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ABSTRACTGut microbiota has demonstrated an increasingly important role in the onset and development of colorectal cancer (CRC). Nonetheless, the association between gut microbiota and KRAS mutation in CRC remains enigmatic. We conducted 16S rRNA sequencing on stool samples from 94 CRC patients and employed the linear discriminant analysis effect size algorithm to identify distinct gut microbiota between KRAS mutant and KRAS wild-type CRC patients. Transcriptome sequencing data from nine CRC patients were transformed into a matrix of immune infiltrating cells, which was then utilized to explore KRAS mutation-associated biological functions, including Gene Ontology items and Kyoto Encyclopedia of Genes and Genomes pathways. Subsequently, we analyzed the correlations among these KRAS mutation-associated gut microbiota, host immunity, and KRAS mutation-associated biological functions. At last, we developed a predictive random forest (RF) machine learning model to predict the KRAS mutation status in CRC patients, based on the gut microbiota associated with KRAS mutation. We identified a total of 26 differential gut microbiota between both groups. Intriguingly, a significant positive correlation was observed between Bifidobacterium spp. and mast cells, as well as between Bifidobacterium longum and chemokine receptor CX3CR1. Additionally, we also observed a notable negative correlation between Bifidobacterium and GOMF:proteasome binding. The RF model constructed using the KRAS mutation-associated gut microbiota demonstrated qualified efficacy in predicting the KRAS phenotype in CRC. Our study ascertained the presence of 26 KRAS mutation-associated gut microbiota in CRC and speculated that Bifidobacterium may exert an essential role in preventing CRC progression, which appeared to correlate with the upregulation of mast cells and CX3CR1 expression, as well as the downregulation of GOMF:proteasome binding. Furthermore, the RF model constructed on the basis of KRAS mutation-associated gut microbiota exhibited substantial potential in predicting KRAS mutation status in CRC patients.IMPORTANCEGut microbiota has emerged as an essential player in the onset and development of colorectal cancer (CRC). However, the relationship between gut microbiota and KRAS mutation in CRC remains elusive. Our study not only identified a total of 26 gut microbiota associated with KRAS mutation in CRC but also unveiled their significant correlations with tumor-infiltrating immune cells, immune-related genes, and biological pathways (Gene Ontology items and Kyoto Encyclopedia of Genes and Genomes pathways). We speculated that Bifidobacterium may play a crucial role in impeding CRC progression, potentially linked to the upregulation of mast cells and CX3CR1 expression, as well as the downregulation of GOMF:Proteasome binding. Furthermore, based on the KRAS mutation-associated gut microbiota, the RF model exhibited promising potential in the prediction of KRAS mutation status for CRC patients. Overall, the findings of our study offered fresh insights into microbiological research and clinical prediction of KRAS mutation status for CRC patients.

Colorectal cancer (CRC) metastasis plays a crucial role in disease progression, yet the regulatory mechanisms underlying metastasis remain incompletely understood. Isobutyric acid (IBA), a short‐chain fatty acid found at high levels in serum of CRC patients, has been shown to be a critical metabolite influencing CRC proliferation. However, its role in tumor metastasis remains unknown. Here, utilizing liquid chromatography tandem mass spectrometry (LC‐MS/MS) analysis, we found that levels of IBA were significantly higher in patients with distant organ metastasis of CRC than in those without. Furthermore, IBA promoted CRC metastasis both in vitro and in vivo. Mass spectrometry, immunofluorescence, and cellular thermal shift assay revealed that IBA interacts with RACK1. Mechanistically, IBA binding to and activating RACK1 promotes regulation of downstream Akt and FAK signaling and CRC metastasis. Collectively, our study highlights the critical interplay between IBA and RACK1 and its impact on tumor metastasis. This study suggests that targeting the IBA–RACK1 signaling axis may be an effective therapeutic strategy for controlling CRC metastasis. [ABSTRACT FROM AUTHOR]

