Digestive System Malignancies Research Articles

#1305 Analysis of clinicopathological characteristics of membranous nephropathy with concomitant malignancy and literature review

Abstract Background and Aims In recent years, the incidence of membranous nephropathy (MN) with malignancy has gradually increased, but the clinical and pathological characteristics of these patients are still unclear. Method Patients diagnosed with renal biopsy-proven MN and comorbid malignancy detected within 5 years before and after MN diagnosis were included. The control group were diagnosed with renal biopsy-proven IMN with no malignancy and no other clear secondary cause for MN. We present a comprehensive analysis of MN with concomitant malignancy in our cohort and literature review. Results A total of 19 MN patients with concomitant malignancy were evaluated at our center; among them, 13 (68.4%) were male, and the median age was 57.0 (45.0, 69.0) years. Malignancy occurred after the onset of renal disease in 61.1% of patients, with digestive system malignancy (36.8%) ranking as the predominant type. 8 (8/11) patients achieved either PR or CR during the follow-up period. Most patients had pathology typical of IMN. IF showed strong positivity for IgG (100%), whereas only 13 (68.4%) patients were positive for C3. IEM showed electron-dense deposits predominantly located in subepithelial. Specific MN antigen staining of renal tissues from 19 patients showed that the highest percentage was 68.4% (13/19) for PLA2R-only positivity followed by 15.8% (3/19) for THSD7A-only positivity. Specific MN antigen staining of malignant tissue was performed in 5 patients whose tumor samples were available. Only 2 patients expressed the same antigen on kidney and tumor. Screening 17 articles encompassing a total of 21 patients in whom MN-specific antigen staining was performed on both renal and tumor tissues simultaneously. Among these patients, 71.4% (15/21) were male, with a median age of 61.0 years (56.3, 72.8). In this cohort, malignancy was diagnosed before or simultaneously with MN in 15 patients (75.0%), with digestive system malignancy constituting the most prevalent comorbid malignancy, at 33.3%. Notably, THSD7A accounted for the highest proportion of MN antigens, at 66.7% (14/21); among these patients, 78.6% (11/14) also exhibited positive tumor THSD7A staining. Of the 21 patients, 72.2% (13/18) achieved CR or PR. No significant difference between the baseline characteristics was observed between the 19 patients from our center and 21 patients documented in the literature. Therefore, the clinicopathological data of these 40 patients were pooled and compared with 101 IMN patients without malignancy at our center. Compared to patients without malignancy, MN patients with malignancy were older at the time of renal biopsy (P = 0.017), had a lower eGFR (P = 0.035) and demonstrated a lower rate of CR or PR after treatment (P < 0.001). The rate of PLA2R positivity in the glomeruli of MN patients with concomitant malignancy was significantly lower (40.0% vs. 92.1%, P < 0.001), while the rate of THSD7A positivity was significantly higher (42.5% vs. 2.0%, P < 0.001). Renal tissue IgG subclass staining showed that the rate of IgG4 positivity was significantly decreased compared with that in IMN patients (59.3% vs. 90.1%, P < 0.001), and the rate of IgG2 positivity was significantly increased (36.0% vs. 16.5%, P = 0.033). Conclusion To conclude, malignancy screening should be more actively performed for MN patients presenting with the above characteristics.

LncRNA TINCR: an irreplaceable biological target in human malignancies.

Currently, malignant tumors of the digestive system tend to affect younger people, which has brought a catastrophic burden to people around the world. lncRNA has gained considerable attention because of its importance in the early diagnosis and treatment of tumors. In addition, since terminal differentiation-induced ncRNA ( abbreviated as TINCR )was reported in a Nature article, it has received focus on targeted therapy of tumors, especially in digestive system malignant tumors. This review aims to reveal and summarize its important molecular mechanisms in digestive system malignancies. In this review, relevant research involving the relationship between TINCR and digestive system malignancies are collected through systematic retrieval of PubMed. TINCR is expressed bidirectionally in malignant tumors of the digestive system. TINCR functions primarily as a ceRNA in digestive system tumors, and TINCR also functions at the transcriptional level. lncRNA TINCR has the potential to become a novel biomolecular marker of the digestive system.

Magnolol promotes the autophagy of esophageal carcinoma cells by upregulating HACE1 gene expression.

