Effect of Fibulin-5 on cell proliferation and invasion in human gastric cancer patients

Objective:To explore the effect of Fibulin-5 expression on cell proliferation and invasion in human gastric cancer patients.Methods:Fibulin-5 expression was detected in 56 samples of surgically resected gastric cancer and paired noncancerous tissues using qRT-PCR and immunoblotting.Fibulin-5 was knocked dowu by Fibulin-5 shRNA in MGC-803 cells,then Brdu cell proliferation and transwell invasion assays were used to determine cell proliferation and invasion.Results:The level of Fibulin-5 mRNA in gastric cancer tissues was significantly higher as compared with that in normal tumor-adjacent tissues(P<0.05).Otherwise,the level of Fibulin-5 protein in cancer and noucancerous tissues was consistent with mRNA expression(P<0.05).Fibulin-5 protein expression in tumor tissues with poorly differentiated.lymph node metastasis and advanced TNM tumor stage was significantly higher(P<0.05.respectively).Fibulin-5 was obviously knocked down by Fibulin-5 shRNA(P<0.05).and Fibulin-5 knockdown significantly inhibited cell proliferation and invasion in MGC-803 cells(P<0.05.respectively).Conclusions:The high-expression of Fibulin-5 is associated with the malignant clinicopathologic parameters in gastric cancer and Fibuliu-5 knockdown inhibits cell proliferation and invasion in MGC-803 cells.suggesting Fibulin-5 may act as a key factor in the progression of gastric cancer.

METTL5 promotes gastric cancer progression via sphingomyelin metabolism

BACKGROUND The treatment of gastric cancer(GC)has caused an enormous social burden worldwide.Accumulating studies have reported that N6-methyladenosine(m6A)is closely related to tumor progression.METTL5 is a m6A methyltransferase that plays a pivotal role in maintaining the metabolic stability of cells.However,its aberrant regulation in GC has not been fully elucidated.AIM To excavate the role of METTL5 in the development of GC.METHODS METTL5 expression and clinicopathological characteristics were analyzed via The Cancer Genome Atlas dataset and further verified via immunohistochemistry,western blotting and real-time quantitative polymerase chain reaction in tissue microarrays and clinical samples.The tumor-promoting effect of METTL5 on HGC-27 and AGS cells was explored in vitro by Cell Counting Kit-8 assays,colony formation assays,scratch healing assays,transwell assays and flow cytometry.The tumor-promoting role of METTL5 in vivo was evaluated in a xenograft tumor model.The EpiQuik m6A RNA Methylation Quantification Kit was used for m6A quantification.Next,liquid chromatography-mass spectrometry was used to evaluate the association between METTL5 and sphingomyelin metabolism,which was confirmed by Enzyme-linked immunosorbent assay and rescue tests.In addition,we investigated whether METTL5 affects the sensitivity of GC cells to cisplatin via colony formation and transwell experiments.RESULTS Our research revealed substantial upregulation of METTL5,which suggested a poor prognosis of GC patients.Increased METTL5 expression indicated distant lymph node metastasis,advanced cancer stage and pathological grade.An increased level of METTL5 correlated with a high degree of m6A methylation.METTL5 markedly promotes the proliferation,migration,and invasion of GC cells in vitro.METTL5 also promotes the growth of GC in animal models.METTL5 knockdown resulted in significant changes in sphingomyelin metabolism,which implies that METTL5 may impact the development of GC via sphingomyelin metabolism.In addition,high METTL5 expression led to cisplatin resistance.CONCLUSION METTL5 was found to be an oncogenic driver of GC and may be a new target for therapy since it facilitates GC carcinogenesis through sphingomyelin metabolism and cisplatin resistance.

MiRNA-145-5p inhibits gastric cancer progression via the serpin family E member 1-extracellular signal-regulated kinase-1/2 axis