Abnormal epigenetic regulation is identified to correlate with cancer progression and renders tumor refractory and resistant to reactive oxygen species (ROS)‐based anti‐tumor actions. To address it, a sequential ubiquitination and phosphorylation epigenetics modulation strategy is developed and exemplified by the well‐established Fe‐metal‐organic framework (Fe‐MOF)‐based chemodynamic therapy (CDT) nanoplatforms that load the 26S proteasome inhibitor (i.e., MG132). The encapsulated MG132 can blockade 26S proteasome, terminate ubiquitination, and further inhibit transcription factor phosphorylation (e.g., NF‐κB p65), which can boost pro‐apoptotic or misfolded protein accumulations, disrupt tumor homeostasis, and down‐regulate driving genes expression of metastatic colorectal cancer (mCRC). Contributed by them, Fe‐MOF‐unlocked CDT is magnified to considerably elevate ROS content for repulsing mCRC, especially after combining with macrophage membrane coating‐enabled tropism accumulation. Systematic experiments reveal the mechanism and signaling pathway of such a sequential ubiquitination and phosphorylation epigenetics modulation and explain how it could blockade ubiquitination and phosphorylation to liberate the therapy resistance to ROS and activate NF‐κB‐related acute immune responses. This unprecedented sequential epigenetics modulation lays a solid foundation to magnify oxidative stress and can serve as a general method to enhance other ROS‐based anti‐tumor methods. [ABSTRACT FROM AUTHOR]

Ferroptosis is an iron-dependent form of cell death induced by lipid oxidation with an essential role in diseases, including cancer. Since prognostic value of ferroptosis-dependent related genes (FDRGs) in colorectal cancer (CRC) remains unclear, we explored the significance of FDRGs in CRC through comprehensive single-cell analysis. We downloaded the GSE161277 dataset for single-cell analyses and calculated the ferroptosis-dependent gene score (FerrScore) for each cell type. According to each cell type-specific median FerrScore, we categorized the cells into low- and high-ferroptosis groups. By analyzing differentially-expressed genes across the two groups, we identified FDRGs. We further screened these prognosis-related genes used to develop a prognostic signature and calculated its correlation with immune infiltration. We also compared immune checkpoint gene efficacy among different risk groups, and qRT-PCR was performed in colorectal normal and cancer cell lines to explore whether the signature genes could be used as clinical prognostic indicators. In total, 523 FDRGs were identified. A prognostic signature including five signature genes was constructed, and patients were divided into two risk groups. The high-risk group had poor survival rates and displayed high levels of immune infiltration. Our newly developed ferroptosis-based prognostic signature possessed a high predictive ability for CRC. [ABSTRACT FROM AUTHOR]

Objective: The relationship between intestinal microbiome and colorectal cancer (CRC) progression is unclear. This study aims to identify the intestinal microbiome associated with CRC progression and construct predictive labels to support the accurate assessment and treatment of CRC. Method: The 192 patients included in the study were divided into stage I-II and stage III-IV CRC patients according to the pathological stages, and preoperative stools were collected from both groups for 16S rDNA sequencing of the intestinal microbiota. Pearson correlation and Spearman correlation coefficient analysis were used to analyze the differential intestinal microbiome and the correlation with tumor microenvironment and to predict the functional pathway. XGBoost model (XGB) and Random Forest model (RF) were used to construct the microbiome-based signature. The total RNA extraction from 17 CRC tumor simples was used for transcriptome sequencing. Result: The Simpson index of intestinal microbiome in stage III-IV CRC were significantly lower than those in stage I-II CRC. Proteus, Parabacteroides, Alistipes and Ruminococcus etc. are significantly enriched genus in feces of CRC patients with stage III-IV. ko00514: Other types of O − glycan biosynthesis pathway is relevant with CRC progression. Alistipes indistinctus was positively correlated with mast cells, immune activators IL-6 and IL6R, and GOBP_PROTEIN_FOLDING_IN_ENDOPLASMIC_RETICULUM dominantly. The Random Forest (RF) model and eXtreme Gradient Boosting (XGBoost) model constructed with 42 CRC progression-associated differential bacteria were effective in distinguishing CRC patients between stage I-II and stage III-IV. Conclusions: The abundance and diversity of intestinal microbiome may increase gradually with the occurrence and progression of CRC. Elevated fetal abundance of Proteus, Parabacteroides, Alistipes and Ruminococcus may contribute to CRC progression. Enhanced synthesis of O − glycans may result in CRC progression. Alistipes indistinctus may play a facilitated role in mast cell maturation by boosting IL-6 production. Alistipes indistinctus may work in the correct folding of endoplasmic reticulum proteins in CRC, reducing ER stress and prompting the survival and deterioration of CRC, which may owe to the enhanced PERK expression and activation of downstream UPR by Alistipes indistinctus. The CRC progression-associated differential intestinal microbiome identified in our study can be served as potential microbial markers for CRC staging prediction. [ABSTRACT FROM AUTHOR]

