Genetic variations in IKZF3, LET7-a2, and CDKN2B-AS1: Exploring associations with metabolic syndrome susceptibility and clinical manifestations.

BACKGROUND AND AIM: Metabolic syndrome (MetS) increases the risk of atherosclerosis and diabetes, but there are no approved predictive markers. This study assessed the role of specific genetic variations in MetS susceptibility and their impact on clinical manifestations. METHOD: In this study, a genotype-phenotype assessment was performed for IKZF3 (rs907091), microRNA-let-7a-2 (rs1143770), and lncRNA-CDKN2B-AS1 (rs1333045). RESULTS: Analyses indicate that while rs907091 and rs1143770 may have potential associations with MetS susceptibility and an increased risk of atherosclerosis and diabetes, there is an observed trend suggesting that the rs1333045 CC genotype may be associated with a decreased risk of MetS. The genotypes and allele frequencies of rs1333045 were significantly different between studied groups (OR = 0.56, 95% CI 0.38-0.81, p = 0.002, and OR = 0.71, 95% CI 0.55-0.92, p = 0.008), with the CC genotype displaying increased levels of HDL. Furthermore, the rs907091 TT genotype was associated with increased triglyceride, cholesterol, and HOMA index in MetS patients. Subjects with the CC genotype for rs1143770 had higher HbA1c and BMI. In silico analyses illustrated that rs907091 C remarkably influences the secondary structure and the target site of a broad spectrum of microRNAs, especially hsa-miR-4497. Moreover, rs1333045 creates a binding site for seven different microRNAs. CONCLUSION: Further studies on other populations may help confirm these SNPs as useful predictive markers in assessing the MetS risk.

Alzheimer's Disease-Related Epigenetic Changes: Novel Therapeutic Targets.

Aging is a significant risk factor for Alzheimer's disease (AD), although the precise mechanism and molecular basis of AD are not yet fully understood. Epigenetic mechanisms, such as DNA methylation and hydroxymethylation, mitochondrial DNA methylation, histone modifications, and non-coding RNAs (ncRNAs), play a role in regulating gene expression related to neuron plasticity and integrity, which are closely associated with learning and memory development. This review describes the impact of dynamic and reversible epigenetic modifications and factors on memory and plasticity throughout life, emphasizing their potential as target for therapeutic intervention in AD. Additionally, we present insight from postmortem and animal studies on abnormal epigenetics regulation in AD, as well as current strategies aiming at targeting these factors in the context of AD therapy.

The epigenetics orchestra of Notch signaling: a symphony for cancer therapy.

The aberrant regulation of the Notch signaling pathway, which is a fundamental developmental pathway, has been implicated in a wide range of human cancers. The Notch pathway can be activated by both canonical and noncanonical Notch ligands, and its role can switch between acting as an oncogene or a tumor suppressor depending on the context. Epigenetic modifications have the potential to modulate Notch and its ligands, thereby influencing Notch signal transduction. Consequently, the utilization of epigenetic regulatory mechanisms may present novel therapeutic opportunities for both single and combined therapeutics targeted at the Notch signaling pathway. This review offers insights into the mechanisms governing the regulation of Notch signaling and explores their therapeutic potential.

Molecular and clinical characterization of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome (APECED) in Iranian non-Jewish patients: report of two novel AIRE gene pathogenic variants.

OBJECTIVE: Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome (APECED) is a rare autosomal recessive systemic autoimmune disease caused by mutations in the autoimmune regulator (AIRE) gene. Incidence of this genetic disorder is estimated at 1/90,000-200,000 worldwide and 1/6500-9000 in genetically isolated populations such as Iran. Here, we investigated AIRE gene mutations in eight independent Iranian non-Jewish families. METHODS: We sequenced the coding regions of the AIRE gene and documented mutations which were further confirmed in respective parents. RESULTS: In total, 11 cases from 8 independent families were recruited. Mucosal candidiasis, Addison's disease and hypoparathyroidism were the most common clinical manifestations in these patients. One novel homozygous splice acceptor mutation (c.308-1G>C), and one novel heterozygous stop-gain mutation (c.1496delC) combined with a known heterozygous c.232T>C missense mutation were found. Moreover, we observed previously described splice donor (c.1095+2T>A), frameshift (c.967-979del), stop-gain (c.415C>T), and missense (c.62C>T) mutations among the patients. All results were co-segregated in parents. CONCLUSION: Here, we reported two novel mutations in the AIRE gene leading to APECED. Our data could provide insight into the phenotypic and genotypic spectrum of APECED in the non-Jewish Iranian population. These findings, in addition to future functional assays, can elucidate disease-causing mechanisms related to the AIRE gene and assist in genetic counseling and diagnosis.