Esophagus cancer (EC) is one of the most aggressive malignant digestive system tumors and has a high clinical incidence worldwide. Magnolol, a natural compound, has anticancer effects on many cancers, including esophageal carcinoma, but the underlying mechanism has not been fully elucidated. Here, we first find that magnolol inhibits the proliferation of esophageal carcinoma cells and enhances their autophagy activity in a dose- and time-dependent manner. This study demonstrates that magnolol increases the protein levels of LC3 II, accompanied by increased HACE1 protein levels in both esophageal carcinoma cells and xenograft tumors. HACE1-knockout (KO) cell lines are generated, and the ablation of HACE1 eliminates the anti-proliferative and autophagy-inducing effects of magnolol on esophageal carcinoma cells. Additionally, our results show that magnolol primarily promotes HACE1 expression at the transcriptional level. Therefore, this study shows that magnolol primarily exerts its antitumor effect by activating HACE1-OPTN axis-mediated autophagy. It can be considered a promising therapeutic drug for esophageal carcinoma.

Colorectal cancer cells with stably expressed SIRT3 demonstrate proliferating retardation by Wnt/β-catenin cascade inactivation.

Colorectal cancer (CRC) is a typical and lethal digestive system malignancy. In this study, we investigated the effect of sirtuin 3 (SIRT3) expression, a fidelity mitochondrial protein, on the proliferation of CRC cells and the mechanisms involved. Using the University of Alabama at Birmingham Cancer Data Analysis Portal database and the Clinical Proteomic Tumour Analysis Consortium database, we discovered that low expression of SIRT3 in CRC was a negative factor for survival prognosis (P < .05). Meanwhile, SIRT3 expression was correlated with distant metastasis and tumour, node, metastasis stage of CRC patients (P < .05). Subsequently, we observed that CRC cells with stable SIRT3 expression exhibited a significant decrease in proliferative capacities both in vitro and in vivo, compared to their counterparts (P < .05). Further investigation using western blot, immunoprecipitation and TOPflash/FOPflash assay showed the mechanism of growth retardation of these cells was highly associated with the degradation of β-catenin in cytosol, and the localization of β-catenin/α-catenin complex in the nucleus. In conclusion, our findings suggest that the inhibition of CRC cell proliferation by SIRT3 is closely associated with the inactivation of the Wnt/β-catenin signalling pathway.

Abstract 7271: Proteasome inhibitor FHND6091: A potent therapeutic candidate forPTEN-deficient cholangiocarcinoma

Abstract Background: Cholangiocarcinoma (CCA), characterized by high genetic heterogeneity, poses a significant challenge due to limited therapeutic options. Notably, the tumor suppressor gene PTEN is frequently altered in more than 50% of CCA clinical specimens. PTEN deficiency enhances proteasome subunit expression and proteasome proteolytic activity, and facilitates the potential therapeutic efficacy of proteasome inhibitors in CCA. The proteasome inhibitor FHND6091, a novel drug developed by Jiangsu Chia Tai Fenghai Pharmaceutical Co., Ltd., has obtained IND approval from NMPA and is currently undergoing a first-in-human phase 1 trial for multiple myeloma (MM) and mantle cell lymphoma (MCL). Method: This study employed a comprehensive approach, encompassing both in vitro and in vivo pharmacology studies. The investigation involved purified human proteasome activity assays, cell viability assays, and in vivo anti-tumor activity studies utilizing a cholangiocarcinoma patient-derived xenograft (CCA PDX) model with PTEN deficiency. Results: FHND6091 exhibited potent inhibitory effects on the β5 subunit of the 20S proteasome, with IC50 value of 2.22 nM. In cell viability assessments, FHND6091 demonstrated selective efficacy in PTEN-deficient CCA cell lines, with IC50 value of 5.87 nM in HCCC-9810 (PTEN deletion, homozygous loss of exon 6 to 9) and 10.08 nM in RBE (PTEN intact expression). In a PDX xenograft model with PTEN deficiency, gavage administration of FHND6091 BIW at 1.0 mg/kg (first week)/1.5 mg/kg (subsequent two weeks) exhibited advanced anti-tumor activity (TGI = 52.32%) compared to intraperitoneal administration of Bortezomib at 0.5 mg/kg BIW (TGI = 31.88%). Tissue distribution studies in rats revealed the preference of FHND6091 for liver accumulation, with an exposure (AUC0-t) approximately 44 times that of plasma after a single dose. These data corroborated that FHND6091 could achieve a specific level of exposure in the target organ liver. Conclusion: FHND6091, characterized by its irreversibility, high potency and oral bioavailability, emerges as a promising proteasome inhibitor for the treatment of both hematologic and solid tumors. These findings strongly support FHND6091 as a potential candidate for the treatment of CCA in clinical settings. Furthermore, the regulating of sensitivity to proteasome inhibitors by the PTEN status extends beyond cholangiocarcinoma to encompass various human cancers, such as ovarian, prostate, and digestive system malignancies. This broader implication establishes a theoretical foundation supporting the potential efficacy of FHND6091 as a therapeutic agent for solid tumors. Citation Format: Yongqiang Zhu, Jingmiao Shi, Chenhui Li. Proteasome inhibitor FHND6091: A potent therapeutic candidate forPTEN-deficient cholangiocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7271.

