Global progress and future prospects of early gastric cancer screening.

Gastric cancer is a prevalent malignancy that poses a serious threat to global health. Despite advances in medical technologies, screening methods, and public awareness, gastric cancer remains a significant cause of morbidity and mortality worldwide. Early gastric cancer frequently does not present with characteristic symptoms, while advanced stage disease is characterized by a dismal prognosis. As such, early screening in gastric cancer is of great importance. In recent years, advances have been made globally in both clinical and basic research for the screening of early gastric cancer. The current predominant screening methods for early gastric cancer include imaging screening, endoscopic screening and serum biomarker screening. Imaging screening encompasses upper gastrointestinal barium meal, multidimensional spiral computed tomography (MDCT), Magnetic resonance imaging (MRI), and ultrasonography. Endoscopic screening methods include white light endoscopy, chromoendoscopy, computed virtual chromoendoscopy, and other endoscopic techniques like endocytoscopy, confocal laser endomicroscopy, optical coherence tomography and so on. Biomarkers screening involves the assessment of conventional biomarkers such as CEA, CA19-9 and CA72-4 as well as more emerging biomarkers such as peptides (PG, G-17, GCAA, TAAs and others), DNA (cfDNA, DNA methylation, MSI), noncoding RNA (miRNA, lncRNA, circRNA, and tsRNA) and others. Each screening method has its strengths and limitations. This article systematically summarizes worldwide progress and future development of early gastric cancer screening methods to provide new perspectives and approaches for early diagnostic and treatment advancements in gastric cancer worldwide.

A tRF-5a fragment that regulates radiation resistance of colorectal cancer cells by targeting MKNK1.

Radiotherapy serves as a crucial strategy in the treatment of colorectal cancer (CRC). However, its efficacy is often hindered by the challenge of radiation resistance. Although the literature suggests that some tRNA-derived small RNAs (tsRNAs) are associated with various cancers, studies reporting the relationship of tsRNAs with cancer cell radiosensitivity have not been published yet. In our study, we utilized tsRNAs sequencing to predict differentially expressed tsRNAs in two CRC cells and their radioresistant cells, and 10 tsRNAs with significant differences in expression were validated by qPCR. The target genes of tRF-16-7X9PN5D were predicted and verified by the bioinformatics, dual-luciferase reporter gene assay and western blotting analyses. Wound healing, colony formation, transwell invasion and CCK-8 assays were performed to detect the effects of tRF-16-7X9PN5D on cell function and radiosensitivity. Western blotting evaluated the relationship between tRF-16-7X9PN5D and the MKNK-eIF4E axis. Our findings demonstrated that tRF-16-7X9PN5D expression was substantially downregulated in radioresistant CRC cells. Furthermore, tRF-16-7X9PN5D could promote CRC cells' ability to proliferate, migrate, invade and obtain radiation resistance by targeting MKNK1. Finally, tRF-16-7X9PN5D could regulate eIF4E phosphorylation via MKNK1. This investigation indicated that tRF-16-7X9PN5D has an essential regulatory role in the radiation resistance of CRC by directly targeting MKNK1, and may be a new pathway for regulating the CRC radiosensitivity.

Dysregulation of Transfer RNA-derived Small RNAs that Regulate Cell Activity and its Related Signaling Pathways in Human Cancers.

tsRNAs are small noncoding RNAs that originate from tRNA cleavage and play important regulatory roles in gene expression, translation, transcription, and epigenetic modification. The dysregulation of tsRNAs in cancer disrupts gene expression and perturbs various cellular activities, including cell proliferation, apoptosis, migration, and invasion. Moreover, tsRNAs may influence cancer development by regulating related cell signaling pathways. In this review, we first examine the origins and classification of tsRNAs and their effects on tumor cell activity. To highlight the latest research progress of tsRNAs and signaling pathways, we summarize the possible mechanisms of tsRNAs in specific tumor-related signaling pathways, including the Wnt, TGFb1, MAPK, PI3K-AKT, Notch, and MDM2/p53 signaling pathways, that have been identified in recent research.

EPAS1 Promoter Hypermethylation is a Diagnostic and Prognostic Biomarker for Non-Small Cell Lung Cancer.

