Clinical Outcome In Colorectal Cancer Patients Research Articles

Pyrimethamine inhibits cell growth by inducing cell senescence and boosting CD8+ T-cell mediated cytotoxicity in colorectal cancer

BackgroundThe emergence of nonresponse or resistance to traditional chemotherapeutic agents is one of the main challenges of colorectal cancer (CRC) therapies. Thus, novel therapeutic drugs that can improve the clinical outcomes of CRC patients are urgently needed. The purpose of this study was to investigate the effects and mechanisms of pyrimethamine in CRC.Methods and resultsIn this study, we assessed the role of pyrimethamine on CRC cell growth by cell counting kit-8 and colony formation assays. Cell cycle distribution and cellular senescence were determined by flow cytometry and senescence-associated β-galactosidase staining respectively. RNA-seq analysis and western blotting were used to investigate the potential pathways of pyrimethamine in CRC development. Moreover, animal experiments were performed to evaluate the effect of pyrimethamine in vivo. Our results demonstrated that pyrimethamine could inhibit cell growth by inducing S phase arrest followed by cellular senescence in CRC cells, and the p38MAPK-p53 axis was probably involved in that effect. In addition, pyrimethamine could also boost CD8+ T-cell mediated cytotoxicity and exert antitumor activity in vivo.ConclusionThese results indicated that pyrimethamine may be a promising candidate agent for CRC treatment.

FOXQ1-mediated SIRT1 upregulation enhances stemness and radio-resistance of colorectal cancer cells and restores intestinal microbiota function by promoting \u03b2-catenin nuclear translocation

BackgroundResistance of colorectal cancer (CRC) cells to radiotherapy considerably contributes to poor clinical outcomes of CRC patients. Microarray profiling in this study revealed the differentially expressed forkhead box Q1 (FOXQ1) in CRC, and thus we aimed to illustrate the role of FOXQ1 in CRC by modulating stemness and radio-resistance of CRC cells.MethodsCRC and adjacent normal tissues were collected from CRC patients, and the correlation between FOXQ1 expression and CRC prognosis was analyzed. Subsequently, we determined the expression of FOXQ1, sirtuin 1 (SIRT1) and β-catenin in CRC tissues and cell lines. The binding affinity between FOXQ1 and SIRT1 and that between SIRT1 and β-catenin were validated with luciferase reporter gene, Co-IP and ChIP assays. Following a metagenomics analysis of CRC intestinal microbiota, the effects of the FOXQ1/SIRT1/β-catenin axis on CRC stem cell phenotypes and radio-resistance was evaluated in vitro and in vivo through manipulation of gene expression. Besides, mouse feces were collected to examine changes in intestinal microbiota.ResultsFOXQ1 was highly expressed in CRC tissues and cells and positively correlated with poor prognosis of CRC patients. FOXQ1 overexpression contributed to resistance of CRC cells to radiation. Knockdown of FOXQ1 inhibited the stemness of CRC cells and reversed their radio-resistance. FOXQ1 enhanced the transcriptional expression of SIRT1, and SIRT1 enhanced the expression and nuclear translocation of β-catenin. Knockdown of FOXQ1 repressed SIRT1 expression, thus reducing the stemness and radio-resistance of CRC cells. Moreover, FOXQ1 knockdown suppressed CRC xenograft formation in xenograft-bearing nude mice through inhibiting SIRT1 and β-catenin to reduce the content of pathological bacteria that were up-regulated in CRC.ConclusionFOXQ1-mediated SIRT1 upregulation augments expression and nuclear translocation of β-catenin and benefits CRC-related intestinal pathological bacterial, thereby enhancing the stemness and radio-resistance of CRC cells.

Clinical significance of Bacteroides fragilis as potential prognostic factor in colorectal cancer patients.

