Overall Survival In Colorectal Cancer Patients Research Articles

Association between long-term energy balance-related factors and survival in colorectal cancer overall and by metabolic Warburg-subtypes.

Long-term energy balance-related factors (i.e. lifestyle and physiological factors that influence the equilibrium between energy intake and energy expenditure over an extended period) like body mass index (BMI) are linked to colorectal cancer (CRC) risk, but their impact on CRC survival is unclear. We explored associations between these long-term energy balance-related factors and survival, and examined potential differences across metabolic Warburg-subtypes. Associations between long-term energy balance-related factors and survival in the total series of CRC patients (n=2,347) obtained from the prospective Netherlands Cohort Study, as well as according to Warburg-subtype (Warburg-low: n=652, Warburg-moderate: n=802, Warburg-high: n=797), were investigated using Cox regression analysis. Among the long-term energy balance-related factors studied, only increasing pre-diagnostic BMI was associated with a borderline significant poorer overall survival in CRC patients (HR5kg/m2 1.07; 95%CI 0.99-1.15). Stratified analyses showed that pre-diagnostic weight gain (HR5kg 1.06; 95%CI 1.00-1.12), and potentially increased height (HR5cm 1.04; 95%CI 0.98-1.11), were associated with poor overall survival only in patients with Warburg-high CRC. Increasing pre-diagnostic BMI was associated with poor survival only in patients with Warburg-moderate CRC (CRC-specific: HR5kg/m2 1.12; 95%CI 0.96-1.32, overall: HR5kg/m2 1.20; 95%CI 1.05-1.36). No consistent patterns were observed across energy-restriction proxies. Maintaining a healthy pre-diagnostic BMI may be beneficial for CRC survival. Moreover, associations between pre-diagnostic BMI, weight change, early-life energy restriction, height and CRC survival differed according to Warburg-subtype. Understanding the biological pathways involved in associations between energy balance-related factors and CRC survival could help refine prevention strategies in the future.

Predictive value of preoperative routine examination for the prognosis of patients with pT2N0M0 or pT3N0M0 colorectal cancer.

In recent years, the incidence of colorectal cancer (CRC) has been increasing. With the popularization of endoscopic technology, a number of early CRC has been diagnosed. However, despite current treatment methods, some patients with early CRC still experience postoperative recurrence and metastasis. To search for indicators associated with early CRC recurrence and metastasis to identify high-risk populations. A total of 513 patients with pT2N0M0 or pT3N0M0 CRC were retrospectively enrolled in this study. Results of blood routine test, liver and kidney function tests and tumor markers were collected before surgery. Patients were followed up through disease-specific database and telephone interviews. Tumor recurrence, metastasis or death were used as the end point of study to find the risk factors and predictive value related to early CRC recurrence and metastasis. We comprehensively compared the predictive value of preoperative blood routine, blood biochemistry and tumor markers for disease-free survival (DFS) and overall survival (OS) of CRC. Cox multivariate analysis demonstrated that low platelet count was significantly associated with poor DFS [hazard ratio (HR) = 0.995, 95% confidence interval (CI): 0.991-0.999, P = 0.015], while serum carcinoembryonic antigen (CEA) level (HR = 1.008, 95%CI: 1.001-1.016, P = 0.027) and serum total cholesterol level (HR = 1.538, 95%CI: 1.026-2.305, P = 0.037) were independent risk factors for OS. The cutoff value of serum CEA level for predicting OS was 2.74 ng/mL. Although the OS of CRC patients with serum CEA higher than the cutoff value was worse than those with lower CEA level, the difference between the two groups was not statistically significant (P = 0.075). For patients with T2N0M0 or T3N0M0 CRC, preoperative platelet count was a protective factor for DFS, while serum CEA level was an independent risk factor for OS. Given that these measures are easier to detect and more acceptable to patients, they may have broader applications.

