The relationship and clinical significance of lactylation modification in digestive system tumors.

Lactylation, an emerging post-translational modification, plays a pivotal role in the initiation and progression of digestive system tumors. This study presents a comprehensive review of lactylation in digestive system tumors, underscoring its critical involvement in tumor development and progression. By focusing on metabolic reprogramming, modulation of the tumor microenvironment, and the molecular mechanisms regulating tumor progression, the potential of targeting lactylation as a therapeutic strategy is highlighted. The research reveals that lactylation participates in gene expression regulation and cell signaling by affecting the post-translational states of histones and non-histone proteins, thereby influencing metabolic pathways and immune evasion mechanisms in tumor cells. Furthermore, this study assesses the feasibility of lactylation as a therapeutic target, providing insights for clinical treatment of gastrointestinal cancers. Future research should concentrate on elucidating the mechanisms of lactylation, developing efficient lactylation inhibitors, and validating their therapeutic efficacy in clinical trials, which could transform current cancer treatment and immunotherapy approaches. In summary, this review emphasizes the crucial role of lactylation in tumorigenesis and progression through a detailed analysis of its molecular mechanisms and clinical significance.

Intratumoral microorganisms in tumors of the digestive system.

Tumors of the digestive system pose a significant threat to human health and longevity. These tumors are associated with high morbidity and mortality rates, leading to a heavy economic burden on healthcare systems. Several intratumoral microorganisms are present in digestive system tumors, and their sources and abundance display significant heterogeneity depending on the specific tumor subtype. These microbes have a complex and precise function in the neoplasm. They can facilitate tumor growth through various mechanisms, such as inducing DNA damage, influencing the antitumor immune response, and promoting the degradation of chemotherapy drugs. Therefore, these microorganisms can be targeted to inhibit tumor progression for improving overall patient prognosis. This review focuses on the current research progress on microorganisms present in the digestive system tumors and how they influence the initiation, progression, and prognosis of tumors. Furthermore, the primary sources and constituents of tumor microbiome are delineated. Finally, we summarize the application potential of intratumoral microbes in the diagnosis, treatment, and prognosis prediction of digestive system tumors. Video Abstract.

[68Ga]Ga-FAPI PET for the evaluation of digestive system tumors: systematic review and meta-analysis.

PURPOSE: Digestive system tumors are a group of tumors with high incidence in the world nowadays. The assessment of digestive system tumor metastasis by conventional imaging seems to be unsatisfactory. [68Ga]Ga-FAPI, which has emerged in recent years, seems to be able to evaluate digestive system tumor metastasis. We aimed to summarize the current evidence of [68Ga]Ga-FAPI PET/CT or PET/MR for the assessment of primary tumors, lymph node metastases, and distant metastases in digestive system tumors. Besides, we also aimed to perform a meta-analysis of the sensitivity of [68Ga]Ga-FAPI PET diagnosis to discriminate between digestive system tumors, primary lesions, and non-primary lesions (lymph node metastases and distant metastases). MATERIALS AND METHODS: PubMed, MEDLINE and Cochrane Library databases were searched from the beginning of the database build to August 12, 2022. All studies undergoing [68Ga]Ga-FAPI PET for the evaluation of digestive tumors were included in the screening and review. Screening and full text review was performed by 3 investigators and data extraction was performed by 2 investigators. Risk of bias was examined with the QUADAS-2 criteria. Diagnostic test meta-analysis was performed with a random-effects model. RESULTS: A total of 541 studies were retrieved. Finally, 22 studies were selected for the systematic review and 18 studies were included in the meta-analysis. In the 18 publications, a total of 524 patients with digestive system tumors, 459 primary tumor lesions of digestive system tumors, and 1921 metastatic lesions of digestive system tumors were included in the meta-analysis. Based on patients, the sensitivity of [68Ga]Ga-FAPI PET for the diagnosis of digestive system tumors was 0.98 (95% CI: 0.94-0.99). Based on lesions, the sensitivity of [68Ga]Ga-FAPI PET for the diagnostic evaluation of primary tumor lesions of the digestive system was 0.97 (95% CI: 0.93-0.99); the sensitivity of [68Ga]Ga-FAPI PET for the diagnostic evaluation of non-primary lesions (lymph node metastases and distant metastases) of the digestive system tumors was 0.94 (95% CI: 0.79-0.99). CONCLUSION: [68Ga]Ga-FAPI PET has high accuracy and its sensitivity is at a high level for the diagnostic evaluation of digestive system tumors. Clinicians, nuclear medicine physicians, and radiologists may consider using [68Ga]Ga-FAPI PET/CT or PET/MR in the evaluation of primary tumors, lymph node metastases, and distant metastases in digestive system tumors.