Background. Colorectal cancer is a digestive tract malignant tumor, ranking the second mortality and the third incidence cancer worldwide. The abnormal expression of NEAT1 is related to the occurrence and development of colorectal cancer. However, the specific mechanism of NEAT1 mediated-inflammatory pathway in the progression of colorectal cancer is still unclear. Methods. In this study, expression of NEAT1 in colorectal cancer patients was analyzed by bioinformatics. Clinical samples including peripheral blood and colorectal cancer tissues were collected for qRT-PCR, Western blot, and immunohistochemistry assay. The role of NEAT1 in the colorectal cancer progression was further confirmed by both in-vivo and in-vitro functional experiments. Results. By bioinformatics prediction, it is found that NEAT1 expression level is significantly higher in the peripheral blood of patients with colorectal cancer and is associated with poor prognosis. In-vitro functional studies indicated that NEAT1 knockdown suppressed the proliferation and migration of colorectal cancer cells by mediating inflammatory response. In-vivo tumorigenesis experiments showed that NEAT1 knockdown suppressed tumor growth. Conclusion. Abnormal high expression level of NEAT1 in colorectal cancer tissues and cells leads to poor prognosis. Mechanistically, NEAT1 triggers off the proliferation and migration of colorectal cancer cells through promoting the inflammatory reaction. Clinically, the expression level of NEAT1 in serum may be a marker for diagnosis and prognosis of colorectal cancer. [ABSTRACT FROM AUTHOR]

aims to analyze the differentially expressed circRNA in colon adenocarcinoma (COAD) and evaluate its diagnostic and prognostic value. Analyze associated circRNA-miRNA-mRNA network in COAD. Methods and Materials: Real-time quantitative PCR (RT-PCR) was used to verify differentially expressed circRNA in COAD tissues and cells; Receiver operator characteristic (ROC) and Cox regression analysis were used to evaluating its diagnostic and prognostic value; Meanwhile we conducted CCK-8, invasion, and migration experiments in cell lines to explore the function of circRNA. In addition, a competitive endogenous RNA (ceRNA) network was established using bioinformatics methods to explore its prognostic value and potential functional mechanisms. Results: Our study found that hsa_circ_0084927 is highly expressed in COAD tissues and cell lines. Plasma hsa_circ_0084927 can be used as a diagnostic marker for COAD patients; hsa_circ_0084927 can promote the proliferation, migration and invasion of COAD cells. In addition, we effectively constructed a ceRNA: network has_circ_0084927/miR-106b-5p/VEGFA. The ceRNA network indicates that hsa_circ_0084927 may affect the prognosis of COAD through the regulation of cell cycle, apoptosis and other pathways. Conclusion: Our research results indicate that hsa_circ_0084927 has a cancer-promoting effect and may be used as a circulating tumor marker for COAD prognosis. In addition, this study proposes a new ceRNA network to provide new insights for the targeted therapy of COAD. [ABSTRACT FROM AUTHOR]