Elevated serum homocysteine levels associated with poor recurrence-free and overall survival in patients with colorectal cancer

This study aimed to evaluate the significance of homocysteine (HCY) levels in predicting recurrence-free survival (RFS) and overall survival (OS) in colorectal cancer (CRC) patients. This retrospective study involved 1272 CRC patients. The risk of mortality increased with increasing HCY levels in CRC patients. The optimal HCY cutoff value in CRC patients was 15.2 μmol/L. The RFS (45.8% vs. 60.5%, p < 0.001) and OS (48.2% vs. 63.2%, p < 0.001) of patients with high HCY levels were significantly lower than those of patients with low HCY levels. Patients with high HCY levels were older, male, had large tumours, high carcinoembryonic antigen (CEA) levels, and long hospital stays, and incurred high hospitalisation costs. Multivariate analysis showed that when HCY levels exceeded 15.2 μmol/L, the risk of adverse RFS and OS increased by 55.7% and 61.4%, respectively. Subgroup analysis showed that HCY levels could supplement CEA levels and pathological staging. We constructed HCY-based prognostic nomograms, which demonstrated feasible discrimination and calibration values better than the traditional tumour, node, metastasis staging system for predicting RFS and OS. Elevated serum HCY levels were strongly associated with poor RFS and OS in CRC patients. HCY-based prognostic models are effective tools for a comprehensive evaluation of prognosis.

Spatial and single-cell colocalisation analysis reveals MDK-mediated immunosuppressive environment with regulatory T cells in colorectal carcinogenesis

Cell-cell interaction factors that facilitate the progression of adenoma to sporadic colorectal cancer (CRC) remain unclear, thereby hindering patient survival. We performed spatial transcriptomics on five early CRC cases, which included adenoma and carcinoma, and one advanced CRC. To elucidate cell-cell interactions within the tumour microenvironment (TME), we investigated the colocalisation network at single-cell resolution using a deep generative model for colocalisation analysis, combined with a single-cell transcriptome, and assessed the clinical significance in CRC patients. CRC cells colocalised with regulatory T cells (Tregs) at the adenoma-carcinoma interface. At early-stage carcinogenesis, cell-cell interaction inference between colocalised adenoma and cancer epithelial cells and Tregs based on the spatial distribution of single cells highlighted midkine (MDK) as a prominent signalling molecule sent from tumour epithelial cells to Tregs. Interaction between MDK-high CRC cells and SPP1+ macrophages and stromal cells proved to be the mechanism underlying immunosuppression in the TME. Additionally, we identified syndecan4 (SDC4) as a receptor for MDK associated with Treg colocalisation. Finally, clinical analysis using CRC datasets indicated that increased MDK/SDC4 levels correlated with poor overall survival in CRC patients. MDK is involved in the immune tolerance shown by Tregs to tumour growth. MDK-mediated formation of the TME could be a potential target for early diagnosis and treatment of CRC. Japan Society for the Promotion of Science (JSPS) Grant-in-Aid for Science Research; OITA Cancer Research Foundation; AMED under Grant Number; Japan Science and Technology Agency (JST); Takeda Science Foundation; The Princess Takamatsu Cancer Research Fund.

ZNF26-Associated Genes as Prognostic Signatures in Colorectal Cancer with Broad Therapeutic Implications.

The identification of biomarkers correlated with colorectal cancer (CRC) prognosis holds substantial importance from both clinical and scientific perspectives. Zinc finger protein 26 (ZNF26) has not been previously investigated or documented in solid tumors; thus, further research is necessary to ascertain its prognostic value in CRC. Gene expression profiles and clinicopathological data were acquired from The Cancer Genome Atlas (TCGA) database. Subsequently, expression correlation was assessed utilizing the TCGA CRC cohort. The prognostic value of ZNF26 was evaluated through Kaplan-Meier (KM) and ROC curve analyses. Following this, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were conducted to perform enrichment analysis between high- and low-ZNF26 expression groups. The association between immune cells, immune checkpoint genes, and ZNF26 expression levels was examined. Lastly, the research findings were further validated using CRC tissue samples. The results revealed that, in comparison to healthy controls, CRC significantly reduced ZNF26 expression. Elevated ZNF26 expression was associated with poorer overall survival in CRC patients. Additionally, high ZNF26 expression exhibited an inverse relationship with the immunological score and immune checkpoint gene expression in CRC patients. The findings from the TCGA data analysis were corroborated by the PCR results obtained from CRC tissue samples. ZNF26 is markedly upregulated in colorectal cancer tissues, potentially serving as a biomarker for CRC.

The m6A modification mediated-lncRNA POU6F2-AS1 reprograms fatty acid metabolism and facilitates the growth of colorectal cancer via upregulation of FASN.

