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BackgroundRecent research has found a new way of cell death: disulfidptosis. Under glucose starvation, abnormal accumulation of disulfide molecules such as Cystine in Solute Carrier Family 7 Member 11 (SLC7A11) overexpression cells induced disulfide stress to trigger cell death. The research on disulfidptosis is still in its early stages, and its role in the occurrence and development of colorectal malignancies is still unclear.MethodIn this study, we employed bioinformatics methods to analyze the expression and mutation characteristics of disulfidptosis-related genes (DRGs) in colorectal cancer. Consensus clustering analysis was used to identify molecular subtypes of Colorectal Adenocarcinoma (COAD) associated with disulfidptosis. The biological behaviors between subtypes were analyzed to explore the impact of disulfidptosis on the tumor microenvironment. Constructing and validating a prognostic risk model for COAD using diverse data. The influence of key genes on prognosis was evaluated through SHapley Additive exPlanations (SHAP) analysis, and the predictive capability of the model was assessed using Overall Survival analysis, Area Under Curve and risk curves. The immunological status of different patients and the prediction of drug treatment response were determined through immune cell infiltration, TMB, MSI status, and drug sensitivity analysis. Single-cell analysis was employed to explore the expression of genes at the cellular level, and finally validated the expression of key genes in clinical samples.ResultBy integrating the public data from two platforms, we identified 2 colorectal cancer subtypes related to DRGs. Ultimately, we established a prognosis risk model for COAD using 7 genes (FABA4+GIPC2+EGR3+HOXC6+CCL11+CXCL10+ITLN1). SHAP analysis can further explained the positive or negative impact of gene expression on prognosis. By dividing patients into high-risk and low-risk groups, we found that patients in the high-risk group had poorer prognosis, higher TMB, and a higher proportion of MSI-H and MSI-L statuses. We also predicted that drugs such as 5-Fluorouracil, Oxaliplatin, Gefitinib, and Sorafenib would be more effective in low-risk patients, while drugs like Luminesib and Staurosporine would be more effective in high-risk patients. Single-cell analysis revealed that these 7 genes not only differ at the level of immune cells but also in epithelial cells, fibroblasts, and myofibroblasts, among other cell types. Finally, the expression of these key genes was verified in clinical samples, with consistent results.ConclusionsOur research findings provide evidence for the role of disulfidptosis in COAD and offer new insights for personalized and precise treatment of COAD.

Abstract Metabolic reprogramming, which is recognized as a hallmark of cancer, refers to the phenomenon by which cancer cells change their metabolism to support their increased biosynthetic demands. Tumor cells undergo substantial alterations in metabolic pathways, such as glycolysis, oxidative phosphorylation, pentose phosphate pathway, tricarboxylic acid cycle, fatty acid metabolism, and amino acid metabolism. Latest studies have revealed that long non-coding RNAs (lncRNAs), a group of non-coding RNAs over 200 nucleotides long, mediate metabolic reprogramming in tumor cells by regulating the transcription, translation and post-translational modification of metabolic-related signaling pathways and metabolism-related enzymes through transcriptional, translational, and post-translational modifications of genes. In addition, lncRNAs are closely related to the tumor microenvironment, and they directly or indirectly affect the proliferation and migration of tumor cells, drug resistance and other processes. Here, we review the mechanisms of lncRNA-mediated regulation of glucose, lipid, amino acid metabolism and tumor immunity in gastrointestinal tumors, aiming to provide more information on effective therapeutic targets and drug molecules for gastrointestinal tumors. Graphical Abstract

Background TMUB1 is a transmembrane protein involved in biological signaling and plays an important role in the stability and transcription of P53. However, its role in tumor remains unknown. Methods Using R language, the expression level of 33 cancer spectrum TMUB1 was analyzed by the public database TCGA, GEO and HPA, the differential expressed gene (DEG) screening and protein interaction (PPI) network was constructed, and the differential genes of TMUB1 in colon cancer were identified. The relevant signaling pathways were identified by gene functional annotation and enrichment analysis. The ssGSEA algorithm in GSVA were used for immune infiltration analysis. The Kaplan-Meier analysis, univariate and multivariate Cox regression analysis, nomogram and calibration map analysis were constructed to evaluate the correlation between TMUB1 expression and clinical prognosis. The expression levels of TMUB1 in intestinal cancer cell lines as well as in 10 intestinal cancer tissues were verified by qPCR experiments. Results Through the bioinformatics analysis of multiple databases and preliminary experimental studies, we found that the expression of TMUB1 was significantly increased in colon cancer tumors, and was correlated with the clinical N stage, pathological grade, lymphatic metastasis and BMI of colon cancer. TMUB1 may be involved in the regulation of the malignant progression of colon cancer. Meanwhile, patients with high expression of TMUB1 mRNA had worse OS and DSS, and TMUB1 expression was an independent prognostic factor for OS and DSS. It was further found that highly expressed TMUB1 tissues showed low levels of immune infiltration and stromal infiltration. Conclusion We reported the expression level of TMUB1 in colon cancer and analyzed its potential prognostic value in colon cancer through the bioinformatics analysis and preliminary experimental studies. The high expression of TMUB1 is a negative prognostic factor for colon cancer patients. TMUB1 may be a potential target for colon cancer.