BACKGROUND MicroRNAs(miRNAs)regulate gene expression and play a critical role in cancer physiology.However,there is still a limited understanding of the function and regulatory mechanism of miRNAs in gastric cancer(GC).AIM To investigate the role and molecular mechanism of miRNA-145-5p(miR145-5p)in the progression of GC.METHODS Real-time polymerase chain reaction(RT-PCR)was used to detect miRNA expression in human GC tissues and cells.The ability of cancer cells to migrate and invade was assessed using wound-healing and transwell assays,respectively.Cell proliferation was measured using cell counting kit-8 and colony formation assays,and apoptosis was evaluated using flow cytometry.Expression of the epithelial-mesenchymal transition(EMT)-associated protein was determined by Western blot.Targets of miR-145-5p were predicated using bioinformatics analysis and verified using a dual-luciferase reporter system.Serpin family E member 1(SERPINE1)expression in GC tissues and cells was evaluated using RT-PCR and immunohistochemical staining.The correlation between SERPINE1 expression and overall patient survival was determined using Kaplan-Meier plot analysis.The association between SERPINE1 and GC progression was also tested.A rescue experiment of SERPINE1 overexpression was conducted to verify the relationship between this protein and miR-145-5p.The mechanism by which miR-145-5p influences GC progression was further explored by assessing tumor formation in nude mice.RESULTS GC tissues and cells had reduced miR-145-5p expression and SERPINE1 was identified as a direct target of this miRNA.Overexpression of miR-145-5p was associated with decreased GC cell proliferation,invasion,migration,and EMT,and these effects were reversed by forcing SERPINE1 expression.Kaplan-Meier plot analysis revealed that patients with higher SERPINE1 expression had a shorter survival rate than those with lower SERPINE1 expression.Nude mouse tumorigenesis experiments confirmed that miR-145-5p targets SERPINE1 to regulate extracellular signal-regulated kinase-1/2(ERK1/2).CONCLUSION This study found that miR-145-5p inhibits tumor progression and is expressed in lower amounts in patients with GC.MiR-145-5p was found to affect GC cell proliferation,migration,and invasion by negatively regulating SERPINE1 levels and controlling the ERK1/2 pathway.

Targeting methyltransferase-like 5-mediated sphingomyelin metabolism:A novel therapeutic approach in gastric cancer

Gastric cancer(GC)is a global health problem and a leading cause of cancerrelated deaths,with its mortality rate ranking third among all cancers.The etiology and progression of GC are characterized by a complex interplay of genetic and epigenetic changes,which present challenges for its early diagnosis and effective treatment.Elucidating the mechanisms underlying the occurrence and development of GC and identifying novel biomarkers for early detection and prognosis are crucial to improving patient outcomes.This editorial examines the role of methyltransferase-like 5(METTL5)in the progression of GC through sphingomyelin metabolism by considering an article published by Zhang et al in the World Journal of Gastrointestinal Oncology in 2024,which is entitled“METTL5 promotes GC progression via sphingomyelin metabolism”.These authors investigated the biological behavior of METTL5 in GC by examining its expression patterns,clinical relevance,functional effect,and potential mechanisms,as well as its response to chemotherapy.This editorial provides valuable insights into the role of METTL5 in the progression of GC and its potential as a therapeutic target.

Expression and significant roles of the long non-coding RNA CASC19/miR-491-5p/HMGA2 axis in the development of gastric cancer

BACKGROUND Gastric cancer(GC)is a common malignant tumor,long non-coding RNA and microRNA(miRNA)are important regulators that affect tumor proliferation,metastasis and chemotherapy resistance,and thus participate in tumor progression.CASC19 is a new bio-marker which can promote tumor invasion and metastasis.However,the mechanism by which CASC19 affects the progression of GC through miRNA is not clear.AIM To explore the role of the CASC19/miR-491-5p/HMGA2 regulatory axis in GC.METHODS To explore the expression and prognosis of CASC19 in GC through clinical samples,and investigate the effects of inhibiting CASC19 on the proliferation,migration,invasion and other functions of GC cells through cell counting Kit-8(CCK-8),ethynyldeoxyuridine,Wound healing assay,Transwell,Western blot and flow cytometry experiments.The effect of miR-491-5p and HMGA2 in GC were also proved.The regulatory relationship between CASC19 and miR-491-5p,miR-491-5p and HMGA2 were validated through Dual-luciferase reporter gene assay and reverse transcription PCR.Then CCK-8,Transwell,Wound healing assay,flow cytometry and animal experiments verify the role of CASC19/miR-491-5p/HMGA2 regulatory axis.RESULTS The expression level of CASC19 is related to the T stage,N stage,and tumor size of patients.Knockdown of the expression of CASC19 can inhibit the ability of proliferation,migration,invasion and EMT conversion of GC cells,and knocking down the expression of CASC19 can promote the apoptosis of GC cells.Increasing the expression of miR-491-5p can inhibit the proliferation of GC cells,miR-491-5p mimics can inhibit EMT conversion,and promote the apoptosis of GC cells,while decreasing the expression of miR-491-5p can promote the proliferation and EMT conversion and inhibit the apoptosis of GC cells.The expression of HMGA2 in GC tissues is higher than that in adjacent tissues.At the same time,the expression level of HMGA2 is related to the N and T stages of the patients.Reducing the level of HMGA2 can promote cell apoptosis and inhibit the proliferation of GC cells.Cell experiments and animal experiments have proved that CASC19 can regulates the expression of HMGA2 through miR-491-5p,thereby affecting the biological functions of GC.CONCLUSION CASC19 regulates the expression of HMGA2 through miR-491-5p to affect the development of GC.This axis may serve as a potential biomarker and therapeutic target of GC.