Long noncoding RNAs (lncRNAs) have emerged as key players in tumorigenesis and tumour progression. However, the biological functions and potential mechanisms of lncRNAs in colorectal cancer (CRC) are unclear. The novel lncRNA POU6F2-AS1 was identified through bioinformatics analysis, and its expression in CRC patients was verified via qRT-PCR and FISH. In vitro and in vivo experiments, such as BODIPY staining, Oil Red O staining, triglyceride (TAG) assays, and liquid chromatography mass spectrometry (LC-MS) were subsequently performed with CRC specimens and cells to determine the clinical significance, and functional roles of POU6F2-AS1. Biotinylated RNA pull-down, RIP, Me-RIP, ChIP, and patient-derived organoid (PDO) culture assays were performed to confirm the underlying mechanism of POU6F2-AS1. The lncRNA POU6F2-AS1 is markedly upregulated in CRC and associated with adverse clinicopathological features and poor overall survival in CRC patients. Functionally, POU6F2-AS1 promotes the growth and lipogenesis of CRC cells both in vitro and in vivo. Mechanistically, METTL3-induced m6A modification is involved in the upregulation of POU6F2-AS1. Furthermore, upregulated POU6F2-AS1 could tether YBX1 to the FASN promoter to induce transcriptional activation, thus facilitating the growth and lipogenesis of CRC cells. Our data revealed that the upregulation of POU6F2-AS1 plays a critical role in CRC fatty acid metabolism and might provide a novel promising biomarker and therapeutic target for CRC.

Identification of macrophage-related molecular subgroups and risk signature in colorectal cancer based on a bioinformatics analysis

Macrophages play a crucial role in tumor initiation and progression, while macrophage-associated gene signature in colorectal cancer (CRC) patients has not been investigated. Our study aimed to identify macrophage-related molecular subgroups and develop a macrophage-related risk model to predict CRC prognosis. The mRNA expression profile and clinical information of CRC patients were obtained from TCGA and GEO databases. CRC patients from TCGA were divided into high and low macrophage subgroups based on the median macrophage score. The ESTIMATE and CIBERSORT algorithms were used to assess immune cell infiltration between subgroups. GSVA and GSEA analyses were performed to investigate differences in enriched pathways between subgroups. Univariate and LASSO Cox regression were used to build a prognostic risk model, which was further validated in the GSE39582 dataset. A high macrophage score subgroup was associated with poor prognosis, highly activated immune-related pathways and an immune-active microenvironment. A total of 547 differentially expressed macrophage-related genes (DEMRGs) were identified, among which seven genes (including RIMKLB, UST, PCOLCE2, ZNF829, TMEM59L, CILP2, DTNA) were identified by COX regression analyses and used to build a risk score model. The risk model shows good predictive and diagnostic values for CRC patients in both TCGA and GSE39852 datasets. Furthermore, multivariate Cox regression analysis showed that the risk score was an independent risk factor for overall survival in CRC patients. Our findings provided a novel insight into macrophage heterogeneity and its immunological role in CRC. This risk score model may serve as an effective prognostic tool and contribute to personalised clinical management of CRC patients.

The role of galanin in the progression and prognosis of colorectal cancer: the unfinished story.

The paper presents a summary of immunohistochemical (IHC) and biochemical investigations on the presence of galanin (Gal), one of the neuropeptides abundant in the enteric nervous systems, and three types of its receptors (GalR1-3) in colorectal cancer (CRC) tissue and non-involved colon wall and their associations with clinical-pathological data of the CRC patients. We were the first to morphologically demonstrate the presence of endogenous Gal in CRC sections and measure its content in homogenates of tumor tissue and dissected compartments of unchanged colon wall. The prominent atrophy of myenteric plexuses displaying Gal immunoreactivity (Gal-Ir) located close to the tumor invasion was found to be accompanied by higher Gal content in the tumor-adjacent muscularis externa than in tumor-distant tissue. In further studies for the first time, we demonstrated by the IHC technique the presence of the GalR1-3 receptors in the CRC tumors and the colon mucosa and found that higher GalR3-Ir in the tumor tissue correlated with longer overall survival of CRC patients. Furthermore, we discovered that lower GalR1 expression in submucosal plexuses located near the tumor correlated with a better prognosis in patients with CRC. These findings suggest that GalR1 could be considered as a novel therapeutic target in CRC. In conclusion, our morphological investigations provided novel data documenting the involvement of Gal and its receptors in the progression of CRC and showed the usefulness of the IHC technique for the prognosis of CRC patients.