Background: Inflammation and nutritional status are highly associated with colorectal cancer (CRC) prognosis. This study aimed to evaluate the prognostic value of the preoperative neutrophil-BMI ratio (NBR) in patients with CRC. Methods: A retrospective analysis was performed on 2471 patients with CRC who underwent surgical resection between 2004 and 2019. Patients were divided into two groups based on the cutoff value for NBR. Cox regression and Kaplan–Meier curves were used to evaluate overall survival (OS). Results: High NBR was associated with female sex, low BMI, colon, right-sided CRC, poor differentiation, T3 to 4 stage, M1 to 2 stage, high carcinoembryonic antigen (CEA) level, III-IV stage, microsatellite instability (MSI), and no adjuvant chemotherapy (all P <.05). The high NBR group had a shorter OS than the low NBR group. Female and right sided patients with CRC and with high NBR had a worse prognosis. Univariate Cox regression suggested that NBR was significantly associated with poor prognosis. Multivariate analysis confirmed that age (P =.019,HR:1.012), differentiation (P =.001,HR:1.306), TNM stage (P <.001,HR:2.432), CEA (P =.014,HR:1.001), and NBR (P <.001, HR: 3.309) were independent poor prognostic factors for OS. Subgroup univariate analysis indicated that female patients with high NBR had a worse prognosis. A nomogram composed of TNM stage, CEA, and NBR was developed, and internal validation was based on female patients with CRC. The nomogram provided good discrimination for both the training and validation sets, with area under the curve values of 0.79 and 0.769, respectively. Conclusions: High preoperative levels of NBR are indicators of poor prognosis in patients with CRC. [ABSTRACT FROM AUTHOR]

Colorectal carcinoma is a highly prevalent and heterogeneous gastrointestinal malignancy. The emergence of organoid technology has provided a new direction for colorectal cancer research. As a novel-type model, organoid has significant advantages compared with conventional tumor research models, characterized with the high success rate of construction and the high matching with the original tumor. These characteristics provide new possibilities to study the mechanism of colorectal carcinogenesis and improve the treatment effects. The present literature would mainly summarize the characteristics of tumor organoids and the up-to-date technique development of patient-derived organoids (PDOs) and application in colorectal cancer. [ABSTRACT FROM AUTHOR]

Background and Purpose: Systemic inflammation and nutritional status have been shown to be associated with the prognosis of colorectal cancer. The purpose of this study was to evaluate the impact of the serum C-reactive protein-to-body mass index ratio on the prognosis of patients with curatively resected colorectal cancer. Methods: We conducted a retrospective analysis of a database of 2,471 eligible patients with colorectal cancer who underwent curative resection at our hospital between 2004 and 2019. The optimal cut-off for CPR-to-BMI ratio was determined using maximally selected rank statistics. Patients were divided into 2 groups according to the cut-off value of the serum C-reactive protein-to-body mass index ratio. Kaplan-Meier curves and Cox regression analysis were used to compare overall survival. A two-sided P -value < 0.05 was considered statistically significant. Results: The proportion of patients with a high C-reactive protein-to-body mass index ratio increased with increasing age, male sex, right-sided colon cancer, poorly differentiated tumors, advanced-stage disease, local/distant metastases, tumor–node–metastasis stage, and microsatellite instability. In subgroup analysis according to tumor–node–metastasis stage, the overall survival of the high C-reactive protein-to-body mass index ratio group was significantly shorter than that of the low C-reactive protein-to-body mass index ratio group (P < 0.001). Multivariate analysis identified age, differentiation, tumor–node–metastasis stage, carcinoembryonic antigen level, and the C-reactive protein-to-body mass index ratio as independent poor prognostic factors for overall survival. Conclusions: The C-reactive protein-to-body mass index ratio predicts the prognosis of patients with curatively resected colorectal cancer and is an independent risk factor for overall survival in patients with colorectal cancer. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to elucidate the prognostic significance of a novel inflammation-joined and nutrition-related clinicopathological marker for colorectal cancer (CRC). Methods: Various factors from preoperative fasting blood samples from 2471 patients with CRC were retrospectively analyzed. Factors related to prognosis were evaluated using univariate and multivariate analyses. The Kaplan–Meier method was used to generate survival curves, while the log-rank test was used to measure survival differences between groups. Results: Univariate analysis revealed that C-reactive protein (CRP)/mean corpuscular volume (MCV) ratio, TNM stage, differentiation, right-sided tumor, age, carcinoembryonic antigen (CEA) level, and CRP level were significantly associated with poor prognosis in CRC. In contrast, adjuvant chemotherapy is regarded as a protective factor. Elevation of CRP/MCV ratio (odds ratio [OR]: 1.535, 95% confidence interval [CI]: 1.121–2.104, P = 0.008), TNM stage (OR: 2.747, 95% CI: 2.175–3.469, P < 0.001), and differentiation (OR, 1.384; 95% CI, 1.150–1.666; P = 0.001) were prognostic risk factors in the multivariate analyses. Subgroup analysis showed that CRP/MCV, TNM staging system, and differentiation also independently affected survival in patients with lymph node-positive CRC. The nomogram based on these three indicators showed that CRP/MCV had a greater prognostic value and clinical significance for lymph node-positive patients with poorly differentiated tumors at the late stage. Conclusion: A novel nomogram using the clinicopathologic index of inflammation and nutrition was constructed to predict the prognosis of CRC. Early interventions should be emphasized for advanced-stage patients with severe inflammation and poor nutritional status. [ABSTRACT FROM AUTHOR]