Expression of Rab25 correlates with the invasion and metastasis of gastric cancer

The objective of this study was to determine the expression of the important vesicle trafficking- regulating factor Rab25 in human gastric cancer tissues, to analyze the correlation between Rab25 protein expression with gastric cancer occurrence and development, and to discuss the correlation of Rab25 protein expression with gastric cancer cell metastasis. The overall aim was to provide experimental evidence that can be used to design future biological treatments of human gastric cancer. Human gastric cancer tissue and the adjacent normal gastric tissue were surgically removed, and immunohistochemistry and Western blotting were used to detect Rab25 protein expression. The correlation between Rab25 protein expression with the development and pathological characteristics of gastric cancer was analyzed. Using RNAi, Rab25 expression was reduced in the gastric cancer cell line MGC80-3, and the changes in MGC80-3 cell invasiveness were then monitored. Immunohistochemistry showed that the Rab25 protein expression rates were 78.21% and 23.08% in gastric carcinoma and the adjacent normal gastric tissue, respectively. Immunohistochemistry and Western blot results showed that Rab25 protein expression in gastric cancer was significantly higher than in adjacent normal gastric tissues （t）〈0.01）. Less differentiated gastric cancer cells had higher expression of Rab25 protein （P〈0.01）. Gastric carcinomas from patients with a late pathological stage （Ⅲ-Ⅳ） had significantly higher Rab25 protein expression than early stage （Ⅰ-Ⅱ） patients （P〈0.01）. Gastric carcinomas from patients with lymph node metastasis had significantly higher Rab25 protein expression than lymph node metastasis- free patients （P〈0.01）. Gastric carcinomas from patients with distant metastases had significantly higher Rab25 protein expression than the distant metastasis-negative patients （P〈0.01）. Rab25 protein expression in gastric cancer was not affected by the patients＇ sex, age, or tumor size （P〉0.05）. MGCS0-3 cells transfected with Rab25 siRNA had significantly lower Rab25 protein expression （P〈0.01） and a significantly lower number of cells that passed through a Transwell chamber compared with non-transfected controls and the transfected control group （P〈0.01）. Rab25 protein expression is associated with the development of gastric cancer, siRNA knockdown of Rab25 protein expression in MGC80-3 gastric cancer cells reduced MGC80-3 cell invasiveness and provided experimental evidence for potential future biological treatment strategies of human gastric cancer.

The F5 gene predicts poor prognosis of patients with gastric cancer by promoting cell migration identified using a weighted gene co-expression network analysis

Distal gastric cancer(DGC)is a subgroup of gastric cancer(GC),which has different molecular characteristics from proximal gastric cancer(PGC).These differences result in different overall survival(OS)rates;however,data pertaining to the survival rate in PGC or DGC are contradictory.This suggests that the location of GC is not the unique cause of the different survival rates,while the molecular characteristics might be more important factors determining the prognosis of DGC.Therefore,the aim of this study was to discover key prognostic factors in DGC using bioinformatic methods and to explore the potential molecular mechanism.The Cancer Genome Atlas(TCGA)public database was employed to screen data relating to DGC,and we conducted a weighted gene co-expression network analysis(WGCNA)on DGC patient samples to establish co-expression modules.High-weight genes(hub genes)in a dominant color module were identified.In vitro experiments and gene set enrichment analyses(GSEA)were carried out to elucidate the potential molecular mechanism.In this study,139 DGC samples were enrolled to perform a co-expression analysis.According to the correlation between gene modules and clinical characteristics,the royal blue module related to stage M of DGC was screened,and a survival analysis was conducted to show that highcoagulation-factor V(F5)expression was related to the short OS of patients with GC.In vitro experiments confirmed that F5 could promote the migration of GC cells.GSEA suggested that F5 might have affected the prognosis of GC by modulating the activities of the Wnt and/or the TGF-βsignaling pathways.Our results indicated that high F5 expression predicts poor prognosis of patients with DGC,and it functions probably by promoting cell migration through the Wnt and/or the TGF-βsignaling pathways.