Construction of a New Ferroptosis-related Prognosis Model for Survival Prediction in Colorectal Cancer.

This study was designed to develop a ferroptosis-related gene signature for guiding the prognostic prediction in colorectal cancer (CRC) and to explore the potential in the molecular functions of the gene signature. Ferroptosis is mainly characterized by lipid peroxide accumulation on the cell membranes in an iron-dependent manner, resulting in cellular oxidative stress, metabolic disorders, and, ultimately, cell death. This study aimed to develop a prognostic ferroptosis signature in CRC and explore its potential molecular function. The present work was designed to devise a ferroptosis signature for CRC prognosis and explore its potential molecular function. Single-cell RNA sequencing data GSE161277 and transcriptome sequencing data GSE17537 and TCGA-CRC from the Gene Expression Omnibus (GEO) and the Cancer Genome Atlas (TCGA) databases were downloaded, respectively. Quality control, dimension reduction, clustering, and clustering of single-cell RNA sequencing (scRNA- seq) data were performed using the Seurat package. A total of 259 ferroptosis-correlated genes from the FerrDb database were acquired. The single sample gene set enrichment analysis (ssGSEA) was performed to calculate the scores of genes related to ferroptosis. ESTIMATE was used to calculate immune infiltration. Independent prognostic factors were determined by performing Weighted Gene Co-Expression Network Analysis (WGCNA), univariate and Cox analyses, and Lasso analyses were used to search for independent prognostic factors. From the scRNA-seq (GSE161277) dataset, 22 cell clusters were initially identified, and according to immune cell markers, only 8 types of cells (Follicular B, central memory T cell, Epithelial, Natural killer T cell, Plasma B, M1 macrophage, Fibroblasts, and Mast cell) were finally determined to be related to CRC prognosis. The results of the scRNA-seq analysis showed that the score of ferroptosis-related genes was higher in tumour tissues and in 8 types of cells in tumour samples. In the TCGA dataset, CRC samples were divided into ferroptosis-related high scores, ferroptosis-related median scores, and ferroptosis-related low scores. Immune cell analysis revealed that ferroptosis- related high scores had the highest abundance of immune cells. An 11-gene signature was developed by WGCNA, univariate Cox, and Lasso Cox regression. The prediction ability of the signature was successfully validated in the GSE17537 dataset. A comprehensive nomogram combining the 11 signature genes and clinical parameters could effectively predict the overall survival of CRC patients. The present molecular signature established based on the 11 ferroptosis-related genes performed well in assessing CRC prognosis. The present discoveries could inspire further research on ferroptosis, providing a new direction for CRC management.

Robust machine−learning based prognostic index using cytotoxic T lymphocyte evasion genes highlights potential therapeutic targets in colorectal cancer

BackgroundA minute fraction of patients stands to derive substantial benefits from immunotherapy, primarily attributable to immune evasion. Our objective was to formulate a predictive signature rooted in genes associated with cytotoxic T lymphocyte evasion (CERGs), with the aim of predicting outcomes and discerning immunotherapeutic response in colorectal cancer (CRC).Methods101 machine learning algorithm combinations were applied to calculate the CERGs prognostic index (CERPI) under the cross−validation framework, and patients with CRC were separated into high− and low−CERPI groups. Relationship between immune cell infiltration levels, immune−related scores, malignant phenotypes and CERPI were further analyzed. Various machine learning methods were used to identify key genes related to both patient survival and immunotherapy benefits. Expression of HOXC6, G0S2, and MX2 was evaluated and the effects of HOXC6 and G0S2 on the viability and migration of a CRC cell line were in−vitro verified.ResultsThe CERPI demonstrated robust prognostic efficacy in predicting the overall survival of CRC patients, establishing itself as an independent predictor of patient outcomes. The low−CERPI group exhibited elevated levels of immune cell infiltration and lower scores for tumor immune dysfunction and exclusion, indicative of a greater potential benefit from immunotherapy. Moreover, there was a positive correlation between CERPI levels and malignant tumor phenotypes, suggesting that heightened CERPI expression contributes to both the occurrence and progression of tumors. Thirteen key genes were identified, and their expression patterns were scrutinized through the analysis of single−cell datasets. Notably, HOXC6, G0S2, and MX2 exhibited upregulation in both CRC cell lines and tissues. Subsequent knockdown experiments targeting G0S2 and HOXC6 resulted in a significant suppression of CRC cell viability and migration.ConclusionWe developed the CERPI for effectively predicting survival and response to immunotherapy in patients, and these results may provide guidance for CRC diagnosis and precise treatment.

