Overall Survival In Colorectal Cancer Patients Research Articles

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.

Correlation of PDL-1 Expression with Tumour Budding and Tumour Infiltrating Lymphocytes in Colorectal Cancers

Objective: To study and correlate PDL-1 expression with Tumour budding and Tumour Infiltrating Lymphocytes in Colorectal Carcinoma. Background: Colorectal cancer (CRC) is third most common cancer with a high mortality. Many attempts have been made to raise overall survival of CRC patients. The immune system plays an important role in clearing the unhealthy cancer cells. Programmed death 1 (PD1) is a regulatory molecule which dampens the immune response when bound to one of its complementary ligands (PDL1). Its expression is related to the response of immunotherapy in CRC treatment which has been exploited in recent times. However, its prognostic value is still controversial, and the distribution of PD-L1 on tumour Cells or Immune Cells has not been comprehensively analysed. Method: A total of 30 patients diagnosed with CRCs were included who underwent surgical intervention. Cases who took preoperative neoadjuvant chemotherapy or radiotherapy were excluded. IHC analyses of PDL1 was done and was correlated with tumour budding and Tumour Infiltrating Lymphocytes (TILs) and statistical significance was assessed. Results: 11 cases showed low bud count at the invasive front out of which only 3 cases showed PDL1 positivity. The rest 19 cases had high bud count out of which 18 were PDL 1 positive. This difference was highly significant (p = 0.002). In Low Bud / High TILs, 75% cases showed no PDL1 expression in tumour cells, whereas 62.5% cases showed PDL1 positivity in TILs whereas in High Bud / Low TILs group, all the cases (100%) showed PDL1 expression in tumour cells whereas only 75% cases showed PDL1 positivity in TILs, again being statistically significant (p &lt;0.001). Conclusion: This study showed an inverse correlation between PDL1 in tumour buds and immune cells, thus emphasising the role of tumour microenvironment. Our study reiterates the fact that high expression of PDL1 in tumour cells suppresses antitumor response whereas its high expression in TILS correlates with a better prognosis.

The neutrophil-to-lymphocyte ratio and lactate dehydrogenase combined in predicting liver metastasis and prognosis of colorectal cancer.

The neutrophil-to-lymphocyte ratio (NLR) and lactate dehydrogenase (LDH) level are inflammatory markers related to tumor growth and metabolism. This study investigated the value of preoperative NLR, LDH and the combination of NLR and LDH (NLR-LDH) for predicting colorectal cancer liver metastasis (CRLM) and tumor prognosis in the early stages of colorectal cancer (CRC). Three hundred patients undergoing CRC resection were included. Logistic regression analysis was used to estimate the correlation between CRLM time and inflammatory markers, and Kaplan-Meier survival and Cox regression analyses were used to estimate overall survival (OS). Forest plots were prepared based on the multivariate Cox analysis model and evaluated by receiver operating characteristic (ROC) curve analysis. The NLR cut-off value was 2.071 according to the ROC curve. The multivariate analysis showed that the elevated LDH level and a high NLR-LDH level were independent predictors of synchronous CRLM and OS (p < 0.05). The combination of a high NLR and elevated LDH and NLR-LDH levels suggested a poor prognosis and a significantly shorter median survival time than a low NLR and low levels of LDH and NLR-LDH. The ROC curve analysis results illustrated that the predictive value of the NLR-LDH score for synchronous CRLM [area under the curve (AUC) = 0.623, p < 0.001] and OS (AUC = 0.614, p = 0.001) was superior to that of the NLR or LDH score used alone. LDH and NLR-LDH are reliable, easy-to-use, independent biomarkers for predicting synchronous or metachronous CRLM and OS in CRC patients. The NLR is an important monitoring index for CRLM. Preoperative NLR, LDH and NLR-LDH may help to guide the use of therapeutic strategies and cancer surveillance.

Serum creatinine/cystatin C ratio as a prognostic indicator for patients with colorectal cancer.