METTL3 promotes oxaliplatin resistance of gastric cancer CD133+ stem cells by promoting PARP1 mRNA stability.

Oxaliplatin is the first-line regime for advanced gastric cancer treatment, while its resistance is a major problem that leads to the failure of clinical treatments. Tumor cell heterogeneity has been considered as one of the main causes for drug resistance in cancer. In this study, the mechanism of oxaliplatin resistance was investigated through in vitro human gastric cancer organoids and gastric cancer oxaliplatin-resistant cell lines and in vivo subcutaneous tumorigenicity experiments. The in vitro and in vivo results indicated that CD133+ stem cell-like cells are the main subpopulation and PARP1 is the central gene mediating oxaliplatin resistance in gastric cancer. It was found that PARP1 can effectively repair DNA damage caused by oxaliplatin by means of mediating the opening of base excision repair pathway, leading to the occurrence of drug resistance. The CD133+ stem cells also exhibited upregulated expression of N6-methyladenosine (m6A) mRNA and its writer METTL3 as showed by immunoprecipitation followed by sequencing and transcriptome analysis. METTTL3 enhances the stability of PARP1 by recruiting YTHDF1 to target the 3'-untranslated Region (3'-UTR) of PARP1 mRNA. The CD133+ tumor stem cells can regulate the stability and expression of m6A to PARP1 through METTL3, and thus exerting the PARP1-mediated DNA damage repair ability. Therefore, our study demonstrated that m6A Methyltransferase METTL3 facilitates oxaliplatin resistance in CD133+ gastric cancer stem cells by Promoting PARP1 mRNA stability which increases base excision repair pathway activity.

Identification of glycolysis related pathways in pancreatic adenocarcinoma and liver hepatocellular carcinoma based on TCGA and GEO datasets.

BACKGROUND: Abnormal energy metabolism is one of the characteristics of tumor cells, and it is also a research hotspot in recent years. Due to the complexity of digestive system structure, the frequency of tumor is relatively high. We aim to clarify the prognostic significance of energy metabolism in digestive system tumors and the underlying mechanisms. METHODS: Gene set variance analysis (GSVA) R package was used to establish the metabolic score, and the score was used to represent the metabolic level. The relationship between the metabolism and prognosis of digestive system tumors was explored using the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Volcano plots and gene ontology (GO) analyze were used to show different genes and different functions enriched between different glycolysis levels, and GSEA was used to analyze the pathway enrichment. Nomogram was constructed by R package based on gene characteristics and clinical parameters. qPCR and Western Blot were applied to analyze gene expression. All statistical analyses were conducted using SPSS, GraphPad Prism 7, and R software. All validated experiments were performed three times independently. RESULTS: High glycolysis metabolism score was significantly associated with poor prognosis in pancreatic adenocarcinoma (PAAD) and liver hepatocellular carcinoma (LIHC). The STAT3 (signal transducer and activator of transcription 3) and YAP1 (Yes1-associated transcriptional regulator) pathways were the most critical signaling pathways in glycolysis modulation in PAAD and LIHC, respectively. Interestingly, elevated glycolysis levels could also enhance STAT3 and YAP1 activity in PAAD and LIHC cells, respectively, forming a positive feedback loop. CONCLUSIONS: Our results may provide new insights into the indispensable role of glycolysis metabolism in digestive system tumors and guide the direction of future metabolism-signaling target combined therapy.

Diagnostic value of endoscopic ultrasound elastography for benign and malignant digestive system tumors.