Artificial intelligence-based analysis of tumor-infiltrating lymphocyte spatial distribution for colorectal cancer prognosis.

Artificial intelligence (AI) technology represented by deep learning has made remarkable achievements in digital pathology, enhancing the accuracy and reliability of diagnosis and prognosis evaluation. The spatial distribution of CD3 + and CD8 + T cells within the tumor microenvironment has been demonstrated to have a significant impact on the prognosis of colorectal cancer (CRC). This study aimed to investigate CD3 CT (CD3 + T cells density in the core of the tumor [CT]) prognostic ability in patients with CRC by using AI technology. The study involved the enrollment of 492 patients from two distinct medical centers, with 358 patients assigned to the training cohort and an additional 134 patients allocated to the validation cohort. To facilitate tissue segmentation and T-cells quantification in whole-slide images (WSIs), a fully automated workflow based on deep learning was devised. Upon the completion of tissue segmentation and subsequent cell segmentation, a comprehensive analysis was conducted. The evaluation of various positive T cell densities revealed comparable discriminatory ability between CD3 CT and CD3-CD8 (the combination of CD3 + and CD8 + T cells density within the CT and invasive margin) in predicting mortality (C-index in training cohort: 0.65 vs. 0.64; validation cohort: 0.69 vs. 0.69). The CD3 CT was confirmed as an independent prognostic factor, with high CD3 CT density associated with increased overall survival (OS) in the training cohort (hazard ratio [HR] = 0.22, 95% confidence interval [CI]: 0.12-0.38, P <0.001) and validation cohort (HR = 0.21, 95% CI: 0.05-0.92, P = 0.037). We quantify the spatial distribution of CD3 + and CD8 + T cells within tissue regions in WSIs using AI technology. The CD3 CT confirmed as a stage-independent predictor for OS in CRC patients. Moreover, CD3 CT shows promise in simplifying the CD3-CD8 system and facilitating its practical application in clinical settings.

SLC11A1 predicts the overall survival of patients with colorectal cancer.

Colorectal cancer (CRC) remains a significant contributor to cancer-related mortality, emphasizing the critical need for identifying biomarkers that can improve clinical management and patient outcomes. In this retrospective study, we analyzed tumor samples from 25 patients with metastatic CRC, categorized based on long-term (> 50 months) or short-term (< 10 months) survival. Employing the PanCancer Immune Profile Panel, encompassing 770 genes, in the discovery dataset, we identified 54 differentially expressed genes (DEGs) within the tumor microenvironment of metastatic CRC. Validation of potential biomarkers was performed using two publicly available RNA-based sequencing datasets (TCGA 1 (n=371) and TCGA 2 (n=566)). Univariate COX regression unveiled that three significant biomarkers were associated with overall survival in CRC within the discovery dataset, which were SLC11A1 (hazard ratio (HR): 4.09, P=0.012), TNFSF11 (HR: 3.67, P=0.02), and MEF2C (HR: 0.34, P=0.037). Kaplan-Meier survival curve analyses confirmed the correlation between SLC11A1 expression and overall survival in CRC across the discovery set (P=0.0071) and the two independent datasets (TCGA 1 (P=0.0016) and TCGA 2 (P=0.025)). Receiver operating characteristic curve analysis demonstrated an area under the curve ranging from 0.64 to 0.76, with sensitivity of 59% to 87% and specificity of 60% to 73% for predicting CRC overall survival. Immunohistochemistry staining further validated the strong expression of SLC11A1 protein in CRC tumor cells, with high expression correlating with short-term survival. These findings suggest that SLC11A1 serves as a predictive biomarker for overall survival in CRC patients.