This study aimed to explore the relationship between creatinine/cystatin C ratio and progression-free survival (PFS) and overall survival (OS) in colorectal cancer (CRC) patients undergoing surgical treatment. A retrospective analysis was conducted on 975 CRC patients who underwent surgical resection from January 2012 to 2015. Restricted three-sample curve to display the non-linear relationship between PFS/OS and creatinine-cystatin C ratio. Cox regression model and Kaplan-Meier method were used to evaluate the effect of the creatinine-cystatin C ratio on the survival of CRC patients. Prognostic variables with p-value ≤0.05 in multivariate analysis were used to construct prognostic nomograms. The receiver operator characteristic curve was used to compare the efficacy of prognostic nomograms and the traditional pathological stage. There was a negative linear relationship between creatinine/cystatin C ratio and adverse PFS in CRC patients. Patients with low creatinine/cystatin C ratio had significantly lower PFS/OS than those with high creatinine/cystatin C ratio (PFS, 50.8% vs. 63.9%, p = 0.002; OS, 52.5% vs. 68.9%, p < 0.001). Multivariate analysis showed that low creatinine/cystatin C ratio was an independent risk factor for PFS (HR=1.286, 95%CI = 1.007-1.642, p=0.044) and OS (HR=1.410, 95%CI=1.087-1.829, p=0.010) of CRC patients. The creatinine/cystatin C ratio-based prognostic nomograms have good predictive performance, with a concordance index above 0.7, which can predict the 1-5-year prognosis. Creatinine/cystatin C ratio may be an effective prognostic marker for predicting PFS and OS in CRC patients, aid in pathological staging, and along with tumour markers help in-depth prognostic stratification in CRC patients.

Screening the key pathogenic mutations in Chinese patients with colorectal cancers using liquid and tissue biopsy.

e15637 Background: Colorectal cancer (CRC) is the third most common cancer worldwide. Over the past decades, significant progress has been made in the clinical treatment of CRC. Targeted therapy is an optional approach that has successfully prolonged overall survival for CRC patients. It is necessary to determine the personalized targets for guiding the usage of specific drugs, which requires biopsy to obtain pathological samples for analysis. Both tissue biopsy and liquid biopsy are commonly used in clinical diagnosis, while each has its own advantages and limitations. The mutation detection rate of tissue biopsy is usually higher, and more genes can be detected, but most tissue biopsies require surgery to obtain samples and may be biased due to the intra-tumor heterogeneity. Liquid biopsy is less harmful to patients, but the detection sensitivity is much lower than tissue biopsy. Methods: In this study, 353 paraffin tissue section samples were used as tissue biopsy samples and 112 blood samples were used as liquid biopsy samples. All samples are from Chinese patients and are collected from December 2021 to August 2022. Whole-genome sequencing was performed, and several processes have been conducted to eliminate noise, duplicates and reads with low depth, therefore the gene mutations detected in the samples were considerably reliable. We selected APC, TP53, KRAS, PIK3CA and BRAF as the key pathogenic genes for CRC, analyzed the mutation detection results in tissue and blood samples. The detection difference between two types of biopsies was assessed using Pearson's Chi-squared test. Results: Among all samples, 21 (5.95%) tissue biopsy samples and 37 (33.04%) liquid biopsy samples did not contain any key pathogenic genes. For all biopsy samples, the detection rates for APC in tissue biopsy samples (n = 236, 66.86%) and liquid biopsy samples (n = 49, 43.75%) demonstrate significant difference (p = 2.02e-05). The differential detection rates were also observed in TP53 (n = 223 vs. n = 51, 63.17% vs. 45.54%, p = 0.0014) and KRAS (n = 183 vs. n = 39, 51.84% vs. 34.82%, p = 0.0024). There is no significant difference in detection rates of PIK3CA (n = 77 vs. n = 15, 21.81% vs. 13.39%, p = 0.0699) and BRAF. Only 25 (7.08%) tissue biopsy samples and 8 (7.14%) liquid biopsy samples were found to detect BRAF (p = 1). Conclusions: Generally, there is no doubt that the overall detection sensitivity of tissue biopsy is higher than that of liquid biopsy for CRC, and our analysis provided the statistical support. But for some relatively rare disease-causing genes, there is not much difference between the two biopsy methods. For patients, tissue biopsies can be more painful than liquid biopsies, so how to improve the detection of liquid biopsy in CRC is still a subject that requires efforts.

Computed tomography-based radiomics nomogram for the pre-operative prediction of BRAF mutation and clinical outcomes in patients with colorectal cancer: a double-center study.