OBJECTIVE: To investigate the effect of endoscopic ultrasound real-time tissue elastography in differential diagnosis of benign and malignant digestive system tumors. METHODS: Forty-two patients with solid tumors of digestive system who were admitted to our hospital between October 2017 and October 2018 were selected. All patients were diagnosed by endoscopic ultrasound real-time tissue elastography. Elastography score was used. The strain ratios (SR) of the lesion and the surrounding control tissues were measured and compared. RESULTS: Lesions with elastography score no more than two points were evaluated as benign, while lesions with elastography score no less than three points were evaluated as malignant. The difference of the elastography score between the benign lesion group and malignant lesion group was statistically significant (P<0.05). The sensitivity, specificity and accuracy of endoscopic ultrasound elastography in the diagnosis of malignant tumors of digestive system were 91.4%, 88.9% and 87.5%, respectively. The SR of the benign lesions ranged from 0.01 to 7.34, with a median SR of 7.33; the SR of the malignant lesions ranged from 1.01 to 47.66, with a median SR of 20.07. The SR of the benign lesions was significantly lower than that of the malignant lesions (P<0.05). CONCLUSION: Elastography of benign and malignant tissues of digestive tract tumors has different image characteristics. Endoscopic ultrasound real-time tissue elastography is effective in differential diagnosis of digestive tract tumors as it can effectively determine whether a tumor is benign or malignant and improve diagnostic accuracy.

Bibliometric analysis of research on digestive system tumors and depression.

Background: Malignant tumors of the digestive system pose a serious threat to human health due to their highly malignant nature. Depression, as the most common psychiatric symptom of digestive system tumors, has attracted much attention regarding its potential relationship with these tumors. A thorough investigation into the connection between digestive system tumors and depression is extremely important for strengthening patients' quality of life and treatment outcomes. Methods: From 2014 to 2023, we conducted a literature search using specific keywords in the Web of Science Core Collection (WoSCC) and performed visual analysis of the selected literature using Microsoft Excel, CiteSpace, and VOSviewer software. In this study, we analyzed countries, institutions, authors, journals, and keywords. Results: A total of 384 research articles on the relationship between digestive system tumors and depression were identified. The number of publications showed a gradual increase over time. In terms of disciplinary distribution, Oncology, Health Care Sciences Services, and Medicine General Internal ranked top in terms of publication volume. In terms of geographical distribution, China and the United States were the countries contributing the most publications. Additionally, Maastricht University contributed the most publications. Regarding authors, Beekman, Aartjan T.F. and Dekker, Joost had the highest number of publications, while Zigmond, A.S. had the most citations. It is worth mentioning that Supportive Care in Cancer was the journal with the most publications in this field. In terms of keyword analysis, research mainly focused on mechanisms and treatment strategies related to the relationship between digestive system tumors and depression. Conclusion: The relationship between digestive system tumors and depression has become a new research hotspot in recent years, offering new directions for future research. This research reveals novel perspectives on comprehending the connection between the two, which can guide future research and practice.

Dendritic cell-derived exosome (DEX) therapy for digestive system cancers: Recent advances and future prospect.

Tumor-mediated immunosuppression is a fundamental obstacle to the development of dendritic cell (DC)-based cancer vaccines, which despite their ability to stimulate host anti-tumor CD8 T cell immunity, have not been able to generate meaningful therapeutic responses. Exosomes are inactive membrane vesicles that are nanoscale in size and are produced by the endocytic pathway. They are essential for intercellular communication. Additionally, DC-derived exosomes (DEXs) contained MHC class I/II (MHCI/II), which is frequently complexed with antigens and co-stimulatory molecules and is therefore able to prime CD4 and CD8 T cells that are specific to particular antigens. Indeed, vaccines with DEXs have been shown to exhibit better anti-tumor efficacy in eradicating tumors compared to DC vaccines in pre-clinical models of digestive system tumors. Also, there is room for improvement in the tumor antigenic peptide (TAA) selection process. DCs release highly targeted exosomes when the right antigenic peptide is chosen, which could aid in the creation of DEX-based antitumor vaccines that elicit more targeted immune responses. Coupled with their resistance to tumor immunosuppression, DEXs-based cancer vaccines have been heralded as the superior alternative cell-free therapeutic vaccines over DC vaccines to treat digestive system tumors. In this review, current studies of DEXs cancer vaccines as well as potential future directions will be deliberated.