Prognostic value of normal levels of preoperative tumor markers in colorectal cancer

Carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA19-9), carbohydrate antigen 125 (CA125), and alpha-fetoprotein (AFP) are widely used tumor markers for colorectal cancer (CRC), but their clinical significance is unknown when the levels of these tumor markers were within the normal range. This retrospective study included 2145 CRC patients. The entire cohort was randomly divided into training and validation datasets. The optimal cut-off values of tumor markers were calculated using X-tile software, and univariate and multivariate analyses were performed to assess its association with overall survival (OS). The nomogram model was constructed and validated. The entire cohort was randomly divided into a training dataset (1502 cases, 70%) and a validation dataset (643 cases,30%). Calculated from the training dataset, the optimal cut-off value was 2.9 ng/mL for CEA, 10.1 ng/mL for CA19-9, 13.4 U/mL for CA125, and 1.8 ng/mL for AFP, respectively. Multivariate analysis revealed that age, tumor location, T stage, N stage, preoperative CA19-9, and CA125 levels were independent prognostic predictors. Even within the normal range, CRC patients with relatively high levels of CA19-9 or CA125 worse OS compared to those with relatively low levels. Then, based on the independent prognostic predictors from multivariate analysis, two models with/without (model I/II) CA19-9 and CA125 were built, model I showed better prediction and reliability than model II. Within the normal range, relatively high levels of preoperative CA19-9 and CA125 were significantly associated with poor OS in CRC patients. The nomogram based on CA19-9 and CA125 levels showed improved predictive accuracy ability for CRC.

High MEIS3 Expression Indicates a Poor Prognosis for Patients with Stage II/III Colorectal Cancer.

The Wnt/β-catenin signaling pathway plays crucial roles in tumor budding and the epithelial-mesenchymal transition (EMT). Myeloid ecotropic viral insertion site 3 (MEIS3)-a direct target of Wnt/β-catenin-promotes vagal neural crest cell migration into the gut tissue during development; however, its role in cancer progression remains unclear. In this study, the role of MEIS3 in colorectal cancer (CRC) progression was investigated. We analyzed the association between MEIS3 protein expression and the clinical stages of CRC patients, and the effect on tumor cell migration and invasion by wound healing and transwell assays. Finally, we analyzed the association between MEIS3 expression and the disease-free survival (DFS) and overall survival of CRC patients through Kaplan-Meier analysis. We found that MEIS3 expression was strongly associated with CRC progression and could be employed to assess DFS in postoperative patients. MEIS3-positive cells were mainly distributed in the growth front and tumor-stroma interface of the CRC tissues, which contain abundant EMT-active and tumor budding cells dominating cancer metastasis. Moreover, MEIS3 promoted CRC cell migration and invasion by regulating effectors including laminin subunit beta 1, matrix metalloprotein 2, and vimentin. MEIS3 protein expression increased with CRC progression according to the clinical stage, which could be used as a biomarker to stratify CRC patients. The 5-year DFS of MEIS3-high patients was poorer than that of MEIS3-low patients (40.6% vs. 61.7%; p < 0.0001). Moreover, the 5-year DFS of stage II patients with MEIS3-high expression (53.4%) was comparable to that of stage III patients with MEIS3-low expression (49.5%), while the 5-year DFS of MEIS3-high patients in stage III (30.9%) was comparable to that of stage IV patients (29.6%). This study showed that MEIS3 can promote cancer cell metastasis and thus may be a promising biomarker for higher rates of recurrence in postoperative patients with stage II/III CRC.

Analysis of prognostic factors in different grades of histologic differentiation in colorectal cancer patients receiving preoperative neoadjuvant chemotherapy and establishment of prognostic nomograms for moderately differentiated grade.