Ninety-six-hour starved peripheral blood mononuclear cell supernatant inhibited LA7 breast cancer stem cells induced tumor via reduction in angiogenesis and alternations in Gch1 and Spr expressions.

Introduction: The microenvironment of solid tumors such as breast cancer is heterogeneous and complex, containing different types of cell, namely, cancer stem cells and immune cells. We previously reported the immunoregulatory behavior of the human immune cell in a solid tumor microenvironment-like culture under serum starvation stress for 96 h. Here, we examined the effect of this culture-derived solution on breast cancer development in rats. Method: Ninety-six-hour starved PBMCs supernatant (96 h-SPS) was collected after culturing human PBMCs for 96 h under serum starvation condition. Breast cancer stem cells, LA7 cell line, was used for in vitro study by analyzing gene expression status and performing cytotoxicity, proliferation, scratch wound healing assays, followed by in vivo tumor induction in three groups of mature female Sprague Dawley rats. Animals were treated with 96 h-SPS or RPMI and normal saline as control, n = 6 for each group. After biochemical analysis of iron, lactate, and pH levels in the dissected tumors, Ki67 antigen expression, angiogenesis, and necrosis evaluation were carried out. Metabolic-related gene expression was assessed using RT-qPCR. Moreover, 96 h-SPS composition was discovered by Nano-LC-ESI-MS/MS. Results: 96 h-SPS solution reduced the LA7 cell viability, proliferation, and migration and Gch1 and Spr genes expression in vitro (p< 0.05), whereas stemness gene Oct4 was upregulated (p< 0.01). The intracellular lactate was significantly decreased in the 96 h-SPS treated group (p = 0.007). In this group, Gch1 and Spr were significantly downregulated (p< 0.05), whereas the Sox2 and Oct4 expression was not changed significantly. The number of vessels and mitosis (Ki67+ cells) in the 96 h-SPS-treated group was significantly reduced (p = 0.024). The increased rate of necrosis in this group was statistically significant (p = 0.04). Last, proteomics analysis revealed candidate effectors' components of 96 h-SPS solution. Conclusion: 96 h-SPS solution may help to prevent cancer stem cell mediated tumor development. This phenomenon could be mediated through direct cytotoxic effects, inhibition of cell proliferation and migration in association with reduction in Gch1 and Spr genes expression, angiogenesis and mitosis rate, and necrosis augmentation. The preliminary data obtained from the present study need to be investigated on a larger scale and can be used as a pilot for further studies on the biology of cancer development.

Patients with Coronary Artery Disease Have Lower Levels of Antibody to Heat-Stressed Fibroblast Derived Proteins, versus Normal Subjects.

Cellular stress response plays an important role in the pathophysiology of coronary artery disease (CAD). Inhibition of cellular stress may provide a novel clinical approach regarding the diagnosis and treatment of CAD. Fibroblasts constitute 60-70% of cardiac cells and have a crucial role in cardiovascular function. Hence, the aim of this study was to show a potential therapeutic application of proteins derived from heat-stressed fibroblast in CAD patients. Fibroblasts were isolated from the foreskin and cultured under heat stress conditions. Surprisingly, 1.06% of the cells exhibited a necrotic death pattern. Furthermore, heat-stressed fibroblasts produced higher level of total proteins than control cells. In SDS-PAGE analysis, a 70 kDa protein band was observed in stressed cell culture supernatants which appeared as two acidic spots with close pI in the two-dimensional electrophoresis. To evaluate the immunogenic properties of fibroblast-derived heat shock proteins (HSPs), the serum immunoglobulin-G (IgG) was measured by ELISA in 50 CAD patients and 50 normal subjects who had been diagnosed through angiography. Interestingly, the level of anti-HSP antibody was significantly higher in non-CAD individuals in comparison with the patient's group (p < 0.05). The odds ratio for CAD was 5.06 (95%CI = 2.15-11.91) in cut-off value of 30 AU/mL of anti-HSP antibody. Moreover, ROC analysis showed that anti-HSP antibodies had a specificity of 74% and a sensitivity of 64%, which is almost equal to 66% sensitivity of exercise stress test (EST) as a CAD diagnostic method. These data revealed that fibroblast-derived HSPs are suitable for the diagnosis and management of CAD through antibody production.