The role of Tetraspanins in digestive system tumor development: update and emerging evidence.

Digestive system malignancies, including cancers of the esophagus, pancreas, stomach, liver, and colorectum, are the leading causes of cancer-related deaths worldwide due to their high morbidity and poor prognosis. The lack of effective early diagnosis methods is a significant factor contributing to the poor prognosis for these malignancies. Tetraspanins (Tspans) are a superfamily of 4-transmembrane proteins (TM4SF), classified as low-molecular-weight glycoproteins, with 33 Tspan family members identified in humans to date. They interact with other membrane proteins or TM4SF members to form a functional platform on the cytoplasmic membrane called Tspan-enriched microdomain and serve multiple functions including cell adhesion, migration, propagation and signal transduction. In this review, we summarize the various roles of Tspans in the progression of digestive system tumors and the underlying molecular mechanisms in recent years. Generally, the expression of CD9, CD151, Tspan1, Tspan5, Tspan8, Tspan12, Tspan15, and Tspan31 are upregulated, facilitating the migration and invasion of digestive system cancer cells. Conversely, Tspan7, CD82, CD63, Tspan7, and Tspan9 are downregulated, suppressing digestive system tumor cell metastasis. Furthermore, the connection between Tspans and the metastasis of malignant bone tumors is reviewed. We also summarize the potential role of Tspans as novel immunotherapy targets and as an approach to overcome drug resistance. Finally, we discuss the potential clinical value and therapeutic targets of Tspans in the treatments of digestive system malignancies and provide some guidance for future research.

The causal relationship between cathepsins and digestive system tumors: a Mendelian randomization study.

Background: Multiple studies have confirmed the significant role of cathepsins in the development and progression of digestive system tumors. However, further investigation is needed to determine the causal relationships. Methods: We conducted a two-sample bidirectional Mendelian randomization (MR) study using pooled data from a genome-wide association study (GWAS) to assess the causal associations between nine cathepsins (cathepsin B, E, F, G, H, L2, O, S, and Z) and six types of digestive system tumors, including hepatocellular carcinoma (HCC), pancreatic cancer (PCa), biliary tract cancer (BTC), colorectal cancer (CRC), gastric carcinoma (GC), and esophageal cancer (EC). We employed the following methods including inverse variance weighting (IVW), MR-Egger, weighted median (WM), Cochran's Q, MR-PRESSO, MR-Egger intercept test and leave-one-out sensitivity analysis. The STROBE-MR checklist for the reporting of MR studies was used in this study. Results: The risk of HCC increased with high levels of cathepsin G (IVW: p = 0.029, odds ratio (OR) = 1.369, 95% confidence interval (CI) = 1.033-1.814). Similarly, BTC was associated with elevated cathepsin B levels (IVW: p = 0.025, OR = 1.693, 95% CI = 1.070-2.681). Conversely, a reduction in PCa risk was associated with increased cathepsin H levels (IVW: p = 0.027, OR = 0.896, 95% CI = 0.812-0.988). Lastly, high levels of cathepsin L2 were found to lower the risk of CRC (IVW: p = 0.034, OR = 0.814, 95% CI = 0.674-0.985). Conclusion: Our findings confirm the causal relationship between cathepsins and digestive system tumors, which can offer valuable insights for the diagnosis and treatment of digestive system tumors.

Nanomaterials modulate tumor-associated macrophages for the treatment of digestive system tumors.

The treatment of digestive system tumors presents challenges, particularly in immunotherapy, owing to the advanced immune tolerance of the digestive system. Nanomaterials have emerged as a promising approach for addressing these challenges. They provide targeted drug delivery, enhanced permeability, high bioavailability, and low toxicity. Additionally, nanomaterials target immunosuppressive cells and reshape the tumor immune microenvironment (TIME). Among the various cells in the TIME, tumor-associated macrophages (TAMs) are the most abundant and play a crucial role in tumor progression. Therefore, investigating the modulation of TAMs by nanomaterials for the treatment of digestive system tumors is of great significance. Here, we present a comprehensive review of the utilization of nanomaterials to modulate TAMs for the treatment of gastric cancer, colorectal cancer, hepatocellular carcinoma, and pancreatic cancer. We also investigated the underlying mechanisms by which nanomaterials modulate TAMs to treat tumors in the digestive system. Furthermore, this review summarizes the role of macrophage-derived nanomaterials in the treatment of digestive system tumors. Overall, this research offers valuable insights into the development of nanomaterials tailored for the treatment of digestive system tumors.