To develop and validate a radiomics nomogram based on CT for the pre-operative prediction of BRAF mutation and clinical outcomes in patients with colorectal cancer (CRC). A total of 451 CRC patients (training cohort = 190; internal validation cohort = 125; external validation cohort = 136) from 2 centers were retrospectively included. Least absolute shrinkage and selection operator regression was used to select radiomics features and the radiomics score (Radscore) was calculated. Nomogram was constructed by combining Radscore and significant clinical predictors. Receiver operating characteristic curve analysis, calibration curve and decision curve analysis were used to evaluate the predictive performance of the nomogram. Kaplan‒Meier survival curves based on the radiomics nomogram were used to assess overall survival (OS) of the entire cohort. The Radscore consisted of nine radiomics features which were the most relevant to BRAF mutation. The radiomics nomogram integrating Radscore and clinical independent predictors (age, tumor location and cN stage) showed good calibration and discrimination with AUCs of 0.86 (95% CI: 0.80-0.91), 0.82 (95% CI: 0.74-0.90) and 0.82 (95% CI: 0.75-0.90) in the training cohort, internal validation and external validation cohorts, respectively. Furthermore,the performance of nomogram was significantly better than that of the clinical model (p < 0.05). The radiomics nomogram-predicted BRAF mutation high-risk group had a worse OS than the low-risk group (p < 0.0001). The radiomics nomogram showed good performance in predicting BRAF mutation and OS of CRC patients, which could provide valuable information for individualized treatment. The radiomics nomogram could effectively predict BRAF mutation and OS in patients with CRC. High-risk BRAF mutation group identified by the radiomics nomogram was independently associated with poor OS.

Prognostic significance of increased preoperative red cell distribution width (RDW) and changes in RDW for colorectal cancer.

Increased preoperative red cell distribution width (RDW) is associated with poor prognosis in several cancers, but the relationships between preoperative RDW and changes in RDW (ΔRDW) and colorectal cancer (CRC) prognosis remain unclear. Our study aimed to demonstrate the prognostic significance of increased preoperative RDW and ΔRDW for CRC. In this retrospective analysis, we enrolled 833 patients who underwent CRC surgery between 2015 and 2019 at the Affiliated Hospital of Xuzhou Medical University, China. ΔRDW in our study was defined as RDW at 1 month after discharge minus preoperative RDW. According to receiver operating characteristic (ROC) curve analysis, we used cut-off values of 13.5% for RDW, 0.9% for ΔRDW. The cumulative survival rate was determined using the Kaplan-Meier method, and significant differences were evaluated by the log-rank test. Multivariable Cox regression model was applied to clarify the independent risk factors for overall survival (OS), which were used to construct a nomogram prediction model. The competing risk method was also applied, and we analyzed only patients with early-stage disease (stage 0-II) for sensitivity analysis. Multivariable Cox regression analysis demonstrated that age, RDW, ΔRDW, postoperative adjuvant chemotherapy, CEA, CA19-9, ASA, TNM stage, and pathological type were independent factors for OS in CRC patients (all p < 0.05). These prognostic factors were used to establish and verify the OS nomogram. Poorer OS was linked to higher RDW (HR = 1.52; 95% CI, 1.11-2.08; p < 0.01) and ΔRDW (HR = 1.65; 95% CI, 1.19-2.28; p < 0.01) in all-stage patients, and was only linked to higher RDW in early-stage patients. In competing risk model, H-RDW and H-ΔRDW were confirmed to be independent risk factors for CSS in CRC patients. High preoperative RDW and ΔRDW are both risk factors for OS and CSS in CRC.

RNA demethylase ALKBH5 promotes colorectal cancer progression by posttranscriptional activation of RAB5A in an m6A‐YTHDF2‐dependent manner

