’s involvement in GC, shedding light on the implications of ferroptosis induction in combatting cancer resilience. These findings emphasize the therapeutic potential of GPX4 in managing gastric cancer and other malignancies, presenting novel opportunities to address the challenges of treatment resistance.

Regulatory mechanism and promising clinical application of exosomal circular RNA in gastric cancer

Gastric cancer (GC) is one of the most common malignancies worldwide and the leading cause of cancer-related deaths. Exosomes are nanoscale extracellular vesicles secreted by a variety of cells and play an important role in cellular communication and epigenetics by transporting bioactive substances in the tumor microenvironment (TME). Circular RNA (circRNA) is a type of non-coding RNA (ncRNA) with a specific structure, which is widely enriched in exosomes and is involved in various pathophysiological processes mediated by exosomes. Exosomal circRNAs play a critical role in the development of GC by regulating epithelial-mesenchymal transition (EMT), angiogenesis, proliferation, invasion, migration, and metastasis of GC. Given the biological characteristics of exosomal circRNAs, they have more significant diagnostic sensitivity and specificity in the clinic and may become biomarkers for GC diagnosis and prognosis. In this review, we briefly describe the biogenesis of exosomes and circRNAs and their biological functions, comprehensively summarize the mechanisms of exosomal circRNAs in the development of GC and chemotherapy resistance, and finally, we discuss the potential clinical application value and challenges of exosomal circRNAs in GC.