IGF2BP2-related modification patterns in pancreatic cancer: A machine learning-driven approach towards personalized treatment

Pancreatic cancer (PC) is a malignant digestive system tumor with a very poor prognosis. N6-methyladenosine (m6A) is mediated by a variety of readers and participates in important regulatory roles in PC. Based on TCGA_PAAD, ICGC_AU_PAAD, ICGC_CA_PAAD, GSE28735 and GSE62452 datasets, We mapped the multi-omics changes of m6A readers in PC and found that m6A readers, especially IGF2BP family genes, had specific changes and were significantly associated with poor prognosis. An unsupervised consensus clustering algorithm was used to explore the correlation between specific expression patterns of m6A readers in PC and enrichment pathways, tumor immunity and clinical molecular subtypes. Then, the principal component analysis (PCA) algorithm was used to quantify specific expression patterns and screen core genes. Machine learning algorithms such as Bootstrapping and RSF were used to quantify the expression patterns of core genes and construct a prognostic scoring model for PC patients. What's more, pharmacogenomic databases were used to screen sensitive drug targets and small molecule compounds for high-risk PC patients in an all-around and multi-angle way. Our study has not only provided new insights into personalized prognostication approaches, but also thrown light on integrating tailored risk stratification with precision therapy based on IGF2BP2-mediated m6A modification patterns.

Global and Regional Burden and Trend of Neoplasms Attributable to Alcohol Consumption in the Past 3 Decades.

To provide valuable insights for targeted cancer screening among high-risk patients, we analyzed the global and regional burden of neoplasms resulting from alcohol consumption between 1990 and 2019. The information used in this study was collected from the Global Burden of Disease 2019 dataset. Initially, the database was used to extract details of mortality rates, disability-adjusted life years (DALYs), and the number of individuals affected by alcohol-related neoplasms (ARNs). Subsequently, the data were compared by cancer type, sex, age, region, and sociodemographic index. Furthermore, the study involved the calculation and comparison of estimated annual percentage changes in age-standardized DALYs rates (ASDRs) and mortality rates. The impact of alcohol on the burden of cancer varied by type of cancer, sex, age, and geographical location. Notably, males exhibited significantly higher ASDRs compared with females. Specifically, in 2019, alcohol emerged as the primary contributor to the number of DALYs associated with esophageal cancer, followed by liver cancer and colorectal cancer in men. Patients aged 50+ years exhibited a heightened rate of DALYs associated with ARNs. From 1990 to 2019, ASDRs among individuals with ARNs did not exhibit a decline in low-middle and low sociodemographic index regions. Alcohol consumption represents a significant risk factor for the burden of cancer, particularly within the realm of digestive system malignancies. Consequently, targeted cancer screening efforts should be directed toward the population that engages in alcohol drinking, with a particular focus on men aged 50 years and older, residing in economically disadvantaged areas.

Connecting atrial fibrillation to digestive neoplasms: exploring mediation via ischemic stroke and heart failure in Mendelian randomization studies.