N6-methyladenosine (m6A) modification is an emerging epigenetic regulatory mechanism in tumourigenesis. Considering that AlkB homolog 5 (ALKBH5) is a well-described m6A demethylase in previous enzyme assays, we aimed to investigate the role of m6A methylation alteration conferred by disturbed ALKBH5 in colorectal cancer (CRC) development. Expression of ALKBH5 and its correlation with clinicopathological characteristics of CRC were evaluated using the prospectively maintained institutional database. The molecular role and underlying mechanism of ALKBH5 in CRC were explored using in vitro and in vivo experiments with methylated RNA immunoprecipitation sequencing (MeRIP-seq), RNA-seq, MeRIP-qPCR, RIP-qPCR and luciferase reporter assays. ALKBH5 expression was significantly upregulated in CRC tissues compared to the paired adjacent normal tissues, and higher expression of ALKBH5 was independently associated with worse overall survival in CRC patients. Functionally, ALKBH5 promoted the proliferative, migrative and invasive abilities of CRC cells in vitro and enhanced subcutaneous tumour growth in vivo. Mechanistically, RAB5A was identified as the downstream target of ALKBH5 in CRC development, and ALKBH5 posttranscriptionally activated RAB5A by m6A demethylation, which impeded the YTHDF2-mediated degradation of RAB5A mRNA. In addition, we demonstrated that dysregulation of the ALKBH5-RAB5A axis could affect the tumourigenicity of CRC. ALKBH5 facilitates the progression of CRC by augmenting the expression of RAB5A via an m6A-YTHDF2-dependent manner. Our findings suggested that ALKBH5-RAB5A axis might serve as valuable biomarkers and effective therapeutic targets for CRC.

Development and validation of a scoring system incorporating tumor growth pattern and perineural invasion for risk stratification in colorectal cancer.

Tumor growth pattern (TGP) and perineural invasion (PNI) at the invasive margin have been recognized as indicators of tumor invasiveness and prognostic events in colorectal cancer (CRC). This study aims to develop a scoring system incorporating TGP and PNI, and further investigate its prognostic significance for CRC risk stratification. A scoring system, termed tumor-invasion score, was established by summing TGP and PNI scores. The discovery cohort (N = 444) and the validation cohort (N = 339) were used to explore the prognostic significance of the tumor-invasion score. The endpoints of the event were disease-free survival (DFS) and overall survival (OS) which were analyzed by the Cox proportional hazard model. In the discovery cohort, Cox regression analysis showed that DFS and OS were inferior for score 4 group compared with score 1 group (DFS, hazard ratio (HR) 4.44, 95% confidence interval (CI) 2.49-7.92, p < 0.001; OS, 4.41, 2.37-8.19,p < 0.001). The validation cohort showed similar results (DFS, 4.73, 2.39-9.37, p < 0.001; OS, 5.52, 2.55-12.0, p < 0.001). The model combining tumor-invasion score and clinicopathologic information showed good discrimination performance than single predictors. TGP and PNI were associated with tumor invasiveness and survival in CRC. The tumor-invasion score generated by TGP and PNI scores served as an independent prognostic parameter of DFS and OS for CRC patients.

Treatment with decitabine induces the expression of stemness markers, PD-L1 and NY-ESO-1 in colorectal cancer: potential for combined chemoimmunotherapy

BackgroundThe mechanism of tumor immune escape and progression in colorectal cancer (CRC) is widely investigated in-vitro to help understand and identify agents that might play a crucial role in response to treatment and improve the overall survival of CRC patients. Several mechanisms of immune escape and tumor progression, including expression of stemness markers, inactivation of immunoregulatory genes by methylation, and epigenetic silencing, have been reported in CRC, indicating the potential of demethylating agents as anti-cancer drugs. Of these, a chemotherapeutic demethylating agent, Decitabine (DAC), has been reported to induce a dual effect on both DNA demethylation and histone changes leading to an increased expression of target biomarkers, thus making it an attractive anti-tumorigenic drug.MethodsWe compared the effect of DAC in primary 1076 Col and metastatic 1872 Col cell lines isolated and generated from patients’ tumor tissues. Both cell lines were treated with DAC, and the expression of the NY-ESO-1 cancer-testis antigen, the PD-L1 immunoinhibitory marker, and the CD44, Nanog, KLF-4, CD133, MSI-1 stemness markers were analyzed using different molecular and immunological assays.ResultsDAC treatment significantly upregulated stemness markers in both primary 1076 Col and meta-static 1872 Col cell lines, although a lower effect occurred on the latter: CD44 (7.85 fold; ***p = 0.0001 vs. (4.19 fold; *p = 0.0120), Nanog (4.1 fold; ***p < 0.0001 vs.1.69 fold; ***p = 0.0008), KLF-4 (4.33 fold; ***p < 0.0001 vs.2.48 fold; ***p = 0.0005), CD133 (16.77 fold; ***p = 0.0003 vs.6.36 fold; *p = 0.0166), and MSI-1 (2.33 fold; ***p = 0.0003 vs.2.3 fold; ***p = 0.0004), respectively. Interestingly, in the metastatic 1872 Col cells treated with DAC, the expression of both PD-L1 and NY-ESO-1 was increased tenfold (*p = 0.0128) and fivefold (***p < 0.0001), respectively.ConclusionsWe conclude that the upregulation of both stemness and immune checkpoint markers by DAC treatment on CRC cells might represent a mechanism of immune evasion. In addition, induction of NY-ESO-1 may represent an immuno-therapeutic option in metastatic CRC patients. Finally, the combination of DAC and anti-PD-1/anti-PD-L1 antibodies treatment should represent a potential therapeutic intervention for this group of patients.