T2DM may exert a protective effect against digestive system tumors in East Asian populations: a Mendelian randomization analysis.

Introduction: Type 2 diabetes mellitus (T2DM) was associated with digestive system tumors. We analyzed publicly available data from GWAS studies using Mendelian randomization methods to clarify its causal relationship and mechanisms. Five common digestive system tumors and four diabetes-related phenotypes were included. Methods: Inverse variance weighted method was the main analytical method. Meta-analysis was used to summarize results of multiple data sources. Horizontal pleiotropy was tested using Egger-intercept method and validated by MRPRESSO method. Heterogeneity and sensitivity analysis were conducted by Cochran's Q test and leave-one-out method, respectively. Results: T2DM is associated with a reduced risk of esophageal (OR: 0.77, 95% CI: 0.71 to 0.83, P< 0.001), gastric (OR: 0.87, 95% CI: 0.84 to 0.90, P< 0.001) and colorectal cancer (OR: 0.88, 95% CI: 0.85 to 0.91, P< 0.001) and hepatocellular carcinoma (OR: 0.92, 95% CI: 0.86 to 0.97, P = 0.005) and an increased risk of pancreatic cancer (OR: 1.92, 95% CI: 1.47 to 2.50, P< 0.001) in East Asian population. T2DM causes decreased fasting insulin levels (OR = 0.966, 95% CI: 0.95 to 0.98, P< 0.001) and increased glycated hemoglobin levels (OR=1.41, 95% CI: 1.39 to 1.44, P<0.001). Elevated fasting insulin levels increase the risk of esophageal cancer (OR = 10.35, 95% CI: 1.10 to 97.25, P = 0.041), while increased glycated hemoglobin levels increase pancreatic cancer risk (OR=2.33, 95% CI: 1.37 to 3.97, P=0.002) but decrease gastric cancer risk (OR=0.801, 95% CI: 0.65 to 0.99, P=0.044). Conclusion: T2DM is associated with a reduced risk of esophageal, gastric and colorectal cancer and hepatocellular carcinoma in East Asian populations. The causal relationships between T2DM with esophageal and gastric cancer are partially mediated by decreased fasting insulin and increased glycated hemoglobin levels, respectively. T2DM indirectly increases the risk of pancreatic cancer by increasing glycated hemoglobin levels.

Emerging function of main RNA methylation modifications in the immune microenvironment of digestive system tumors.

Digestive system tumors have been reported in more than 25% of all cancer cases worldwide, bringing a huge burden on the healthcare system. RNA methylation modification-an important post-transcriptional modification-has become an active research area in gene regulation. It is a dynamic and reversible process involving several enzymes, such as methyltransferases, demethylases, and methylation reader proteins. This review provides insights into the role of three major methylation modifications, namely m6A, m5C, and m1A, in the development of digestive system tumors, specifically in the development of tumor immune microenvironment (TIME) of these malignancies. Abnormal methylation modification affects immunosuppression and antitumor immune response by regulating the recruitment of immune cells and the release of immune factors. Understanding the mechanisms by which RNA methylation regulates digestive system tumors will be helpful in exploring new therapeutic targets.

Dynamics of Peripheral Blood Immune Cells during the Perioperative Period after Digestive System Resections: A Systematic Analysis of the Literature.