The aim of this study is to analyze the differences in independent prognostic factors of cancer-specific survival (CSS) and overall survival (OS) in patients with different grades of histologic differentiation of colorectal cancer (CRC) who received preoperative neoadjuvant chemotherapy (NAC) and to establish a nomogram for predicting postoperative survival based on moderately differentiated CRC. We analyzed CRC patients from the SEER database who received NAC before operation between 2010 and 2015. The Kaplan-Meier curves were drawn to describe the differences in CSS and OS of CRC patients with different histologic grades of differentiation. Cox regression analysis was used to determine the independent prognostic factors. Nomograms were established to predict CSS and OS at 3 and 5 years by integrating independent prognostic factors. The calibration curve, receiver operating characteristic (ROC) curve, and C-index were used to verify nomograms. A total of 6481 patients with CRC who received preoperative NAC were included in this study. Patients with different grades of histologic differentiation had significant differences in CSS and OS (P < 0.001), and the independent prognostic factors of different grades of histologic differentiation showed heterogeneity. In patients with moderately differentiated grade CRC, the independent prognostic factors for CSS and OS were age, race, marital status, serum carcinoembryonic antigen (CEA) level before treatment, site of primary tumor, histologic type, pT stage, pN stage, liver metastasis, and lung metastasis. Nomograms were established based on the independent prognostic factors of moderately differentiated grade CRC, and its calibration curves, area under the curve (AUC), and C-index showed good prediction accuracy. The independent prognostic factors of CSS and OS are different in patients with different grades of histologic differentiation of CRC who received NAC before the operation. Nomograms can be used to predict the survival of patients with moderately differentiated grade CRC who received preoperative NAC and to assist clinicians in making clinical decisions.

Estrogen receptor β affects hypoxia response in colorectal cancer cells

The occurrence of colorectal cancer (CRC) is inversely correlated with estrogen receptor beta (ERβ) presence. Additionally, multiple studies associate low ERβ expression with poorer overall survival of CRC patients. Molecular pathways involved in ERβ - related reduced tumorigenesis include enhanced apoptosis, decreased proliferation, or repression of oncogenes. Moreover, the development of solid tumors, such as CRC, is often associated with an increased tumor mass that results in decreased oxygen partial tension, known as hypoxia, clinically associated with decreased prognosis and therapeutic resistance. Our high-throughput study suggests that ERβ also represses a hypoxic response in CRC cells. We observed a significantly altered transcriptional profile in HCT116 ERβ overexpressing cells that was further stimulated by E2 treatment under hypoxic conditions. The achieved data for downregulation of VEGFA, PDGFA and ANGPTL4 were validated in a time course experiment in DLD-1 cells. In addition, using an ERβ construct with a mutated DNA binding domain we observed that the downregulation of selected genes is dependent on the direct binding of this receptor to regulatory region genes. In addition, we observed that ERβ may affect the expression of the main hypoxia regulator, HIF1A, at the transcriptional and translational levels. In summary, ERβ alters the hypoxic outcome in CRC cells.

Expression and clinical significance of METTL3 in colorectal cancer.

Methyltransferase-like 3 (METTL3) belongs to the class I MTase family, and it has been proved that METTL3 is highly expressed in a variety of tumors and promotes tumor progression. Our previous studies have shown that METTL3 is highly expressed in gastric cancer tissues compared with para-cancer tissues, and its expression level is negatively correlated with good postoperative prognosis of patients. To explore the expression of METTL3 in colorectal cancer (CRC) tissue and the relationship between METTL3 and the clinicopathologic features and prognosis of CRC patients. The expression of METTL3 in cancer tissues and adjacent tissues of 180 patients with colorectal cancer was analyzed by tissue microarray and immunohistochemistry. The clinicopathologic features of patients with different METTL3 expression levels were analyzed. The expression level of METTL3 in colorectal cancer tissues was higher than that in adjacent tissues (P < .05). There were statistically significant differences in the expression of METTL3 in clinical stage, survival time and distant metastasis (all P < .05). The expression level of METTL3 in colorectal cancer tissues with tumor-node-metastasis stage III and IV and distant metastasis was higher than that in clinical stage I and II and without distant metastasis (P < .05). Patients with high METTL3 expression had a higher overall mortality rate compared to patients with low METTL3 expression, and the difference was statistically significant (P < .05). Univariate Cox regression analysis suggested that tumor distant metastasis, vascular invasion, pathological grade, lymph node metastasis and METTL3 expression level were risk factors for overall survival in CRC patients (all P < .05). Multivariate Cox regression analysis suggested that low pathological grade (hazard ratio = 1.695, 95% confidence interval: 1.116-2.274, P = .005) and high METTL3 expression (hazard ratio = 2.156, 95% confidence interval: 1.587-2.725, P < .001) could be used as independent risk factors for prognosis assessment. The expression of METTL3 was increased in colorectal cancer, and METTL3 was closely related to clinical stage, distant metastasis and prognosis of colorectal cancer.