Downregulation of Stemness Genes and Induction of Necrosis in Rat LA7 Cancer Stem Cells Induced Tumors Treated with Starved Fibroblasts Culture Supernatant.

BACKGROUND: Stem cell differentiation therapy is a promising strategy in cancer treatment. we show that protein cocktail prepared from serum starved fibroblasts has therapeutic potential based on this strategy. METHODS: The condition medium was prepared from foreskin isolated fibroblasts and analyzed by Liquid chromatography electrospray ionization mass spectrometry-mass spectrometry (LC-ESI-MS/MS). LA7 mammary gland cancer stem cells originated tumors were induced in Sprague Dawley rats. The rats treated subcutaneously with DMEM (group A), condition medium (group B), or normal saline (group C) once daily for 7 days. Then the tumors were removed and divided into the two parts, one part was used to quantify gene expression by stem-loop RT-qPCR assay and the other part was used for Hematoxylin & Eosin (H & E), Giemsa, and immunohistochemistry (IHC) staining. RESULTS: All induced tumors appeared as sarcomatoid carcinoma (SC). Immunohistochemistry staining confirmed this conclusion by recognizing the tumor as Ki67+, cytokeratin+, vimentine+, and estrogen receptor negative SC. RT-qPCR analysis revealed that Oct4-, Sox-2, Nanog- gene expression was much reduced in the condition medium treated tumors versus proper controls (p< 0.05). Tissue necrosis was more prevalent in this group while tumors volume was diminished almost by 40%. The LC-ESI-MS/MS analysis unrevealed the stemness reducing and the cell death inducing proteins such as, pigment epithelium-derived factor (PEDF), insulin like growth factor binding protein-5 (IGFBP-5) and -7 (IGFBP-7) in the condition medium. CONCLUSION: This study showed that the substances released from starved human fibroblasts were able to down-regulate the stemness-related genes and induce necrosis in LA7 derived tumors.

LINC02688 and PP7080 as novel biomarkers in early diagnosis of gastric cancer.

Despite considerable progress in gastric cancer screening, prevention, and treatment, it remains a major cause of morbidity and mortality worldwide. Due to late diagnosis of the disease, early potential diagnostic biomarkers are needed. Accumulating evidence indicates that non-coding RNAs have potential applications as diagnostic and prognostic biomarkers in gastric cancer. Herein, we investigated the expression levels of two novel non-coding RNAs, long intergenic non-protein coding RNA 2688 (LINC02688) and LOC25845 (PP7080) by real-time PCR for the first time in 47 gastric cancer patients. We found significant downregulation of LINC02688 and LOC25845 (PP7080) with 3.44 and 2.2-fold decrease, respectively in tumoral tissues in comparison with their adjacent non-tumoral counterparts (P < 0.0001). Our data also indicates that more than 96% and 88% of patients showed unchanged or decreased expression of LINC02688 and LOC25845 (PP7080), respectively. As most gastric cancer patients showed lower expression of these two lncRNAs, no significant association between clinicopathological features of the patients and the level of LINC02688 and LOC25845 (PP7080) expression could be detected. Furthermore, ROC curve analysis indicated that LINC02688 and PP7080 can serve as good predictive biomarkers for distinguishing tumoral tissues from their adjacent non-tumoral counterparts. Taken together, our findings suggested that these two novel tumor suppressor non-coding RNAs may act as novel diagnostic biomarkers for diagnosis of carcinogenesis event even at earlier stages of gastric adenocarcinoma.

RNA Sequencing of Early-Stage Gastric Adenocarcinoma Reveals Multiple Activated Pathways and Novel Long Non-Coding RNAs in Patient Tissue Samples.