Notwithstanding the acknowledged interplay between atrial fibrillation (AF) and the emergence of digestive system neoplasms, the intricacies of this relationship remain ambiguous. By capitalizing univariable Mendelian Randomization (MR) complemented by a mediated MR tactic, our pursuit was to elucidate the causative roles of AF in precipitating digestive system malignancies and potential intermediary pathways. This research endeavor seeks to scrutinize the causal clinical implications of whether genetic predispositions to AF correlate with an increased risk of digestive system malignancies, employing MR analytical techniques. Utilizing a dataset amalgamated from six studies related to AF, encompassing over 1,000,000 subjects, we performed univariable MR assessments, employing the random-effects inverse-variance weighted (IVW) methodology as our principal analytical paradigm. Subsequently, a mediated MR framework was employed to probe the potential mediating influence of AF on the nexus between hypertension (HT), heart failure (HF), ischemic stroke (IS), coronary artery disease (CAD), and digestive system neoplasms. The univariable MR evaluation unveiled a notable causal nexus between the genetic inclination toward AF and the genetic susceptibility to colon, esophageal, and small intestine malignancies. The mediated MR scrutiny ascertained that the genetic inclination for AF amplifies the risk profile for colon cancer via IS pathways and partially explains the susceptibility to esophageal and small intestine tumors through the HF pathway. Our investigative endeavor has highlighted a definitive causative association between genetic inclination to AF and specific digestive system neoplasms, spotlighting IS and HF as instrumental mediators. Such revelations furnish pivotal perspectives on the complex genetic interconnections between cardiovascular anomalies and certain digestive tract tumors, emphasizing prospective therapeutic and diagnostic worthy of pursuit.

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.

Liensinine inhibits progression of intrahepatic cholangiocarcinoma by regulating TGF-β1 /P-smad3 signaling through HIF-1a.

Intrahepatic cholangiocarcinoma (ICC) is a high-grade malignant digestive system tumor with an insidious onset and unfavorable prognosis. Liensinine, a small molecule derived from plants, has been proven to have significant tumor suppressor activity in other cancers. However, there are no reports on whether liensinine can inhibit the proliferation or metastasis of ICC. This study aimed to explore the tumor-suppressive activity of liensinine in ICC and its underlying mechanisms. The phenotypic changes in ICC cells were monitored in vitro using cell function tests. Western blot and immunofluorescence analyses verified the efficacy of liensinine. Tumor-bearing nude mice were used to explore the effect of liensinine on tumors and its toxicity and side effects in vivo. Liensinine suppressed ICC cell proliferation and arrested the cell cycle at the G1 phase. The epithelial-mesenchymal transition (EMT) of ICC cells was also inhibited, thereby restraining their invasion and migration of tumor cells. In addition, this study found that the potential mechanism of liensinine inhibiting EMT may be via suppression of the TGF-β1/P-smad3 signaling pathway through hypoxia-inducible factor 1 alpha (HIF-1a). In vivo experiments showed that liensinine inhibited the growth of Hucc-T1 transplanted tumors in nude mice. Liensinine restrained the proliferation of ICC cells and suppressed EMT in ICC via the HIF-1a-mediated TGF-β1/P-smad3 signaling pathway.

Timosaponin AIII induces lipid peroxidation and ferroptosis by enhancing Rab7-mediated lipophagy in colorectal cancer cells.

Colorectal cancer (CRC) is a common digestive system malignancy, and despite significant therapeutic advancements, more effective treatments are needed. Timosaponin AIII (TA-III), a major steroidal saponin derived from Anemarrhena asphodeloides Bge, is a potential anticancer agent. Ferroptosis plays an important role in cancer treatment. To investigate the molecular mechanism of TA-III as a novel ferroptosis inducer in suppressing CRC through lipophagy. Ferroptosis, an autophagy-dependent mode of cell death, has been implicated in CRC. CRC cells were treated with TA-III, and lipophagy levels were evaluated via BODIPY493/503 staining and western blotting. Autophagy turnover was tracked using GFP-RFP-LC3B. Lipid peroxidation was quantified using an malondialdehyde kit and C11-BODIPY flow assay. Mitochondrial morphology was observed using transmission electron microscopy. GC-MS/MS was used to detect lipid metabolism changes. The role of ras related protein Rab 7a (Rab7) was assessed by western blotting and glutathione S-transferase pull-down assays. In vivo, the anticancer efficacy of TA-III was tested using a xenograft model. RNA-seq analysis unveiled the potential of TA-III as an anticancer agent through ferroptosis. In vivo experiments revealed how TA-III treatment triggered degradation of lipid droplets in CRC cells, resulting in an accumulation of FFAs, heightened unsaturated free fatty acids, and increased lipid peroxidation. These events ultimately lead to mitochondrial shrinkage and downregulation of ferroptosis markers (FSP1 and GPX4). Intriguingly, the Rab7 protein emerged as a crucial bridge between lipophagy and ferroptosis, underlining its significance in the anticancer mechanism of TA-III. Moreover, TA-III treatment in a xenograft tumour model substantially reduced tumour volume via ferroptosis, underscoring its therapeutic efficacy. Our study is the first to establish that TA-III triggers lipophagy in CRC cells via the Rab7 gene, subsequently promoting ferroptosis. This suggests its potential use as an antitumour agent.