Background: The importance of promoter methylation in non-small cell lung cancers (NSCLC) remains to be understood. Thus, we aimed to determine the diagnostic and prognostic value of the methylation of the endothelial PAS domain containing protein-1 (EPAS1) promoter in NSCLC. Methods: EPAS1 promoter methylation levels were quantitated by methylation-specific PCR. Further, we evaluated the expression, promoter methylation, prognostic value, and impact on immune cell infiltration of EPAS1 by analyzing the TCGA database using web-based bioinformatics tools including GEPIA, UALCAN and MethSurv. Results: Our results demonstrated that promoter methylation of EPAS1 downregulated its expression in NSCLC tissues. Additionally, an AUC value of 0.772 indicated that the methylation of the EPAS1 promoter is a potential diagnostic marker for NSCLC. A Kaplan-Meier analysis demonstrated that high methylation levels of CpG sites in the EPAS1 promoter were indicative of poorer overall survival. Further, EPAS1 expression levels were highly correlated with the infiltration of several types of immune cells, including γδ T cells, T follicular helper cells, CD8+ T cells, and CD4+ T-cells. Conclusion: Collectively, our findings suggest that methylation analyses of the EPAS1 promoter could be used as a prognostic biomarker for NSCLC and that EPAS1 potentially plays an important role in immune cell infiltration in NSCLC.

PRKCDBP Methylation is a Potential and Promising Candidate Biomarker for Non-small Cell Lung Cancer.

BACKGROUND: The occurrence and development of lung cancer are closely linked to epigenetic modification. Abnormal DNA methylation in the CpG island region of genes has been found in many cancers. Protein kinase C delta binding protein (PRKCDBP) is a potential tumor suppressor and its epigenetic changes are found in many human malignancies. This study investigated the possibility of PRKCDBP methylation as a potential biomarker for non-small cell lung cancer (NSCLC). METHODS: We measured the methylation levels of PRKCDBP in the three groups of NSCLC tissues. Promoter activity was measured by the dual luciferase assay, with 5'-aza-deoxycytidine to examine the effect of demethylation on the expression level of PRKCDBP. RESULTS: The methylation levels of PRKCDBP in tumor tissues and 3 cm para-tumor were higher than those of distant (>10 cm) non-tumor tissues. Receiver operating characteristic (ROC) curve analysis between tumor tissues and distant non-tumor tissues showed that the area under the line (AUC) was 0.717. Dual luciferase experiment confirmed that the promoter region was able to promote gene expression. Meanwhile, in vitro methylation of the fragment (PRKCDBP_Me) could significantly reduce the promoter activity of the fragment. Demethylation of 5'-aza-deoxycytidine in lung cancer cell lines A549 and H1299 showed a significant up-regulation of PRKCDBP mRNA levels. CONCLUSIONS: PRKCDBP methylation is a potential and promising candidate biomarker for non-small cell lung cancer.

Hypermethylation of tumor necrosis factor decoy receptor gene in non-small cell lung cancer.

Abnormal methylation of the TNFRSF10C and TNFRSF10D genes has been observed in numerous types of cancer; however, no studies have investigated the methylation of these genes in non-small cell lung cancer (NSCLC). The aim of the present study was to investigate the association between TNFRSF10C and TNFRSF10D methylation and NSCLC. Methylation levels of 44 pairs of NSCLC tumor tissues and distant non-tumor tissues were analyzed using quantitative methylation specific PCR and methylation reference percentage values (PMR). The methylation levels of the TNFRSF10C gene in NSCLC tumor tissue samples were significantly higher compared with those in the distant non-tumor tissues (median PMR, 2.73% vs. 0.75%; P=0.013). Subgroup analysis demonstrated that the methylation levels of TNFRSF10C in tumor tissues from male patients were significantly higher compared with those in distant non-tumor tissues (median PMR, 2.73% vs. 0.75%; P=0.041). The levels of TNFRSF10C methylation were also higher in the tumor tissues of patients who were non-smokers compared with their distant non-tumor tissues (median PMR, 2.50% vs. 0.63%; P=0.013). TNFRSF10C methylation levels were higher in the tumor tissues from male patients compared with those from female patients (median PMR, 2.50% vs. 0.63%; P=0.031). However, no significant differences in the methylation levels of the TNFRSF10D gene were observed between the sexes. Using the cBioPortal and The Cancer Genome Atlas lung cancer data, it was demonstrated that TNFRSF10C methylation levels were inversely correlated with TNFRSF10C mRNA expression levels (r=-0.379; P=0.008). In addition, demethylation of lung cancer cell lines A549 and NCI-H1299 using 5'-aza-deoxycytidine further confirmed that TNFRSF10C hypomethylation was associated with significant upregulation of TNFRSF10C mRNA expression levels [A549 fold-change (FC)=8; P=1.0×10-4; NCI-H1299 FC=3.163; P=1.143×10-5]. A dual luciferase reporter gene assay was also performed with the insert of TNFRSF10C promoter region, and the results revealed that the TNFRSF10C gene fragment significantly enhanced the transcriptional activity of the reporter gene compared with that in the control group (FC=1.570; P=0.032). Overall, the results of the present study demonstrated that hypermethylation of TNFRSF10C was associated with NSCLC.