BACKGROUND: Gastric cancer is among the most common cancers worldwide that currently lacks effective diagnostic biomarkers and therapeutic targets. Next-generation RNA sequencing is a powerful tool that allows rapid and accurate transcriptome-wide profiling to detect differentially expressed transcripts involved in normal biological and pathological processes. Given the function of this technique, it has the potential to identify new molecular targets for the early diagnosis of disease, particularly in gastric adenocarcinoma. METHODS: In this study, whole-transcriptome analysis was performed with RNA sequencing on tumoral and non-tumoral tissue samples from patients with early-stage gastric cancer. Gene ontology and pathway enrichment analysis were used to determine the main function of the specific genes and pathways present in tissue samples. RESULTS: Analysis of the differentially expressed genes revealed 5 upregulated and 234 downregulated genes in gastric cancer tissues. Pathway enrichment analysis revealed significantly dysregulated signalling pathways, including those involved in gastric acid secretion, drug metabolism and transporters, molecular toxicology, O-linked glycosylation of mucins, immunotoxicity, metabolism of xenobiotics by cytochrome P450, and glycosylation. We also found novel downregulated non-coding RNAs present in gastric cancer tissues, including GATA6 antisense RNA 1, antisense to LYZ, antisense P4HB, overlapping ACER2, long intergenic non-protein coding RNA 2688 (LINC02688) and uncharacterized LOC25845 (PP7080). CONCLUSION: The transcriptomic data found in this study illustrates the power of RNA-sequencing in discovering novel genes and tumorigenic pathways involved in human carcinogenesis. The anomalies present in these genes may serve as promising tools for the development of accurate diagnostic biomarkers for the detection of early-stage gastric cancer.

Association of sonic hedgehog signaling pathway genes IHH, BOC, RAB23a and MIR195-5p, MIR509-3-5p, MIR6738-3p with gastric cancer stage.

Gastric cancer is the leading cause of cancer-related mortality worldwide. Given the importance of gastric cancer in public health, identifying biomarkers associated with disease onset is an important part of precision medicine. The hedgehog signaling pathway is considered as one of the most significant widespread pathways of intracellular signaling in the early events of embryonic development. This pathway contributes also to the maintenance of pluripotency of cancer stem cells pluripotency. In this study, we analyzed the expression levels of sonic hedgehog (Shh) signaling pathway genes IHH, BOC, RAB23a and their regulatory miRNAs including MIR-195-5p, MIR-509-3-5p, MIR-6738-3p in gastric cancer patients. In addition, the impact of infection status on the expression level of those genes and their regulatory miRNAs was investigated. One hundred samples taken from 50 gastric cancer patients (50 tumoral tissues and their adjacent non-tumoral counterparts) were included in this study. There was a significant difference in all studied genes and miRNAs in tumoral tissues in comparison with their adjacent non-tumoral counterparts. The lower expression of IHH, BOC, RAB23, miR-195-5p, and miR-6738-3p was significantly associated with more advanced cancer stage. Additionally, IHH upregulation was significantly associated with CMV infection (P < 0.001). Also, receiver operating characteristic (ROC) curve analysis indicated that mir-195 was significantly related to several clinicopathological features including tumor stage, grade, age, gender, and infection status of gastric cancer and can be considered as a potential diagnostic biomarker for gastric cancer. This study confirms the important role of Shh signaling pathway genes in gastric cancer tumorigenesis and their potential as novel molecular biomarkers and therapeutic targets.

Insights into the Links between MYC and 3D Chromatin Structure and Epigenetics Regulation: Implications for Cancer Therapy.

MYC is embedded in the transcriptional oasis of the 8q24 gene desert. A plethora of genomic elements has roles in MYC aberrant expression in cancer development by interacting with transcription factors and epigenetics regulators as well as altering the structure of chromatin at the MYC locus and tissue-specific long-range enhancer-promoter contacts. Furthermore, MYC is a master regulator of several human cancers by modulating the transcription of numerous cancer-related genes through epigenetic mechanisms. This review provides a comprehensive overview of the three-dimensional genomic organization around MYC and the role of epigenetic machinery in transcription and function of MYC as well as discusses various epigenetic-targeted therapeutic strategies in MYC-driven cancers.

First comprehensive computational analysis of functional consequences of TMPRSS2 SNPs in susceptibility to SARS-CoV-2 among different populations.