Iron, as one of the essential trace elements in the human body, is involved in a wide range of critical biochemical reactions and physiological processes, including the maintenance of the normal cell cycle, mitochondrial function, nucleotide metabolism, and immune response. In this context, iron is naturally associated with cancer occurrence. Cellular iron deficiency can induce apoptosis, however, iron can also engage in potentially harmful reactions that produce free radicals because of its capacity to gain and lose electrons. Studies suggest that dietary iron, particularly heme iron, may be one of the leading causes of colorectal cancer (CRC). Moreover, patients with CRC have abnormal iron absorption, storage, utilization, and exportation. Therefore, iron is crucial for the development and progression of CRC. Elaborating on the alterations in iron metabolism during the onset and advancement of CRC would help to further explain the role and mechanism of iron inside the body. Thus, we reviewed the alterations in numerous iron metabolism-related molecules and their roles in CRC, which may provide new clues between iron metabolism and CRC.

Copper is an essential trace element in an organism, and changes in copper levels in vivo often indicate a diseased state. Copper and immunity have been discussed since the last century, with copper deficiency significantly affecting the development and function of the immune system, such as increased host susceptibility to various pathogens, decreased number and impaired function of neutrophils, reduced antibacterial activity of macrophages, decreased proliferation of splenocytes, impaired B cell ability to produce antibodies and impaired function of cytotoxic T lymphocyte and helper T cells. In the past 20 years, some studies have shown that copper ions are related to the development of many tumors, including lung cancer, acute lymphoid leukaemia, multiple myeloma and other tumors, wherein copper ion levels were significantly elevated, and current studies reveal that copper ions are involved in the development, growth and metastasis of tumors through various pathways. Moreover, recent studies have shown that copper ions can regulate the expression of PD-L1, thus, attention should be paid to the important role of copper in tumor immunity. By exploring and studying copper ions and tumor immunity, new insights into tumor immunity could be generated and novel therapeutic approaches to improve the clinical prognosis of patients can be provided.

Background: Glycolysis is closely related to the occurrence and progression of gastric cancer (GC). Currently, there is no systematic study on using the glycolysis-related long non-coding RNA (lncRNA) as a model for predicting the survival time in patients with GC. Therefore, it was essential to develop a signature for predicting the survival based on glycolysis-related lncRNA in patients with GC.Materials and methods: LncRNA expression profiles, containing 375 stomach adenocarcinoma (STAD) samples, were obtained from The Cancer Genome Atlas (TCGA) database. The co-expression network of lncRNA and glycolysis-related genes was used to identify the glycolysis-related lncRNAs. The Kaplan-Meier survival analysis and univariate Cox regression analysis were used to detect the glycolysis-related lncRNA with prognostic significance. Then, Bayesian Lasso-logistic and multivariate Cox regression analyses were performed to screen the glycolysis-related lncRNA with independent prognostic significance and to develop the risk model. Patients were assigned into the low- and high-risk cohorts according to their risk scores. A nomogram model was constructed based on clinical information and risk scores. Gene Set Enrichment Analysis (GSEA) was performed to visualize the functional and pathway enrichment analyses of the glycolysis-related lncRNA. Finally, the robustness of the results obtained was verified in an internal validation data set.Results: Seven glycolysis-related lncRNAs (AL353804.1, AC010719.1, TNFRSF10A-AS1, AC005586.1, AL355574.1, AC009948.1, and AL161785.1) were obtained to construct a risk model for prognosis prediction in the STAD patients using Lasso regression and multivariate Cox regression analyses. The risk score was identified as an independent prognostic factor for the patients with STAD [HR = 1.315, 95% CI (1.056–1.130), p < 0.001] via multivariate Cox regression analysis. Receiver operating characteristic (ROC) curves were drawn and the area under curve (AUC) values of 1-, 3-, and 5-year overall survival (OS) were calculated to be 0.691, 0.717, and 0.723 respectively. Similar results were obtained in the validation data set. In addition, seven glycolysis-related lncRNAs were significantly enriched in the classical tumor processes and pathways including cell adhesion, positive regulation of vascular endothelial growth factor, leukocyte transendothelial migration, and JAK_STAT signaling pathway.Conclusion: The prognostic prediction model constructed using seven glycolysis-related lncRNA could be used to predict the prognosis in patients with STAD, which might help clinicians in the clinical treatment for STAD.