[Correlation between methylation level of CDKN2A and CDKN2B genes and aging in healthy individuals].

OBJECTIVE: To analyze the relationship between CDKN2A and CDKN2B gene methylation with aging in the general population. METHODS: We collected peripheral blood samples from 284 male and 246 female healthy subjects for detection of methylation levels of CDKN2A and CDKN2B genes using quantitative methylation-specific PCR (qMSP). The relationship between the methylation levels of CDKN2A and CDKN2B genes and aging was analyzed using Spearman or Pearson correlation test. RESULTS: We found a significant positive correlation between the methylation levels of the two genes in these subjects (P < 0.05). In the overall population as well in the female subjects, CDKN2A methylation was found to be inversely correlated with age (P < 0.05). The methylation levels of CDKN2A and CDKN2B genes were inversely correlated with TG, ApoE, Lp(a) and AST in the overall population (P < 0.05). In both the female and male subjects, the methylation levels of the two genes were inversely correlated with Lp(a) (P < 0.05). In the male subjects, CDKN2A methylation was inversely correlated with AST (P < 0.05), while CDKN2B methylation was inversely correlated with HDL and ApoE (P < 0.05). In the female subjects, CDKN2A methylation was positively correlated with LDL and inversely correlated with ApoE and AST (P < 0.05). CONCLUSIONS: The methylation levels of CDKN2A and CDKN2B are closely related to age and the levels of multiple proteins in healthy subjects.

Association between GPX3 promoter methylation and malignant tumors: A meta-analysis.

Glutathione peroxidase 3 (GPX3) has an important function of scavenging hydrogen peroxide and preventing cancer. The purpose of this meta-analysis was to analyze the relationship between GPX3 gene methylation and cancer and to further evaluate its diagnostic value for cancer. We screened eligible literatures from the PubMed, Embase, CNKI and Wanfang databases. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were used to measure the association of GPX3 methylation with cancer. Summary receiver operating characteristics (SROC) analysis was used to assess the diagnostic value of GPX3 methylation for cancer. A total of 17 eligible articles were included in the meta-analysis involving a total of 960 tumor samples and 445 non-tumor samples. The results showed that GPX3 hypermethylation was significantly associated with cancer (OR = 17.32, 95% CI = 8.22-36.51, P < 0.00001). Compared with cancer patients without lymph node metastasis, cancer patients with lymph node metastasis were more associated with GPX3 hypermethylation (OR = 2.97, 95% CI = 1.53-5.76, P = 0.001). SROC analysis showed for GPX3 methylation was a promising biomarker for cancer risk (AUC = 0.89, pooled sensitivity = 0.93, pooled specificity = 0.54, NLR = 0.15, PLR = 2.05, DOR = 17.32). TCGA database bioinformatics analysis of 696 pairs of tumor and non-tumor tissues further validate the association of GPX3 methylation with the risk of cancer [cg21504918: 0.10 (0.08, 0.15) vs. 0.09 (0.08, 0.11), P = 5.8E-28; cg26638444: 0.05 (0.04, 011) vs. 0.04 (0.03, 0.06), P = 8.7E-29]. In summary, our study indicates that GPX3 methylation is associated with cancer and has the potential to become a broad-spectrum tumor screening marker and has a value in predicting tumor lymph node metastasis.