Current SARS-CoV-2 pandemy mortality created the hypothesis that some populations may be more susceptible to SARS-CoV-2. TMPRSS2 encodes a transmembrane serine protease which plays a crucial role in SARS-CoV-2 cell entry. Single nucleotide polymorphisms (SNPs) in TMPRSS2 might influence SARS-CoV2 entry into the cell. This study aimed to investigate the impact of SNPs on TMPRSS2 function and structure. In silico tools such as Ensembl, Gtex, ExPASY 2, GEPIA, CCLE, KEGG and GO were engaged to characterize TMPRSS2 and its expression profile. The functional effects of SNPs were analyzed by PolyPhen-2, PROVEN, SNAP2, SIFT and HSF. Also, Phyre2, GOR IV and PSIPRED were used to predict the secondary structure of TMPRSS2. Moreover, post-translational modification (PTM) and secretory properties were analyzed through Modpredand Phobius, respectively. Finally, miRNA profiles were investigated by PolymiRTS and miRSNPs. Out of 11,184 retrieved SNPs from dbSNP, 92 showed a different frequency between Asians and other populations. Only 21 SNPs affected the function and structure of TMPRSS2 by influencing the protein folding, PTM, splicing and miRNA function. Particularly, rs12329760 may create a de novo pocket protein. rs875393 can create a donor site, silencer and broken enhancer motifs. rs12627374 affects a wide spectrum of miRNAs profile. This study highlighted the role of TMPRSS2 SNPs and epigenetic mechanisms especially non-coding RNAs in appearance of different susceptibility to SARS-CoV-2 among different populations. Also, this study could pave the way to potential therapeutic implication of TMPRSS2 in designing antiviral drugs.Communicated by Ramaswamy H. Sarma.

Comprehensive in silico identification of impacts of ACE2 SNPs on COVID-19 susceptibility in different populations.

The COVID-19 pandemic emerges a reminder that wide spectrum discrepancy in response to SARS-CoV-2 infection and antiviral drugs among different populations might be due to their different ACE2 SNPs and/or miRNAs profile. ACE2 is the major component for SARS-CoV-2s' cell entry, and disruption of its 3D structure could influence virus-ACE2 interaction. In this study we aimed to investigate the consequence of 16,860 SNPs within ACE2 on its expression as well as protein folding, function, and stability by using several beneficial bioinformatics tools. Only 64 SNPs including 60 intronic, and 4 missense showed different frequencies among different populations. Two missense SNPs including rs149039346 and rs147311723 have been predicted to strongly influence the function and stability of ACE2. rs1514283 creates new acceptor splice site. Also, rs4646175 creates new donor and acceptor splice site. PolymiRTS, and miRSNPs have predicted that rs3746444, rs113808830, and rs3751304 showed a MAF > 0.001, and disrupted mRNA target sites or mRNA function. Finally, rs3746444 hsa-miR-499a-3p, rs113808830 hsa-miR-4532, rs3751304 hsa-miR-6763-3p and hsa-miR-26b-5p were strongly hybridized with ACE2 and might influence its function. Collectively, this study shed some light on fundamental roles of ACE2 SNPs for its interaction with COVID-19, and consequently susceptibility to virus. Therefore, different responses of patients with COVID-19 to ACE2 blocker drugs might be due to their unique ACE2 SNPs. We further discussed the impact of SNPs on miRNAs profile as a factor that may modulate drug response or susceptibility to COVID-19.

Association of HLA-DRA and IL2RA Polymorphisms with the Severity and Relapses Rate of Multiple Sclerosis in an Iranian Population.

BACKGROUND: Multiple sclerosis (MS) is a multifactorial condition in which many genetic and environmental factors interfere. The association between genes involved in the immune system and MS was previously reported. The aims of this study were to evaluate 14 SNPs of HLA-DRA, 14 SNPs of IL2RA with severity of MS through Expanded Disability Status Scale (EDSS) and Annualized Relapse Rate (ARR). METHODS: 102 patients with MS referred to Sina hospital in Tehran, Iran, were diagnosed and studied based on McDonald's guideline, clinical signs, and brain imaging procedures. All patients were included in the study following informed consent. Genotyping study of 14 variants in the HLA-DRA, and 14 variants in IL2RA was conducted by Sanger sequencing. Disease outcomes including EDSS and ARR were registered. Outcome measures between different genotypes of each SNPs were compared separately. RESULTS: Among 14 SNPs in IL 2RA the genotypes of rs12722489 showed a significant association with ARR in two consecutive years. Mean ARR1 was 1.06±1.12, 0.20±0.34 and 0.31±.50 for AA, GA, and GG genotypes, respectively (p value= 0.008). Mean ARR2 was 1.5±1.08, 0.28±0.40, and 0.42±0.55 for AA, GA, and GG, respectively (p value= 0.001). Regression analysis showed a significant association between rs12722489 with ARR1 and ARR2, removing the potential confounding mediators. No significant association was found between SNPs in HLA-DRA with the attack rate and severity of MS. CONCLUSION: The rs12722489 of IL-2RA has an association with ARR, but not with EDSS.