Integrated Single-Cell and Transcriptome Sequencing Analyses Develop a Ubiquitination-Associated Signature in Gastric Cancer and Identified OTULIN as a Novel Biomarker.

Gastric cancer (GC) is the most commonly diagnosed digestive system malignancy with a dismal survival outcome. The prognostic value of ubiquitination-related genes (URGs) in GC has yet to be discovered. Two GC cohort datasets were obtained from the Cancer Genome Atlas Program (TCGA) and Gene Expression Omnibus (GEO) databases. Stepwise Cox analysis was employed to generate a signature. Then, we applied unsupervised clustering analysis to determine subclusters in GC based on URGs. Single-cell analysis was carried out to depict the cellular location of model genes. The CIBERSORT method was performed to estimate the immune landscape. Finally, preliminary wet lab work was utilized to disclose the potential effect of OTULIN. Our proposed signature was set up based on five URGs (OTULIN, UBE2C, USP1, USP2, and MAPT) which could serve as a risk classifier to categorize GC cases. In addition, it was demonstrated that the ubiquitination-associated model could depict the immune landscape and forecast immunotherapy response for GC patients. Furthermore, in vitro experiments determined the function and effect of OUTLIN in GC. We observed that the knockdown of OUTLIN could suppress cell viability and metastatic ability of GC cell lines. Our data lays the groundwork for a comprehensive investigation into the role of URGs in GC and determined OTULIN as a candidate GC biomarker.

Genomic insights and prognostic significance of novel biomarkers in pancreatic ductal adenocarcinoma: A comprehensive analysis

Pancreatic ductal adenocarcinoma (PDAC) is a highly prevalent digestive system malignancy, with a significant impact on public health, especially in the elderly population. The advent of the Human Genome Project has opened new avenues for precision medicine, allowing researchers to explore genetic markers and molecular targets for cancer diagnosis and treatment. Despite significant advances in genomic research, early diagnosis of pancreatic cancer remains elusive due to the lack of highly sensitive and specific markers. Therefore, there is a need for in-depth research to identify more precise and reliable diagnostic markers for pancreatic cancer. In this study, we utilized a combination of public databases from different sources to meticulously screen genes associated with prognosis in pancreatic cancer. We used gene differential analysis, univariate cox regression analysis, least absolute selection and shrinkage operator (LASSO) regression, and multivariate cox regression analysis to identify genes associated with prognosis. Subsequently, we constructed a scoring system, validated its validity using survival analysis and ROC analysis, and further confirmed its reliability by nomogram and decision curve analysis (DCA). We evaluated the diagnostic value of this scoring system for pancreatic cancer prognosis and validated the function of the genes using single cell data analysis. Our analysis identifies six genes, including GABRA3, IL20RB, CDK1, GPR87, TTYH3, and KCNA2, that were strongly associated with PDAC prognosis. Clinical prognostic models based on these genes showed strong predictive power not only in the training set but also in external datasets. Functional enrichment analysis revealed significant differences between high- and low-risk groups mainly in immune-related functions. Additionally, we explored the potential of the risk score as a marker for immunotherapy response and identified key factors within the tumor microenvironment. The single-cell RNA sequencing analysis further enriched our understanding of cell clusters and six hub genes expressions. This comprehensive investigation provides valuable insights into pancreatic PDAC and its intricate immune landscape. The identified genes and their functional significance underscore the importance of continued research into improving diagnosis and treatment strategies for PDAC.