An operation in itself is a kind of trauma and may lead to immunosuppression followed by a bounce back. Not many studies exist that describe dynamics of the distribution of peripheral blood (PB) immune cells during the perioperative period. Considering this scarcity, we aggregated the data on the dynamics of immune cells in patients with digestive system resections during the perioperative period and the relationship with short- and long-term prognoses. By the systematic retrieval of documents, we collected perioperative period data on white blood cells (WBC), lymphocytes, neutrophil-lymphocyte ratio (NLR), CD4+ T cells, CD8+ T cells, helper T cells (Th), B cells, natural killer cells (NK), dendritic cells (DCs), regulatory T cells (Tregs), regulatory B cells (Bregs), and Myeloid derived suppressor cells (MDSC). The frequency and distribution of these immune cells and the relationship with the patient's prognosis were summarized. A total of 1916 patients' data were included. Compared with before surgery, WBC, lymphocytes, CD4+ cells, CD8+ T cells, MDSC, and NK cells decreased after surgery, and then returned to preoperative levels. After operation DCs increased, then gradually recovered to the preoperative level. No significant changes were found in B cell levels during the perioperative period. Compared with the preoperative time-point, Tregs and Bregs both increased postoperatively. Only high levels of the preoperative and/or postoperative NLR were found to be related to the patient's prognosis. In summary, the surgery itself can cause changes in peripheral blood immune cells, which might change the immunogenicity. Therefore, the immunosuppression caused by the surgical trauma should be minimized. In oncological patients this might even influence long-term results.

HSV: The scout and assault for digestive system tumors.

More than 25% of all malignant tumors are digestive system tumors (DSTs), which mostly include esophageal cancer, gastric cancer, pancreatic cancer, liver cancer, gallbladder cancer and cholangiocarcinoma, and colorectal cancer. DSTs have emerged as one of the prominent reasons of morbidity and death in many nations and areas around the world, posing a serious threat to human life and health. General treatments such as radiotherapy, chemotherapy, and surgical resection can poorly cure the patients and have a bad prognosis. A type of immunotherapy known as oncolytic virus therapy, have recently shown extraordinary anti-tumor effectiveness. One of the viruses that has been the subject of the greatest research in this field, the herpes simplex virus (HSV), has shown excellent potential in DSTs. With a discussion of HSV-1 based on recent studies, we outline the therapeutic effects of HSV on a number of DSTs in this review. Additionally, the critical function of HSV in the detection of cancers is discussed, and some HSV future possibilities are shown.

Diagnosis and prognosis prediction model for digestive system tumors based on immunologic gene sets.

According to 2020 global cancer statistics, digestive system tumors (DST) are ranked first in both incidence and mortality. This study systematically investigated the immunologic gene set (IGS) to discover effective diagnostic and prognostic biomarkers. Gene set variation (GSVA) analysis was used to calculate enrichment scores for 4,872 IGSs in patients with digestive system tumors. Using the machine learning algorithm XGBoost to build a classifier that distinguishes between normal samples and cancer samples, it shows high specificity and sensitivity on both the validation set and the overall dataset (area under the receptor operating characteristic curve [AUC]: validation set = 0.993, overall dataset = 0.999). IGS-based digestive system tumor subtypes (IGTS) were constructed using a consistent clustering approach. A risk prediction model was developed using the Least Absolute Shrinkage and Selection Operator (LASSO) method. DST is divided into three subtypes: subtype 1 has the best prognosis, subtype 3 is the second, and subtype 2 is the worst. The prognosis model constructed using nine gene sets can effectively predict prognosis. Prognostic models were significantly associated with tumor mutational burden (TMB), tumor immune microenvironment (TIME), immune checkpoints, and somatic mutations. A composite nomogram was constructed based on the risk score and the patient's clinical information, with a well-fitted calibration curve (AUC = 0.762). We further confirmed the reliability and validity of the diagnostic and prognostic models using other cohorts from the Gene Expression Omnibus database. We identified diagnostic and prognostic models based on IGS that provide a strong basis for early diagnosis and effective treatment of digestive system tumors.

NLRP3 inflammasome-induced pyroptosis in digestive system tumors.