Background: Tumor mutational burden (TMB) could be a measure of response to immune checkpoint inhibitors therapy for patients with colorectal cancer (CRC). MicroRNAs (miRNAs) participate in anticancer immune responses. In the present study, we determined miRNA expression patterns in patients with CRC and built a signature that predicts TMB. Methods: Next generation sequencing (NGS) on formalin-fixed paraffin-embedded samples from CRC patients was performed to measure TMB levels. We used datasets from The Cancer Genome Atlas to compare miRNA expression patterns in samples with high and low TMB from patients with CRC. We created an miRNA-based signature index using the selection operator (LASSO) and least absolute shrinkage method from the training set. We used an independent test set as internal validation. We used real-time polymerase chain reaction (RT-PCR) to validate the miRNA-based signature classifier. Results: Twenty-seven samples from CRC patients underwent NGS to determine the TMB level. We identified four miRNA candidates in the training set for predicting TMB (N = 311). We used the test set (N = 204) for internal validation. The four-miRNA-based signature classifier was an accurate predictor of TMB, with accuracy 0.963 in the training set. In the test set, it was 0.902; and it was 0.946 in the total set. The classifier was superior to microsatellite instability (MSI) for predicting TMB in TCGA dataset. In the validation cohort, MSI status more positively correlated with TMB levels than did the classifier. Validation from RT-qPCR showed good target discrimination of the classifier for TMB prediction. Conclusion: To our knowledge, this is the first miRNA-based signature classifier validated using high quality clinical data to accurately predict TMB level in patients with CRC. [ABSTRACT FROM AUTHOR]

Background: Epithelial mesenchymal transformation (EMT) and DNA repair status represent intrinsic features of colorectal cancer (CRC) and are associated with patient prognosis and treatment responsiveness. We sought to develop a combined EMT and DNA repair gene panel with potential application in patient classification and precise treatment. Methods: We comprehensively evaluated the EMT and DNA repair patterns of 1,652 CRC patients from four datasets. Unsupervised clustering was used for classification. The clinical features, genetic mutation, tumor mutation load, and chemotherapy as well as immunotherapy sensitivity among different clusters were systematically compared. The least absolute shrinkage and selection operator regression method was used to develop the risk model. Results: Three distinct CRC clusters were determined. Clustet1 was characterized by down-regulated DNA repair pathways but active epithelial markers and metabolism pathway and had intermediate prognosis. Clustet2 was characterized by down-regulated both epithelial markers and DNA repair pathways and had poor outcome. Clustet3 presented with activation of DNA repair pathway and epithelial markers had favorable prognosis. Clustet1 might benefit form chemotherapy and Clustet3 had a higher response rate to immunotherapy. An EMT and DNA repair risk model related to prognosis and treatment response was developed. Conclusions: This work developed and validated a combined EMT and DNA repair gene panel for CRC classification, which may be an effective tool for survival prediction and treatment guidance in CRC patients. [ABSTRACT FROM AUTHOR]

A T4B hepatic flexure of colon cancer that had invaded the liver, gall bladder, and pancreas/duodenum was removed through a D3 expanded right hemicolectomy + pancreaticoduodenectomy +sectional VI and VII hepatic segmentectomy. [ABSTRACT FROM AUTHOR]