LGR5 is a promising biomarker for patients with stage Ⅰ and Ⅱ gastric cancer

Objective： To investigate Leucine-rich repeat-containing G protein-coupled receptor 5 （LGR5） expressions in gastric cancer and to evaluate its clinical significance. Methods： LGR5 expression was assessed by immunohistochemistry in 257 gastric cancer patients after surgery. The relationships between LGR5 expression and clinicopathological features and patients prognosis were statistically analyzed. Results： The expression of LGR5 was significantly higher in gastric cancers as a cancer stem cell marker than in adjacent normal tissues （P〈0.001）, and more frequently in patients with intestinal type, well-moderate differentiation and stage I and II （P〈0.05）. Although we found gastric cancer patients with LGR5 positive expression had a poorer prognosis, it didn＇t meet statistical significance （P〉0.05）. LGR5 negative expression was significantly related to the favorable overall survival in stage I and II gastric cancer patients （P〈0.05）. Furthermore, patients with high LGR5 expression tended to be more likely to get progression and have poorer progress-free survival （P〈0.05）. Multivariate Cox regression analysis revealed that LGR5 expression was an independent factor of overall survival for the patients with stage I and II gastric cancer （P〈0.05）. Conclusions： Our results show that LGR5 may play an important role in tumorigenesis and progression and would be a powerful marker to predict the prognosis of patients with stage I and II gastric cancer.

Synergistic anticancer properties of docosahexaenoic acid and 5-fluorouracil through interference with energy metabolism and cell cycle arrest in human gastric cancer cell line AGS cells

AIM: To explore the synergistic effect of docosahexaenoic acid(DHA)/5-fluorouracil(5-FU) on the human gastric cancer cell line AGS and examine the underlying mechanism.METHODS: AGS cells were cultured and treated with a series of concentrations of DHA and 5-FU alone or in combination for 24 and 48 h. To investigate the synergistic effect of DHA and 5-FU on AGS cells, the inhibition of cell proliferation was determined by MTT assay and cell morphology. Flow cytometric analysis was also used to assess cell cycle distribution, and the expression of mitochondrial electron transfer chain complexes(METCs)?Ⅰ, Ⅱ and Ⅴ in AGS cells was further determined by Western blot analysis. RESULTS: DHA and 5-FU alone or in combination could markedly suppress the proliferation of AGS cells in a significant time and dose-dependent manner. DHA markedly strengthened the antiproliferative effect of 5-FU, decreasing the IC50 by 3.56-2.15-fold in an apparent synergy. The morphological changes of the cells were characterized by shrinkage, cell membrane blebbing and decreased adherence. Cell cycle analysis showed a shift of cells into the G0/G1 phase from the S phase following treatment with DHA or 5-FU(G0/G1 phase: 30.04% ± 1.54% vs 49.05% ± 6.41% and 63.39% ± 6.83%, respectively, P < 0.05; S phase: 56.76% ± 3.14% vs 34.75% ± 2.35% and 25.63% ± 2.21%, respectively, P < 0.05). Combination treatment of DHA and 5-FU resulted in a significantly larger shift toward the G0/G1 phase and subsequent reduction in S phase(G0/G1 phase: 69.06% ± 2.63% vs 49.05% ± 6.41% and 63.39% ± 6.83%, respectively, P < 0.05; S phase: 19.80% ± 4.30% vs 34.75% ± 2.35% and 25.63% ± 2.21%, respectively, P < 0.05). This synergy was also reflected in the significant downregulation of the expression of METCs in AGS cells.CONCLUSION: Synergistic anticancer properties of DHA and 5-FU may involve interference with energy production of AGS cells via downregulation of METCs and cell cycle arrest.