Programmed cell death (PCD) refers to cell death in a manner that depends on specific genes encoding signals or activities. PCD includes apoptosis, pyroptosis, autophagy and necrosis (programmed necrosis). Among these mechanisms, pyroptosis is mediated by the gasdermin family and is accompanied by inflammatory and immune responses. When pathogens or other danger signals are detected, cytokine action and inflammasomes (cytoplasmic multiprotein complexes) lead to pyroptosis. The relationship between pyroptosis and cancer is complex and the effect of pyroptosis on cancer varies in different tissue and genetic backgrounds. On the one hand, pyroptosis can inhibit tumorigenesis and progression; on the other hand, pyroptosis, as a pro-inflammatory death, can promote tumor growth by creating a microenvironment suitable for tumor cell growth. Indeed, the NLRP3 inflammasome is known to mediate pyroptosis in digestive system tumors, such as gastric cancer, pancreatic ductal adenocarcinoma, gallbladder cancer, oral squamous cell carcinoma, esophageal squamous cell carcinoma, in which a pyroptosis-induced cellular inflammatory response inhibits tumor development. The same process occurs in hepatocellular carcinoma and some colorectal cancers. The current review summarizes mechanisms and pathways of pyroptosis, outlining the involvement of NLRP3 inflammasome-mediated pyroptosis in digestive system tumors.

The Emerging Role of Super-enhancers as Therapeutic Targets in The Digestive System Tumors.

Digestive system tumors include malignancies of the stomach, pancreas, colon, rectum, and the esophagus, and are associated with high morbidity and mortality. Aberrant epigenetic modifications play a vital role in the progression of digestive system tumors. The aberrant transcription of key oncogenes is driven by super-enhancers (SEs), which are characterized by large clusters of enhancers with significantly high density of transcription factors, cofactors, and epigenetic modulatory proteins. The SEs consist of critical epigenetic regulatory elements, which modulate the biological characteristics of digestive system tumors including tumor cell identity and differentiation, tumorigenesis, environmental response, immune response, and chemotherapeutic resistance. The core transcription regulatory loop of the digestive system tumors is complex and a high density of transcription regulatory complexes in the SEs and the crosstalk between SEs and the noncoding RNAs. In this review, we summarized the known characteristics and functions of the SEs in the digestive system tumors. Furthermore, we discuss the oncogenic roles and regulatory mechanisms of SEs in the digestive system tumors. We highlight the role of SE-driven genes, enhancer RNAs (eRNAs), lncRNAs, and miRNAs in the digestive system tumor growth and progression. Finally, we discuss clinical significance of the CRISPR-Cas9 gene editing system and inhibitors of SE-related proteins such as BET and CDK7 as potential cancer therapeutics.

METTL14­mediated RNA methylation in digestive system tumors.

N6­methyladenosine (m6A) RNA methylation is one of the most common post­transcriptional modification mechanism in eukaryotes. m6A is involved in almost all stages of the mRNA life cycle, specifically regulating its stability, splicing, export and translation. Methyltransferase­like 14 (METTL14) is a particularly important m6A methylation 'writer' that can recognize RNA substrates. METTL14 has been documented to improve the activity and catalytic efficiency of METTL3. However, as individual proteins they can also regulate different biological processes. Malignancies in the digestive system are some of the most common malignancies found in humans, which are typically associated with poor prognoses with limited clinical solutions. METTL14­mediated methylation has been implicated in both the potentiation and inhibition of digestive system tumor growth, cell invasion and metastasis, in addition to drug resistance. In the present review, the research progress and regulatory mechanisms of METTL14­mediated methylation in digestive system malignancies were summarized. In addition, future research directions and the potential for its clinical application were examined.

The Functional Mechanisms of Toll-Like Receptor 3 and Its Implications in Digestive System Tumors.

Toll-like receptor 3 (TLR3) is a prominent member of the Toll-like receptor (TLR) family and has the ability to recognize and bind intracellular double-stranded RNA (dsRNA). Once triggered by a viral infection or other pathological condition, TLR3 activates immune cells and induces the production of interferons and other immune response molecules. Additionally, TLR3 is considered an important immune modulator, as it can regulate cell apoptosis and promote anticancer immunity. The investigation and application of TLR3 agonists in digestive system tumors have attracted widespread attention and are regarded as a promising cancer treatment strategy with potential clinical applications. TLR3 expression levels are generally elevated in most digestive system tumors, and higher TLR3 expression is associated with a better prognosis. Therefore, TLR3 has emerged as a novel therapeutic target for digestive system tumors. It has been used in combination with chemotherapy, radiotherapy, and targeted therapy and demonstrated excellent efficacy and tolerability. This has provided new ideas and hopes for the treatment of digestive system tumors. This review discusses the mechanisms of TLR3 and its frontier research in digestive system tumors.