Purpose: The overall survival (OS) of patients diagnosed with stage II‐III colorectal cancer (CRC) can vary greatly, even between patients with the same tumor stage. We aimed to design a nomogram to predict OS in resected, stage II‐III CRC and stratify patients with CRC into different risk groups. Patients and Methods: Based on data from 873 patients with CRC, we used univariate Cox regression analysis to select the significant prognostic features, which were subjected to the least absolute shrinkage and selection operator (LASSO) regression algorithm for feature selection. Cross‐validation was used to confirm suitable tuning parameters (λ) for LASSO logistic regression. Then, the nomogram was used to estimate 3‐ and 5‐year OS based on the multivariable Cox regression model. The survival curves of the two groups were produced using the Kaplan‐Meier method. Risk group stratification was performed to assess the predictive capacity of the nomogram. Results: Preoperative mean platelet volume, preoperative platelet distribution width, monocytes, and postoperative adjuvant chemotherapy were identified as independent prognostic factors by LASSO regression and integrated for the construction of the nomogram. The nomogram provided good discrimination, with C‐indices of 0.67 and 0.69 for the training and validation sets, respectively. Calibration plots illustrated excellent agreement between the nomogram predictions and actual observations for 3‐ and 5‐year OS. Moreover, a significant difference in OS was shown between patients stratified into different risk groups (P <.001). Conclusion: We constructed and validated an original predictive nomogram for OS in patients with CRC after surgery, facilitating physicians to appraise the individual survival of postoperative patients accurately and identify high‐risk patients who need more aggressive treatment and follow‐up strategies. [ABSTRACT FROM AUTHOR]

Fluoropyrimidine-based chemotherapy is an essential component of systemic chemotherapy for colorectal cancer (CRC). The immune response is implicated in chemotherapy-induced cytotoxicity. Here, we reported an immune risk (Imm-R) model for prognostic prediction in patients receiving fluoropyrimidine-based chemotherapy. Gene expression profiles and corresponding clinical information were collected from four data sets and divided into training set (n = 183) and validation set (validation set1: n = 34; validation set2: n = 99). The composition of 22 tumor-infiltrating immune cells (TIICs) populations was characterized with the CIBERSORT deconvolution algorithm. A prognostic Imm-R model for predicting overall survival was established by performing least absolute shrinkage and selection operator (LASSO) penalized COX regression analysis. T follicular helper cells and M0 macrophages were associated with better survival, while eosinophils were associated with worse survival. TIICs signature was constructed based on the above three immune cell types. Furthermore, a Imm-R model was created by integrating TIICs signature with immune-related genes (IRGs), which effectively in distinguishing CRC patients with poorer prognosis. The Imm-R model was associated with activation of the TGF-beta signaling and suppression of DNA damage. Results of this research provide new insights into the role of immunity for in fluoropyrimidine-based chemotherapy as well as a useful tools to predict the outcome of CRC patients receiving fluoropyrimidine-based chemotherapy. [ABSTRACT FROM AUTHOR]

Vascular invasion (VI) is an important feature for systemic recurrence and an indicator for the application of adjuvant therapy in colorectal cancer (CRC). Preoperative knowledge of VI is important in determining whether adjuvant therapy is necessary, as well as the adequacy of surgical resection. In the present study, a predictive nomogram for VI in patients with CRC was constructed. The prediction model consisted of 664 eligible patients with CRC, who were divided into a training set (n=468) and a validation set (n=196). Data were collected between August 2013 and April 2018. The feature selection model was established using the least absolute shrinkage and selection operator regression model. Multivariable logistic regression analysis was used to construct the predictive nomogram. The performance of the nomogram was evaluated by calibration, discrimination and clinical usefulness. Differentiation, computed tomography (CT)-based on N stage (CT N stage), hemameba and tumor distance from the anus (cm) were integrated into the nomogram. The nomogram exhibited good discrimination, with an area under the curve (AUC) of 0.731 and good calibration. Application of the nomogram in the validation cohort showed acceptable discrimination, with an AUC of 0.710 and good calibration. Decision curve analysis revealed that the nomogram was clinically useful. These findings suggests, to the best of our knowledge, that this may be the first nomogram for individual preoperative prediction of VI in patients with CRC, which may promote preoperative optimization strategies for this selected group of patients. [ABSTRACT FROM AUTHOR]