Regulation of demethylation and re-expression of RASSF1A gene in gastric cancer cell lines by combined treatment of 5-Aza-CdR and NaB

AIM： To investigate the changes of methylation state and expression of RASSF1A gene in human gastric cancer cell lines SGC7901 and BGC823 which were treated in vitro with demethlylating agent 5-Aza-CdR in combination with histone deacetylase inhibitor NaB. METHODS： After SGC7901 and BGC823 cells were treated with 5-Aza-CdR and/or NaB, the methylation state of RASSFIA gene was detected by methylationspecific PCR, and the changes in expression of mRNA and protein level of RASSFIA gene were observed by RT-PCR and Western-blotting before and after drug treatment. RESULTS： Hypermethylation was detected in the promoter region of RASSF1A gene in both SGC7901 and BGC823 cells, and there was no expression of this gene at both mRNA and protein level. After treatment with 5-Aza-CdR, demethylation occurred in the promoter region of RASSFIA gene, which subsequently induced re-expression of this gene. The treatment with NaB alone showed no effect on the methylation state and expression of RASSFIA gene. The combined treatment of 5-Aza-CdR and NaB induced complete demethylation of RASSFIA gene, leading to a significantly higher reexpression of the mRNA and protein of RASSFIA than those treated with 5-Aza-CdR alone （P 〈 0.05）. CONCLUSION： Hypermethylation in the promoter region is related to inactivation of RASSFIA gene in human gastric cancer cell lines SGC7901 and BGC823, while demethlylating agent 5-Aza-CdR can reverse the methylation state of RASSF1A gene and induce itsre-expression. Histone deacetylase inhibitor NaB had a synergistic effect with 5-Aza-CdR in both demethylation and gene transcriptional regulation.

Extract of Cycas revoluta Thunb. enhances the inhibitory effect of 5-fluorouracil on gastric cancer cells through the AKT-mTOR pathway

BACKGROUND Gastric cancer is one of the most common and deadly malignancies worldwide.Despite recent medical progress, the 5-year survival rate of gastric cancer is still unsatisfactory. 5-fluorouracil(5-Fu) is one of the first-line antineoplastic treatments for gastric cancer, as it can effectively induce cancer cell apoptosis.However, the effect of 5-Fu is limited due to drug resistance of the malignant tumor. Previous studies have reported that Sotetsuflavone from Cycas revoluta Thunb. can markedly suppress lung cancer cell proliferation by apoptosis,though its effect on gastric cancer remains unknown.AIM To investigate the inhibitory effect of Cycas revoluta Thunb. and to determine whether it can overcome gastric cancer cell drug resistance to 5-Fu.METHODS Cell viability was examined to determine whether the natural extract of Cycas revoluta Thunb. induced gastric cancer cell death. The half-maximal effective concentration and the half-maximal lethal concentration were calculatede.Wound-healing and transwell assays were performed to examine gastric cancer cell motility. Clonogenic assays were performed to investigate the synergistic effects of Cycas revoluta Thunb. with 5-Fu, and apoptotic bodies were detected by Hoechst staining. Western blotting was performed to examine the expression of related proteins and to investigate the molecular mechanism of Cycas revoluta Thunb.-induced cancer cell apoptosis. The expressions of proteins, including mammalian target of rapamycin(mTOR) and p-AKT, were detected in different combinations of treatments for 48 h, then analyzed by ECL detection.RESULTS Gastric cancer cells were more sensitive to the natural extract of Cycas revoluta Thunb. compared to normal gastric epithelial cells, and the extract effectively inhibited gastric cancer cell migration and invasion. The extract improved the anti-cancer effect of 5-Fu by enhancing the chemosensitization of gastric cancer cells. Extract plus 5-Fu further reduced the expression of the drug-resistancerelated proteins p-AKT and mTOR after 48 h compared to 5-Fu alone. Compared to 5-Fu treatment alone, mTOR and p-AKT expression was significantly reduced by about 50% and 75%, respectively. We also found that the natural extract of Cycas revoluta Thunb. further increased 5-Fu-induced gastric cancer cell apoptosis. Expression of apoptosis-related protein X-linked inhibitor of apoptosis protein and apoptosis inducing factor were significantly reduced and increased,respectively, in the 5-Fu-resistant gastric cancer line SGC-7901/R treated with extract plus 5-Fu, while the expression of survivin did not change.CONCLUSION The natural extract of Cycas revoluta Thunb. effectively inhibited gastric cancer cell growth and enhanced the anti-cancer effect of 5-Fu through the AKT-mTOR pathway.