The Potential Dual Role of H2.0-like Homeobox in the Tumorgenesis and Development of Colorectal Cancer and Its Prognostic Value.

H2.0-like homeobox (HLX) is highly expressed in several hematopoietic malignancies. However, the role of HLX in the carcinogenesis and progression of colorectal cancer (CRC) patients has rarely been reported. In this study, the data were collected from The Cancer Genome Atlas and Gene Expression Omnibus databases. The diagnostic value of HLX was analyzed by the R package "pROC." The overall survival was estimated using the "survival" and "survminer" packages. A nomogram was established to predict 1-, 3-, and 5-year overall survival of CRC patients. The CIBERSORT software was employed to calculate the relative proportions of 22 immune cells. HLX expression was downregulated in CRC patients. Remarkably, HLX expression was increased with stage (stage I-stage III) of CRC, and the CRC patients with high HLX expression exhibited a poor prognosis. The promoter methylation level of HLX was prominently increased in CRC samples compared to paracancerous samples. We also found that the six miRNAs target HLX genes, leading to its downregulation, and HLX expression had a negative correlation with its downstream target gene BRI3BP in both CRC and normal samples. Finally, we found that the 12 immune infiltrating cells were observably different between high and low HLX expression groups. The HLX had a significant positive correlation with 8 immune checkpoints (PD-1 (PDCD1), CTLA4, PDL-1 (CD274), PDL-2 (PDCD1LG2), CD80, CD86, LAG3, and TIGIT) expressions. HLX probably played a carcinostasis role in the early stages of CRC but exhibited a cancer-promoting effect in the advanced stages. Meanwhile, HLX could serve as a reliable prognostic indicator for CRC.

Membrane Trafficking-Related Genes Predict Tumor Immune Microenvironment and Prognosis in Colorectal Cancer.

Colorectal cancer (CRC) is a heterogeneous disease with varying clinical outcomes. The identification of distinct subgroups of CRC patients based on molecular profiling can aid in better understanding the disease and improving patient outcomes. This study aimed to investigate the potential of membrane trafficking-related genes (MTRGs) in sub-grouping colorectal cancer patients based on their overall survival and immune microenvironments. Consensus clustering analysis identified two distinct clusters with different expression profiles of membrane trafficking-related genes. The patients in cluster 1 had a significantly better overall survival than those in cluster 2. Furthermore, the immune microenvironments in the two clusters were also found to be significantly different, with cluster 1 having a higher immune score and more immune cells present. Functional analysis of differentially expressed genes between the two clusters revealed that MTRGs were involved in immune response and metabolic processes, and a risk signature model based on MTRGs was established to predict the prognosis of CRC patients. These findings suggest that MTRGs play a crucial role in the immune microenvironment and overall survival of CRC patients and may provide a potential target for personalized therapy.

Cell-free circulating ALU repeats in serum have a prognostic value for colorectal cancer patients.

Carcinoembryonic antigen (CEA) is the only established serum biomarker for colorectal cancer (CRC). To facilitate therapy decisions and improve the overall survival of CRC patients, prognostic biomarkers are required. We studied the prognostic value of five different cell free circulating DNA (fcDNA) fragments. The potential markers were ALU115, ALU247, LINE1-79, LINE1-300 and ND1-mt. The copy numbers of the DNA fragments were measured in the peripheral blood serum of 268 CRC patients using qPCR, the results were compared to common and previously described markers. We found that ALU115 and ALU247 fcDNA levels correlate significantly with several clinicopathological parameters. An increased amount of ALU115 and ALU247 fcDNA fragments coincides with methylation of HPP1 (P< 0.001; P< 0.01), which proved to be a prognostic marker itself in former studies and also with increased CEA level (P< 0.001). ALU115 and ALU247 can define patients with poor survival in UICC stage IV (Alu115: HR = 2.9; 95% Cl 1.8-4.8, P< 0.001; Alu247: HR = 2.2; 95% Cl 1.3-3.6; P= 0.001). Combining ALU115 and HPP1, the prognostic value in UICC stage IV is highly significant (P< 0.001). This study shows that an increased level of ALU fcDNA is an independent prognostic biomarker for advanced colorectal cancer disease.