Xanthatin suppresses pancreatic cancer cell growth via the ROS/RBL1 signaling pathway: In vitro and in vivo insights

BackgroundAs a malignant digestive system tumor, pancreatic cancer has a high mortality rate. Xanthatin is a sesquiterpene lactone monomer compound purified from the traditional Chinese herb Xanthium strumarium L. It has been reported that Xanthatin exhibits inhibitory effects on various cancer cells in retinoblastoma, glioma, hepatoma, colon cancer, lung cancer, as well as breast cancer. However, in pancreatic cancer cells, only one report exists on the suppression of Prostaglandin E2 synthesis and the induction of caspase 3/7 activation in Xanthatin-treated MIA PaCa-2 cells, while systematic in vitro and in vivo investigations and related mechanisms have yet to be explored. PurposeThis research aims to explore the in vitro and in vivo effects of Xanthatin on pancreatic cancer and its molecular mechanisms. MethodsThe anticancer effects and mechanisms of Xanthatin on pancreatic cancer cells were assessed through employing cell counting kit-8 (CCK-8) assay, lactate dehydrogenase (LDH) assay, carboxyfluorescein diacetate succinimidyl ester (CFDA SE) cell proliferation assay, colony formation assay, wound healing assay, transwell assay, Annexin V-FITC/propidium iodide (PI) dual staining, Hoechst nuclear staining, Western blot analysis, phosphoproteomics, and reactive oxygen species (ROS) measurement. The in vivo anticancer effects of Xanthatin on pancreatic cancer cells were studied using a nude mouse model. ResultsThe present study showed that Xanthatin can prevent the proliferation and metastasis of pancreatic cancer cells and trigger the exposure of phosphatidylserine (PS), chromatin condensation, and caspase activation, thereby inducing apoptosis. Phosphoproteomic analysis indicated that Xanthatin inhibits the phosphorylation of the proliferation-associated protein RBL1, and oxidative stress can lead to RBL1 dephosphorylation. Further investigation revealed that Xanthatin significantly upregulates ROS levels in pancreatic cancer cells, and the antioxidant N-acetylcysteine (NAC) can reverse Xanthatin-induced cell proliferation inhibition and apoptosis. In addition, Xanthatin can suppress pancreatic cancer cell growth in a xenograft nude mouse model with low toxicity to the mice. ConclusionXanthatin may inhibit the proliferation of pancreatic cancer cells and trigger apoptosis through the ROS/RBL1 signaling pathway.

The underlying regulatory mechanisms of colorectal carcinoma by combining Vitexin and Aspirin: based on systems biology, molecular docking, molecular dynamics simulation, and in vitro study.

Colorectal cancer (CRC) is a highly prevalent digestive system malignancy. Aspirin is currently one of the most promising chemopreventive agents for CRC, and the combination of aspirin and natural compounds helps to enhance the anticancer activity of aspirin. Natural flavonoids like vitexin have an anticancer activity focusing on colorectal carcinoma. This study investigated the potential mechanism of action of the novel combination of vitexin and aspirin against colorectal cancer through network pharmacology, molecular docking, molecular dynamics simulation, and in vitro experiments. The results of network pharmacology suggested that vitexin and aspirin regulate multiple signaling pathways through various target proteins such as NFKB1, PTGS2 (COX-2), MAPK1, MAPK3, and TP53. Cellular experiments revealed that the combined effect of vitexin and aspirin significantly inhibited HT-29 cell growth. Vitexin dose-dependently inhibited COX-2 expression in cells and enhanced the down-regulation of COX-2 and NF-κB expression in colorectal cancer cells by aspirin. This study provides a pharmacodynamic material and theoretical basis for applying agents against colorectal cancer to delay the development of drug resistance and improve the prognosis of cancer patients.

ENTPD1-AS1-miR-144-3p-mediated high expression of COL5A2 correlates with poor prognosis and macrophage infiltration in gastric cancer.