Decreased expression of prolyl hydroxylase 1 is associated with poor prognosis in colorectal cancers

BackgroundProlyl hydroxylase 1 (PHD1) is a prognostic marker in several cancers.Aims and scopesThis study was undertaken to elucidate the clinical relevance of PHD1 in colorectal cancer (CRC) prognosis.Materials and methodsWe compared PHD1 expression on a tissue microarray (TMA) containing samples from 1800 CRCs with corresponding clinicopathological tumor variables and patient survival.ResultsWhile PHD1 staining was always high in benign colorectal epithelium, high PHD1 staining was detectable in only 71.8% of CRCs. Low PHD1 staining was associated with advanced tumor stage (p = 0.0101) and shortened overall survival in CRC patients (p = 0.0011). In a multivariable analysis including tumor stage, histological type and PHD1 staining revealed tumor stage and histological type (p < 0.0001 each), but also PHD1 staining (p = 0.0202) to be independent prognostic markers for CRC.ConclusionsIn our cohort, loss of PHD1 expression independently identified a subset of CRC patients with poor overall survival and might, thus, be a promising prognostic marker. PHD1 targeting may even allow for specific therapeutic approaches for these patients.

CAF signature predicts the prognosis of colorectal cancer patients: A retrospective study based on bulk RNA sequencing and single-cell RNA sequencing data.

The incidence rate and mortality rate of colorectal cancer (CRC) ranks third and second globally. Cancer-associated fibroblasts (CAFs) are the major constituent of the stromal cells in the tumor microenvironment (TME) and are closely associated with patients' prognoses. Our study intended to establish a prognostic model for CRC using hallmark genes of CAFs. The expression values of genes and clinicopathological characteristics of patients were enrolled from the cancer genome atlas database as well as the gene expression omnibus database. The single-cell RNA sequencing data were collected and analyzed in the deeply integrated human single-cell omics database and cancer single-cell expression map databases. The ESTIMATE algorithm was applied to access the infiltration levels of immune and stromal cells. The prognostic genes were selected by the Cox regression analysis and the prognostic signature was constructed by the least absolute shrinkage and selection operator algorithm. gene set enrichment analysis was used to explore the enriched gene sets. In this study, based on bulk RNA sequencing and single-cell RNA sequencing data, and we found that more CAFs were infiltrated in the tumor microenvironment and consisted of 3 subtypes. Then we constructed a prognostic signature for CRC using hallmark genes of CAFs and proved that this signature exhibited high values to predict the overall survival of CRC patients in independent training and validating cohorts. Besides, function enrichment analysis revealed that our prognostic model was significantly associated with immune regulation. Further analysis showed that the infiltrated levels of tumor-suppressing immune cells and the expression of higher immune checkpoint genes in CRC tissues were higher in patients with high-risk scores. Furthermore, immunohistochemistry analysis exhibited that these genes in our prognostic signature were markedly upregulated in CRC tissues. We first constructed a signature based on CAFs hallmark genes to predict the survival of CRC patients and further revealed that the tumor-suppressing microenvironment and dysregulated immune checkpoint genes in CRC tissues were partly responsible for the poor prognosis of patients.

Prognostic significance of sarcopenia diagnosed based on the anthropometric equation for progression-free survival and overall survival in patients with colorectal cancer.