Abstract Background The dysfunction of type I interferon (IFN) signaling is an important mechanism of immune escape and metastasis in tumors. Increased NOS1 expression has been detected in melanoma, which correlated with dysfunctional IFN signaling and poor response to immunotherapy, but the specific mechanism has not been determined. In this study, we investigated the regulation of NOS1 on the interferon response and clarified the relevant molecular mechanisms. Methods After stable transfection of A375 cells with NOS1 expression plasmids, the transcription and expression of IFNα-stimulated genes (ISGs) were assessed using pISRE luciferase reporter gene analysis, RT-PCR, and western blotting, respectively. The effect of NOS1 on lung metastasis was assessed in melanoma mouse models. A biotin-switch assay was performed to detect the S-nitrosylation of HDAC2 by NOS1. ChIP-qPCR was conducted to measure the binding of HDAC2, H4K16ac, H4K5ac, H3ac, and RNA polymerase II in the promoters of ISGs after IFNα stimulation. This effect was further evaluated by altering the expression level of HDAC2 or by transfecting the HDAC2-C262A/C274A site mutant plasmids into cells. The coimmunoprecipitation assay was performed to detect the interaction of HDAC2 with STAT1 and STAT2. Loss-of-function and gain-of-function approaches were used to examine the effect of HDAC2-C262A/C274A on lung metastasis. Tumor infiltrating lymphocytes were analyzed by flow cytometry. Results HDAC2 is recruited to the promoter of ISGs and deacetylates H4K16 for the optimal expression of ISGs in response to IFNα treatment. Overexpression of NOS1 in melanoma cells decreases IFNα-responsiveness and induces the S-nitrosylation of HDAC2-C262/C274. This modification decreases the binding of HDAC2 with STAT1, thereby reducing the recruitment of HDAC2 to the ISG promoter and the deacetylation of H4K16. Moreover, expression of a mutant form of HDAC2, which cannot be nitrosylated, reverses the inhibition of ISG expression by NOS1 in vitro and decreases NOS1-induced lung metastasis and inhibition of tumor infiltrating lymphocytes in a melanoma mouse model. Conclusions This study provides evidence that NOS1 induces dysfunctional IFN signaling to promote lung metastasis in melanoma, highlighting NOS1-induced S-nitrosylation of HDAC2 in the regulation of IFN signaling via histone modification.

Aim. To compare the clinical efficacies between laparoscopic and conventional open surgery in lateral lymph node dissection (LLND) for advanced rectal cancer. Methods. We comprehensively searched PubMed, Embase, Cochrane Library, CNKI, and Wanfang Data and performed a cumulative meta-analysis. According to inclusion criteria and exclusion criteria, all eligible randomized controlled trials (RCTs) or retrospective or prospective comparative studies assessing the two techniques were included, and then a meta-analysis was performed by using RevMan 5.3 software to assess the difference in clinical and oncological outcomes between the two treatment approaches. Results. Eight studies involving a total of 892 patients were finally selected, with 394 cases in the laparoscopic surgery group and 498 cases in the traditional open surgery group. Compared with the traditional open group, the laparoscopic group had a longer operative time (WMD=81.56, 95% CI (2.09, 142.03), P=0.008), but less intraoperative blood loss (WMD=−452.18, 95% CI (-652.23, -252.13), P0.05). Conclusion. Laparoscopic LLND has a similar efficacy in oncological outcomes and postoperative complications to the conventional open surgery, with the advantages of reduced intraoperative blood loss, shorter postoperative hospital stay, and higher R0 resection rate, and tumor radical cure is similar to traditional open surgery. Laparoscopic LLND is a safe and feasible surgical approach, and it may be used as a standard procedure in LLND for advanced rectal cancer.

Introduction Total gastrectomy is often recommended for upper body gastric cancer, and totally laparoscopic total gastrectomy (TLTG) is deemed to be a promising surgical method with the well-known advantages such as less invasion and fast recovery. However, the anastomosis between oesophagus and jejunum is the difficulty of TLTG. Although staplers have promoted the development of TLTG, the choice of suitable staplers to complete oesophagojejunostomy is controversial and unclear. Therefore, a higher level of research evidence is needed to compare the two types of staplers in terms of safety and efficacy for oesophagojejunostomy in TLTG among patients with gastric cancer. Methods and analysis PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure (CNKI) and Wanfang Databases will be comprehensively searched from January 1990 to July 2019. All eligible randomised controlled trials (RCTs), non-RCTs or observational studies comparing the two types of staplers will be included. A meta-analysis will be performed using Review Manager V.5.3 software to compare the safety and efficacy of linear and circular staplers for oesophagojejunostomy in TLTG. The primary outcomes are anastomotic leakage, anastomotic stricture, anastomotic haemorrhage. The secondary outcomes include time to first instance of passing gas after surgery, first feeding time, total operation time, reconstruction time, estimated blood loss. The heterogeneity of this study will be assessed by p values and I² statistic. Subgroup analyses and sensitivity analyses will be used to explore and explain the heterogeneity. The risk of bias will be assessed using the Cochrane tool or the Newcastle-Ottawa Quality Assessment Scale. Ethics and dissemination Ethical approval will not be required because this proposed systematic review and metaanalysis is based on previously published data, which does not include intervention data on patients. The findings of this study will be submitted to a peer-reviewed journal and will be presented at a relevant congress. [ABSTRACT FROM AUTHOR]