Gastric cancer (GC) is a malignant tumor with high morbidity and mortality. Expression of COL5A2 is significantly elevated in GC. Abnormal expression of noncoding RNAs (ncRNAs) have been found in GC, including microRNA (miRNA) and long noncoding RNA (lncRNA). Competing endogenous RNA network plays an important regulatory role in GC. However, its specific regulatory mechanism has not been elucidated. To gain insight into the ncRNA regulatory mechanism and immune microenvironment related to COL5A2 in GC. RNA sequencing data and clinical information from The Cancer Genome Atlas data portal were used to analyze the expressions of COL5A2, miRNA and lncRNA related to the prognosis of GC. Cox regression analysis and Kyoto Encyclopedia of Genes and Genomes analysis were performed to assess the risk factors and relevant function of COL5A2. StarBase was used to predict the interaction of miRNA-lncRNA or miRNA-mRNA in GC. The relationship between COL5A2, miR-144-3p and ENTPD1-AS1 were verified by dual luciferase reporter assay. The association of COL5A2 with immune cell infiltration were analyzed using the Tumor Immune Estimation Resource database and single sample gene set enrichment analysis. The expression of COL5A2 and macrophages in paired GC tissues were detected by immunohistochemical staining. We verified that the upregulation of COL5A2 expression was associated with the prognosis of GC and was an independent risk factor for GC. miR-144-3p was downregulated and correlated with the prognosis of GC. miR-144-3p regulated the expression of COL5A2 through direct interaction with COL5A2. ENTPD1-AS1 was elevated in GC and competitively bound to miR-144-3p, thus inhibiting the expression of miR-144-3p. ENTPD1-AS1 enhanced the expression of COL5A2 through sponging miR-144-3p. Compared to paired normal tissue, COL5A2 expression was upregulated at the protein level, especially in the middle and late stages of GC. The high expression of COL5A2 was positively linked to macrophage infiltration in GC. COL5A2 regulated by ENTPD1-AS1-miR-144-3p was associated with poor prognosis and macrophage infiltration in GC. This could be a new biomarker and therapeutic target in GC.

Proteomics-based identification of proteins in tumor-derived exosomes as candidate biomarkers for colorectal cancer.

Colorectal cancer (CRC) is the second leading cause of cancer-related death, with high morbidity worldwide. There is an urgent need to find reliable diagnostic biomarkers of CRC and explore the underlying molecular mechanisms. Exosomes are involved in intercellular communication and participate in multiple pathological processes, serving as an important part of the tumor microenvironment. To investigate the proteomic characteristics of CRC tumor-derived exosomes and to identify candidate exosomal protein markers for CRC. In this study, 10 patients over 50 years old who were diagnosed with moderately differentiated adenocarcinoma were recruited. We paired CRC tissues and adjacent normal intestinal tissues (> 5 cm) to form the experimental and control groups. Purified exosomes were extracted separately from each tissue sample. Data-independent acquisition mass spectrometry was implemented in 8 matched samples of exosomes to explore the proteomic expression profiles, and differentially expressed proteins (DEPs) were screened by bioinformatics analysis. Promising exosomal proteins were verified using parallel reaction monitoring (PRM) analysis in 10 matched exosome samples. A total of 1393 proteins were identified in the CRC tissue group, 1304 proteins were identified in the adjacent tissue group, and 283 proteins were significantly differentially expressed between them. Enrichment analysis revealed that DEPs were involved in multiple biological processes related to cytoskeleton construction, cell movement and migration, immune response, tumor growth and telomere metabolism, as well as ECM-receptor interaction, focal adhesion and mTOR signaling pathways. Six differentially expressed exosomal proteins (NHP2, OLFM4, TOP1, SAMP, TAGL and TRIM28) were validated by PRM analysis and evaluated by receiver operating characteristic curve (ROC) analysis. The area under the ROC curve was 0.93, 0.96, 0.97, 0.78, 0.75, and 0.88 (P < 0.05) for NHP2, OLFM4, TOP1, SAMP, TAGL, and TRIM28, respectively, indicating their good ability to distinguish CRC tissues from adjacent intestinal tissues. In our study, comprehensive proteomic profiles were obtained for CRC tissue exosomes. Six exosomal proteins, NHP2, OLFM4, TOP1, SAMP, TAGL and TRIM28, may be promising diagnostic markers and effective therapeutic targets for CRC, but further experimental investigation is needed.

Integrated analysis of single-cell and bulk RNA-seq establishes a novel signature for prediction in gastric cancer.