The purpose of this study was to investigate the prognostic significance of sarcopenia diagnosed based on anthropometric equations for progression-free survival (PFS) and overall survival (OS) in patients with colorectal cancer (CRC). A total of 1,441 CRC patients who underwent surgical treatment between January 2012 and December 2016 were enrolled in this study. Sarcopenia was diagnosed according to validated anthropometric equations. The Kaplan-Meier method with the log-rank test was used to estimate the survival curve. Cox proportional hazards regression models with forward selection were used to evaluate risk factors affecting the prognosis of CRC patients. R package "survival" was used to build the prognostic nomograms to predict 1-5 years of PFS and OS in CRC patients. The concordance index (C-index) and calibration curve were used to evaluate the prognostic accuracy of the prognostic nomogram. Two hundred and seventy-one patients (18.8%) were diagnosed with sarcopenia. Sarcopenia was significantly associated with advanced age, large tumor size, and high mortality. Compared with the non-sarcopenia patients, the PFS of sarcopenia patients was worse (5-year PFS, 48.34 vs. 58.80%, p = 0.003). Multivariate survival analysis showed that patients with sarcopenia had a higher risk (23.9%) of adverse PFS (HR, 1.239; 95%CI: 1.019-1.505, p = 0.031) than patients without sarcopenia. The OS of patients with sarcopenia was significantly worse than that of patients without sarcopenia (5-year OS: 50.92 vs. 61.62%, p = 0.001). In CRC patients, sarcopenia was independently associated with poor OS (HR: 1.273, 95%CI: 1.042-1.556, p < 0.001). Moreover, sarcopenia effectively differentiated the OS of CRC patients in the normal carcinoembryonic antigen (CEA) subgroup but not in the high CEA subgroup. Notably, sarcopenia can provide effective prognostic stratification in CRC patients at different pathological stages. Nomograms that integrated prognostic features were built to predict the risk of adverse outcomes in CRC patients. The C-index and calibration curves showed that these nomograms had good prediction accuracy. Internal validation confirmed that our nomogram has wide application potential. Sarcopenia diagnosed based on anthropometric equations is an independent risk factor for PFS and OS in CRC patients.

Anti-silencing function 1B knockdown suppresses the malignant phenotype of colorectal cancer by inactivating the phosphatidylinositol 3-kinase/AKT pathway.

Mounting studies have highlighted the pivotal influence of anti-silencing function 1B (ASF1B) on the malignancy of cancers. To explore the influence and mechanism of ASF1B in colorectal cancer (CRC). Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect mRNA expression of ASF1B. Immunohistochemical staining was performed to detect protein expression of ASF1B and Ki67 in tumor tissues. Western blot analysis was used to determine levels of ASF1B and proliferation/epithelial mesenchymal transition (EMT)/stemness-related proteins. In addition, the proliferation of CRC cells was assessed using Cell Counting Kit-8 and 5-Ethynyl-2'-Deoxyuridine assays. The migration and invasion of CRC cells were evaluated using transwell assays. Stemness of CRC cells was tested using the sphere formation assay. To construct a xenograft tumor model, HCT116 cells were introduced into mouse flanks via subcutaneous injection. ASF1B expression was markedly increased in CRC tissues and cells, and it was inversely correlated with overall survival of CRC patients and was positively associated with the tumor node metastasis (TNM) stage of CRC patients. Silencing of ASF1B suppressed proliferation, migration, invasion, stemness and EMT of CRC cells as well as tumorigenesis of xenograft mice. Furthermore, protein levels of P-phosphatidylinositol 3-kinase (p-PI3K) and p-AKT were decreased after silencing of ASF1B in CRC cells. The inhibitory effects of ASF1B knockdown on cell proliferation, stemness and EMT were partly abolished by PI3K activator in CRC cells. Silencing of ASF1B inactivated the PI3K/AKT pathway to suppress CRC malignancy in vitro.

Mid-Arm Muscle Circumference or Body Weight-Standardized Hand Grip Strength in the GLIM Superiorly Predicts Survival in Chinese Colorectal Cancer Patients.