Analysis of Single Nucleotide Polymorphisms in HLA-DRA, IL2RA , and HMGB1 Genes in Multiple Sclerosis.

BACKGROUND: Multiple sclerosis (MS) is a common demyelinating neurodegenerative disorder with significant heritability. Previous studies have associated genetic variants in human leukocyte antigen (HLA) complex, IL2RA , and HMGB1 genes with the pathophysiology of MS. METHODS: In order to investigate the gene association in the Iranian population, we performed a genotyping study of 36 variants in the mentioned genes using Sanger sequencing in 102 MS patients and 113 healthy controls. RESULTS: Our results identified significant associations as well as significant allele frequency differences in some of the studied single-nucleotide polymorphisms including rs4935356, rs3177928, and rs7197 from HLA-DRA gene, and rs12722489 and rs12722490 variants from IL2RA gene (p< 0.05). Moreover, the strong linkage disequilibrium of two common haplotypes was estimated from the HLA-DRA gene. CONCLUSION: This association study may suggest the role of these polymorphisms in the genetic susceptibility of MS in the Iranian population and would facilitate the recognition of causative variants in this disease.

Molecular Detection of Epstein-Barr Virus, Human Herpes Virus 6, Cytomegalovirus, and Hepatitis B Virus in Patients with Multiple Sclerosis.

BACKGROUND Multiple sclerosis (MS) is a chronic disease with significant morbidity. A wide spectrum of risk factors has been suggested that triggers the development of MS. Among them, several viral infections have been implicated to play a role in MS pathogenesis. We aimed to evaluate the relationship between viral diseases, including Epstein-Barr virus (EBV), human herpes virus 6 (HHV-6), cytomegalovirus (CMV), and hepatitis B virus (HBV) and MS in the present case-control study. METHODS About 100 patients with confirmed MS and age- and sex-matched individuals were selected as case and control groups, respectively. The patients were randomly selected from individuals diagnosed by neurologists based on the clinical signs and symptoms and imaging procedures. RESULTS More than 100 patients with MS and patients who were referred for other causes were analyzed for the presence of DNA of EBV, HHV6, CMV, and HBV separately. 9.37% of the control group had a positive test for the DNA of EBV in a real-time polymerase chain reaction (PCR), while the frequency of positive test result was zero in the case group (p = 0.0012). HBV DNA was not detected in both the case and control groups. The prevalence of CMV was 0.88 and zero in the control and case groups, respectively (p = 0.3410). For HHV6, 9.73 % of the control group had a positive result, while this test was positive in 5.88% of the patients with MS (p = 0.2959). CONCLUSION We detected a significantly higher number of individuals with DNA of EBV in their blood among the control group compared with the case group. In conclusion, the results suggest a surprisingly adverse association between MS and EBV, and no association was found between the presence of DNA of HBV, CMV, and HHV6 and MS.

PI3K/AKT/mTOR signaling in gastric cancer: Epigenetics and beyond.

PI3K/AKT/mTOR pathway is one of the most important signaling pathways involved in normal cellular processes. Its aberrant activation modulates autophagy, epithelial-mesenchymal transition, apoptosis, chemoresistance, and metastasis in many human cancers. Emerging evidence demonstrates that some infections as well as epigenetic regulatory mechanisms can control PI3K/AKT/mTOR signaling pathway. In this review, we focused on the role of this pathway in gastric cancer development, prognosis, and metastasis, with an emphasis on epigenetic alterations including DNA methylation, histone modifications, and post-transcriptional modulations through non-coding RNAs fluctuations as well as H. pylori and Epstein-Barr virus infections. Finally, we reviewed different molecular targets and therapeutic agents in clinical trials as a potential strategy for gastric cancer treatment through the PI3K/AKT/mTOR pathway.