Single-cell sequencing technology provides the capability to analyze changes in specific cell types during the progression of disease. However, previous single-cell sequencing studies on gastric cancer (GC) have largely focused on immune cells and stromal cells, and further elucidation is required regarding the alterations that occur in gastric epithelial cells during the development of GC. To create a GC prediction model based on single-cell and bulk RNA sequencing (bulk RNA-seq) data. In this study, we conducted a comprehensive analysis by integrating three single-cell RNA sequencing (scRNA-seq) datasets and ten bulk RNA-seq datasets. Our analysis mainly focused on determining cell proportions and identifying differentially expressed genes (DEGs). Specifically, we performed differential expression analysis among epithelial cells in GC tissues and normal gastric tissues (NAGs) and utilized both single-cell and bulk RNA-seq data to establish a prediction model for GC. We further validated the accuracy of the GC prediction model in bulk RNA-seq data. We also used Kaplan-Meier plots to verify the correlation between genes in the prediction model and the prognosis of GC. By analyzing scRNA-seq data from a total of 70707 cells from GC tissue, NAG, and chronic gastric tissue, 10 cell types were identified, and DEGs in GC and normal epithelial cells were screened. After determining the DEGs in GC and normal gastric samples identified by bulk RNA-seq data, a GC predictive classifier was constructed using the Least absolute shrinkage and selection operator (LASSO) and random forest methods. The LASSO classifier showed good performance in both validation and model verification using The Cancer Genome Atlas and Genotype-Tissue Expression (GTEx) datasets [area under the curve (AUC)_min = 0.988, AUC_1se = 0.994], and the random forest model also achieved good results with the validation set (AUC = 0.92). Genes TIMP1, PLOD3, CKS2, TYMP, TNFRSF10B, CPNE1, GDF15, BCAP31, and CLDN7 were identified to have high importance values in multiple GC predictive models, and KM-PLOTTER analysis showed their relevance to GC prognosis, suggesting their potential for use in GC diagnosis and treatment. A predictive classifier was established based on the analysis of RNA-seq data, and the genes in it are expected to serve as auxiliary markers in the clinical diagnosis of GC.

Clinical significance and potential application of cuproptosis-related genes in gastric cancer.

Worldwide, gastric cancer (GC) is a common lethal solid malignancy with a poor prognosis. Cuproptosis is a novel type of cell death mediated by protein lipoylation and may be related to GC prognosis. To offer new insights to predict GC prognosis and provide multiple therapeutic targets related to cuproptosis-related genes (CRGs) for future therapy. We collected data from several public data portals, systematically estimated the expression level and prognostic values of CRGs in GC samples, and investigated related mechanisms using public databases and bioinformatics. Our results revealed that FDX1, LIAS, and MTF1 were differentially expressed in GC samples and exhibited important prognostic significance in The Cancer Genome Atlas (TCGA) cohort. We constructed a nomogram model for overall survival and disease-specific survival prediction and validated it via calibration plots. Mecha-nistically, immune cell infiltration and DNA methylation prominently affected the survival time of GC patients. Moreover, protein-protein interaction network, KEGG pathway and gene ontology enrichment analyses demonstrated that FDX1, LIAS, MTF1 and related proteins play key roles in the tricarboxylic acid cycle and cuproptosis. Gene Expression Omnibus database validation showed that the expression levels of FDX1, LIAS, and MTF1 were consistent with those in the TCGA cohort. Top 10 perturbagens has been filtered by Connectivity Map. In conclusion, FDX1, LIAS, and MTF1 could serve as potential prognostic biomarkers for GC patients and provide novel targets for immunotarget therapy.

Role of ferroptosis in esophageal cancer and corresponding immunotherapy.

Esophageal cancer (EC) is one of the most common digestive system malignancies in the world. The combined modality treatment of EC is usually surgery and radiation therapy, however, its clinical efficacy for advanced patients is relatively limited. Ferroptosis, a new type of iron-dependent programmed cell death, is different from apoptosis, necrosis and autophagy. In recent years, many studies have further enlightened that ferroptosis plays an essential role in the occurrence, development and metastasis of tumors. Targeting ferroptosis stimulates a new direction for further exploration of oncologic treatment regimens. Furthermore, ferroptosis has a critical role in the immune microenvironment of tumors. This paper reviews the mechanism of ferroptosis and the ferroptosis research progress in the treatment of EC. We further elaborate the interaction between ferroptosis and immunotherapy, and the related mechanisms of ferroptosis participation in the immunotherapy of EC, so as to provide new directions and ideas for the treatment of EC.