Our objective was to identify the optimal method to assess reduced muscle mass (RMM) using the Global Leadership Initiative on Malnutrition (GLIM) approach and investigate the roles of the GLIM approach in nutrition assessment and survival prediction in colorectal cancer (CRC) patients. During a median follow-up period of 4.2 (4.0, 4.4) years, a development cohort of 3612 CRC patients with a mean age of 64.09 ± 12.45 years was observed, as well as an external validation cohort of 875 CRC patients. Kaplan−Meier curves and multivariate Cox regression were adopted to analyze the association between GLIM-diagnosed malnutrition and the overall survival (OS) of CRC patients. A nomogram predicting individualized survival was constructed based on independent prognostic predictors. The concordance index, calibration curve, and decision curve were applied to appraise the discrimination, accuracy, and clinical efficacy of the nomogram, respectively. Patients diagnosed with severe malnutrition based on either the mid-arm muscle circumference (MAMC) or body weight-standardized hand grip strength (HGS/W) method had the highest mortality hazard ratio (HR, 1.51; 95% CI, 1.34−1.70; p < 0.001). GLIM-defined malnutrition was diagnosed in 47.6% of patients. Severe malnutrition was an independent mortality risk factor for OS (HR, 1.25; 95% CI, 1.10−1.42; p < 0.001). The GLIM nomogram showed good performance in predicting the survival of CRC patients and was clinically beneficial. Our findings support the effectiveness of GLIM in diagnosing malnutrition and predicting OS in CRC patients.

Galanin Receptors (GALR1, GALR2, and GALR3) Immunoexpression in Enteric Plexuses of Colorectal Cancer Patients: Correlation with the Clinico-Pathological Parameters.

Galanin (GAL) is an important neurotransmitter released by the enteric nervous system (ENS) neurons located in the muscularis externa and submucosa enteric plexuses that acts by binding to GAL receptors 1, 2 and 3 (GALR1, 2 and 3). In our previous studies, the GAL immunoexpression was compared in colorectal cancer (CRC) tissue and the adjacent parts of the large intestine wall including myenteric and submucosal plexuses. Recently we have also found that expression levels of GALR1 and GALR3 proteins are elevated in CRC tissue as compared with their expression in epithelial cells of unchanged mucosa. Moreover, higher GALR3 immunoreactivity in CRC cells correlated with better prognosis of CRC patients. To understand the distribution of GALRs in enteric plexuses distal and close to CRC invasion, in the present study we decided to evaluate GALRs expression within the myenteric and submucosal plexuses located proximally and distally to the cancer invasion and correlated the GALRs expression levels with the clinico-pathological data of CRC patients. The immunohistochemical and immunofluorescent methods showed only slightly decreased immunoexpression of GALR1 and GALR3 in myenteric plexuses close to cancer but did not reveal any correlation in the immunoexpression of all three GAL receptors in myenteric plexuses and tumour progression. No significant changes were found between the expression levels of GALRs in submucosal plexuses distal and close to the tumour. However, elevated GALR1 expression in submucosal plexuses in vicinity of CRC correlated with poor prognosis, higher tumour grading and shorter overall survival. When myenteric plexuses undergo morphological and functional alterations characteristic for atrophy, GALRs maintain or only slightly decrease their expression status. In contrast, the correlation between high expression of GALR1 in the submucosal plexuses and overall survival of CRC patients suggest that GAL and GALRs can act as a components of local neuro-paracrine pro-proliferative pathways accelerating the invasion and metastasis of cancer cell. The obtained results suggest an important role of GALR1 in submucosal plexuses function during the progression of CRC and imply that GALR1 expression in submucosal plexuses of ENS could be an important predictive factor for CRC progression.

Progress in the relationship between P2X7R and colorectal cancer.

Purinergic ligand-gated ion channel 7 receptor (P2X7R) is a nonselective cation channel of the purinergic receptor family. P2X7R is activated by adenosine triphosphate (ATP) and plays a significant role in inflammatory and autoimmune diseases by triggering cellular signal transduction. More importantly, P2X7R is abnormally expressed in many tumor cells and is involved in the progression of various tumor cells. Studies have shown that the irregular expression of P2X7R in colorectal cancer (CRC) can not only indirectly affect the occurrence and development of CRC by promoting inflammatory bowel disease but also directly affect the proliferation and metastasis of CRC cells. P2X7R plays a bidirectional role in cancer induction and inhibition by mediating complex signaling pathways in CRC, and its expression level is closely related to the overall survival of CRC patients. Therefore, P2X7R may be a biomarker and potential therapeutic target for the development and prognosis of CRC. In this paper, we review the research progress on P2X7R in CRC.