Non-platinum-based chemotherapy for treatment of advanced gastric cancer:5-fluorouracil,taxanes,and irinotecan

Despite numerous advances in treatment options,advanced gastric cancer(AGC)remains a major public health issue and the leading cause of cancer-related deaths.Cisplatin is one of the most effective broadspectrum anticancer drugs for AGC and a doublet combination regimen of either cisplatin-based or 5-fluorouracil(5FU)-based chemotherapy is generally used for treatment of patients with AGC.However,there is still no consensus on the best regimen for treating AGC.Recently,various new chemotherapeutic agents,including oral 5FU,taxanes,and irinotecan,have been identified as improving the outcomes for AGC when used as a single agent or in combination with nonplatinum chemotherapy.Nonetheless,it is still unclear whether non-platinum-based chemotherapy is a viable treatment option for patients with AGC.Accordingly,this review focuses on the efficacy and tolerability of non-platinum-based chemotherapy for patients with AGC.

Docetaxel, cisplatin, and 5-fluorouracil compared with epirubicin,cisplatin, and 5-fluorouracil regimen for advanced gastric cancer:A systematic review and meta-analysis

BACKGROUND As the first-line regimens for the treatment of advanced gastric cancer, both docetaxel, cisplatin, and 5-fluorouracil(DCF) and epirubicin, cisplatin, and 5-fluorouracil(ECF) regimens are commonly used in clinical practice, but there is still controversy about which is better.AIM To compare the efficacy and safety of DCF and ECF regimens by conducting this meta-analysis.METHODS Computer searches in PubMed, EMBASE, Ovid MEDLINE, Science Direct, Web of Science, The Cochrane Library and Scopus were performed to find the clinical studies of all comparisons between DCF and ECF regimens. We used progression-free survival(PFS), overall survival(OS), objective response rate(ORR), disease control rate(DCR), and adverse effects(AEs) as endpoints for analysis.RESULTS Our meta-analysis included seven qualified studies involving a total of 598 patients. The pooled hazard ratios between the DCF and ECF groups were comparable in PFS(95%CI: 0.58-1.46, P = 0.73), OS(95%CI: 0.65-1.10, P = 0.21),and total AEs(95%CI: 0.93-1.29, P = 0.30). The DCF group was significantly better than the ECF group in terms of ORR(95%CI: 1.13-1.75, P = 0.002) and DCR(95%CI: 1.03-1.41, P = 0.02). However, the incidence rate of grade 3-4 AEs was also greater in the DCF group than in the ECF group(95%CI: 1.16-1.88, P = 0.002),especially for neutropenia and febrile neutropenia.CONCLUSION With better ORR and DCR values, the DCF regimen seems to be more suitable for advanced gastric cancer than the ECF regimen. However, the higher rate of AEs in the DCF group still needs to be noticed.

Impact of SNP-SNP interactions of DNA repair gene ERCC5 and metabolic gene GSTP1 on gastric cancer/atrophic gastritis risk in a Chinese population

AIM To investigate the interactions of the DNA repair gene excision repair cross complementing group 5(ERCC5) and the metabolic gene glutathione S-transferase pi 1(GSTP1) and their effects on atrophic gastritis(AG) and gastric cancer(GC) risk.METHODS Seven ERCC5 single nucleotide polymorphisms(SNPs)(rs1047768, rs2094258, rs2228959, rs4150291, rs4150383, rs751402, and rs873601) and GSTP1 SNP rs1695 were detected using the Sequenom MassA RRAY platform in 450 GC patients, 634 AG cases, and 621 healthy control subjects in a Chinese population.RESULTS Two pairwise combinations(ERCC5 rs2094258 and rs873601 with GSTP1 rs1695) influenced AG risk(P_(interaction) = 0.008 and 0.043, respectively), and the ERCC5 rs2094258-GSTP1 rs1695 SNP pair demonstrated an antagonistic effect, while ERCC5 rs873601-GSTP1 rs1695 showed a synergistic effect on AG risk OR = 0.51 and 1.79, respectively). No pairwise combinations were observed in relation to GC risk. There were no cumulative effects among the pairwise interactions(ERCC5 rs2094258 and rs873601 with GSTP1 rs1695) on AG susceptibility(P_(trend) > 0.05). When the modification effect of Helicobacter pylori(H. pylori) infection was evaluated, the cumulative effect of one of the aforementioned pairwise interactions(ERCC5 rs873601-GSTP1 rs1695) was associated with an increased AG risk in the case of negative H. pylori status(P_(trend)= 0.043).CONCLUSION There is a multifarious interaction between the DNA repair gene ERCC5 SNPs(rs2094258 and rs873601) and the metabolic gene GSTP1 rs1695, which may form the basis for various inter-individual susceptibilities to AG.

Circular RNA circVAPA promotes chemotherapy drug resistance in gastric cancer progression by regulating miR-125b-5p/STAT3 axis

BACKGROUND Gastric cancer(GC)is a prevalent malignancy,leading to a high incidence of cancer-associated death.Cisplatin(DDP)-based chemotherapy is the principal therapy for clinical GC treatment,but DDP resistance is a severe clinical challenge and the mechanism remains poorly understood.Circular RNAs(circRNAs)have been identified to play crucial roles in modulating the chemoresistance of gastric cancer cells.AIM To explore the effect of circVAPA on chemotherapy resistance during GC progression.METHODS The effect of circVAPA on GC progression and chemotherapy resistance was analyzed by MTT assay,colony formation assay,Transwell assay,wound healing assay,and flow cytometry analysis in GC cells and DDP resistant GC cell lines,and tumorigenicity analysis in nude mice in vivo.The mechanism was investigated by luciferase reporter assay,quantitative real-time PCR,and Western blot analysis.RESULTS CircVAPA expression was up-regulated in clinical GC tissues compared with normal samples.CircVAPA depletion inhibited proliferation,migration,and invasion and increased apoptosis of GC cells.The expression of circVAPA,STAT3,and STAT3 downstream genes was elevated in DDP resistant SGC7901/DDP cell lines.CircVAPA knockdown attenuated the DDP resistance of GC cells.Mechanically,circVAPA was able to sponge miR-125b-5p,and miR-125b-5p could target STAT3 in the GC cells.MiR-125b-5p inhibitor reversed circVAPA depletion-enhanced inhibitory effect of DDP on GC cells,and STAT3 knockdown blocked circVAPA overexpression-induced proliferation of DDPtreated SGC7901/DDP cells.The depletion of STAT3 and miR-125b-5p inhibitor reversed circVAPA depletion-induced GC cell apoptosis.Functionally,circVAPA contributed to the tumor growth of SGC7901/DDP cells in vivo.CONCLUSION CircVAPA promotes chemotherapy resistance and malignant progression in GC by miR-125b-5p/STAT3 signaling.Our findings present novel insights into the mechanism by which circVAPA regulates chemotherapy resistance of GC cells.CircVAPA and miR-125b-5p may be considered as the potential targets for GC therapy.

miR-374b-5p suppresses RECK expression and promotes gastric cancer cell invasion and metastasis

AIM: To profile expression of microRNAs (miRNAs) in gastric cancer cells and investigate the effect of miR-374b-5p on gastric cancer cell invasion and metastasis.

miR-122-5p as a novel biomarker for alpha-fetoproteinproducing gastric cancer

AIM To investigate the clinical utility of alpha-fetoprotein(AFP)-producing gastric cancer(AFPGC)-specific microRNA(mi RNA)for monitoring and prognostic prediction of patients.METHODS We performed a comprehensive miRNA array-based approach to compare miRNA expression levels between AFP-positive and AFP-negative cells in three patients with primary AFPGC.We next examined the expression levels of the selected miRNAs in five AFPGC and ten non-AFPGC tissue samples by quantitative reverse transcription-polymerase chain reaction to validate their utility.We also investigated the expression levels of the selected miRNA not only in tissue but also in plasma samples.Moreover,we investigated the relationship between plasma AFP levels and plasma selected miRNA expression levels,and also investigated the correlation of the selected miRNA expression levels and malignant potential.RESULTS Among the five miRNAs selected from the miRNA array results,the expression levels of miR-122-5p were significantly higher in the AFPGC patients than in the non-AFPGC patients(P<0.05).In tissue samples,mi R-122-5p expression level tended to be lower in the non-AFPGC tissue than the normal gastric mucosa.Conversely,in the AFPGC tissue,miR-122-5p expression level was significantly higher in the AFPGC tissue than both the normal gastric mucosa and the nonAFPGC tissue samples(P<0.05).Plasma mi R-122-5p expression levels were also significantly higher in the AFPGC patients than the health volunteers and the nonAFPGC patients(P<0.05)and were strongly correlated with plasma AFP levels(r=0.7975,P<0.0001).Moreover,the correlation of miR-122-5p expression in tissue samples with malignant potential was stronger than that of plasma AFP level in the AFPGC patients.In contrast,no correlation was found between mi R-122-5p expression levels and liver metastasis in the non-AFPGC patients.CONCLUSION miR-122-5p might be a useful biomarker for early detection and disease monitoring in AFPGC.

Thymidylate synthase and thymidine phosphorylase gene expression as predictive parameters for the efficacy of 5-fluorouraci-based adjuvant chemotherapy for gastric cancer

AIM： To investigate the prognostic role of thymidylate synthase （TS） and thymidine phosphorylase （TP） mRNA levels in T3 or T4 gastric cancer treated with 5-fluorouraci-based adjuvant chemotherapy. METHODS： Fifty-one patients with T3 or T4 gastric cancer received systemic 5-fluorouraci-based adjuvant chemotherapy, and intratumoral expression of TS and TP in 51 gastric cancer tissue samples was tested by realtime quantitative PCR.RESULTS： The median disease-free survival （DFS） time was 10.2 mo in the patients. There were no significant differences in DFS between the groups with high and low levels of TP. However, the group with low level of TS had a longer DFS （14.4 mo vs 8.3 mo, P = 0.017）. The median overall survival （OS） time was 18.5 mo, and there were significant differences in OS between the groups with high and low levels of TS or TP （for TS, 17.0 mo vs 21.3 mo, P = 0.010; for TP, 16.6 mo vs 22.5 too, P = 0.009）. Moreover, the coupled low expression of these two genes was strongly associated with a longer survival time of patients as compared with that of a single gene.CONCLUSION： Expression of TS and TP mRNA is a useful predictive parameter for the survival of postoperative gastric cancer patients after 5-fluorouracilbased adjuvant chemotherapy.

Clinical applications of 5-aminolevulinic acid-mediated fluorescence for gastric cancer

5-aminolevulinic acid(ALA) is a naturally occurring amino acid that is a protoporphyrin IX(Pp IX) precursor and a next-generation photosensitive substance. After exogenous administration of ALA, Pp IX specifically accumulates in cancer cells owing to the impaired metabolism of ALA to Pp IX in mitochondria, which results in a red fluorescence following irradiation with blue light and the formation of singlet oxygen. Fluorescence navigation by photodynamic diagnosis(PDD) using ALA provides good visualization and detection of gastric cancer lesions and is a potentially valuable diagnostic tool for gastric cancer for evaluating both the surgical resection margins and extension of the lesion. Furthermore, PDD using ALA might be used to detect peritoneal metastases during preoperative staging laparoscopy, where it could provide useful information for the selection of a therapeutic approach. Another promising application for this modality is in the evaluation of lymph node metastases. Photodynamic therapy(PDT) using ALA to cause selective damage based on the accumulation of a photosensitizer in malignant tissue is expected to be a non-invasive endoscopic treatment for superficial early gastric cancer. ALA has the potential to be used not only as a diagnostic agent but also as a therapeutic drug, resulting in a new strategy for cancer diagnosis and therapy. Here, we review the current use of PDD and PDT in gastric cancer and evaluate its future potential beyond conventional modalities combined with a light energy upconverter, a light-emitting diode and nearinfrared rays as light sources.

Propofol induces ferroptosis and inhibits malignant phenotypes of gastric cancer cells by regulating miR-125b-5p/STAT3 axis

BACKGROUND Gastric cancer is a common malignancy with poor prognosis,in which ferroptosis plays a crucial function in its development.Propofol is a widely used anesthetic and has antitumor potential in gastric cancer.However,the effect of propofol on ferroptosis during gastric cancer progression remains unreported.AIM To explore the function of propofol in the regulation of ferroptosis and malignant phenotypes of gastric cancer cells.METHODS MTT assays,colony formation assays,Transwell assays,wound healing assay,analysis of apoptosis,ferroptosis measurement,luciferase reporter gene assay,and quantitative reverse transcription polymerase chain reaction were used in this study.RESULTS Our data showed that propofol was able to inhibit proliferation and induce apoptosis of gastric cancer cells.Meanwhile,propofol markedly repressed the invasion and migration of gastric cancer cells.Importantly,propofol enhanced the erastin-induced inhibition of growth of gastric cancer cells.Consistently,propofol increased the levels of reactive oxygen species,iron,and Fe2+in gastric cancer cells.Moreover,propofol suppressed signal transducer and activator of transcription(STAT)3 expression by upregulating miR-125b-5p and propofol induced ferroptosis by targeting STAT3 in gastric cancer cells.The miR-125b-5p inhibitor or STAT3 overexpression reversed propofol-attenuated malignant phenotypes of gastric cancer cells.CONCLUSION Propofol induced ferroptosis and inhibited malignant phenotypes of gastric cancer cells by regulating the miR-125b-5p/STAT3 axis.Propofol may serve as a potential therapeutic candidate for gastric cancer.