137 Background: Bacteroides fragilis ( B. fragilis) is an obligate anaerobe and generally acts as anti-inflammatory manner on the intestinal tract. Enterotoxigenic Bacteroides fragilis (ETBF), a subtype of B. fragilis, produces Bacteroides fragilis toxin (BFT) leading to either asymptomatic chronic colonic inflammation or colonic tumor formation. However, the impact of B. fragilis and ETBF on colorectal cancer (CRC) prognoses still remains unclear. We tested whether the presence of B. fragilis and ETBF affect clinical outcome in CRC patients who underwent curative surgery. Methods: We obtained 197 pairs of matched FFPE samples from colorectal cancerous and adjusted non-cancerous tissues of patients with stage II and III CRC who underwent curative resection between 2014 and 2016. Quantitative analyses of B. fragilis and ETBF in the colon tissues were performed using quantitative PCR with primers, 16S rRNA for B. fragilis and bft DNA, respectively. Recurrence-free survival (RFS) and overall survival (OS) were analyzed using Kaplan-Meier curves, log-rank test, and Cox proportional hazards regression. Results: Among 197 patients, 16S rRNA for B. fragilis DNA and bft DNA were detected in 120 patients (60.9%) and 12 patients (6.1%), respectively. B. fragilis-positive patients had better RFS (5-y RFS rate: 81.4% vs. 73.4%, HR0.59, 95% CI: 0.31-1.12, p =0.10) and OS (5-y OS rate: 88.9% vs 78.3%, HR0.53, 95% CI: 0.26-1.11, p =0.091) compared with B. fragilis-negative patients though statistically not significant. In multivariable analysis for RFS, B. fragilis-positive remained as an independent prognostic factor (HR0.53, 95% CI: 0.28-0.99, p =0.049) along with tumor depth T4 and Stage III, while there was no significance in OS. No significant differences were observed between ETBF and nontoxigenic B. fragilis in patients' characteristics and clinical outcomes. Conclusions: Our findings suggest that the presence of B. fragilis may predict outcome especially RFS in patients with curatively resected stage II and III CRC. Further research are warranted to explore whether B. fragilis status could be involved in a novel prediction model for outcome in early-stage CRC and develop probiotics treatments to prevent recurrence.

Ano1 is a Prognostic Biomarker That is Correlated with Immune Infiltration in Colorectal Cancer.

BackgroundAnoctamin 1 (ANO1) has been observed to be overexpressed in gastrointestinal and pulmonary epithelial cells, as well as in a number of cancers. Although Ano1 is involved in the prognosis of colorectal cancer (CRC), its mechanism of action in metastatic CRC has not been fully elucidated.MethodsThe expression of Ano1 was assessed in samples obtained from The Cancer Genome Atlas (TCGA) database. Then, we used Gene Ontology (GO) enrichment, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, Gene set enrichment analysis (GSEA), Gene set variation analysis (GSVA), and Weighted Correlation Network Analysis (WGCNA) to determine the functions of Ano1. Additionally, random survival forest, Cox multivariate analysis, Kaplan Meier analysis, and ROC were used to determine the predictive value of Ano1 on clinical outcomes in CRC patients. Finally, HE staining, immunohistochemical (IHC) analysis and qRT-PCR were used to explore the expression of the Ano1 gene in CRC tissue.ResultsThe expression level of Ano1 in CRC was significantly elevated, and the prognosis was poor. The modules with a higher proportion of upregulated genes tended to be positively correlated with Ano1-high. KNG1, GNG4, F2, POSTN, THBS2, SPP1 and FGA were identified as hub proteins of the PPI network. The heatmap showed that the expression level of the Ano1-high group was significantly negatively correlated with immune infiltrate. The overexpression of the Ano1 gene in CRC tissue samples was also confirmed by HE staining, immunohistochemical (IHC) analysis and qRT-PCR.ConclusionHigh expression of Ano1 is closely related to a poor prognosis in patients with colorectal cancer. Ano1 may participate in the metastasis and progression, as well as the immune regulation of CRC. In summary, Ano1 can act as a potential prognostic biomarker and a novel target for CRC therapy.

PBK Enhances Cellular Proliferation With Histone H3 Phosphorylation and Suppresses Migration and Invasion With CDH1 Stabilization in Colorectal Cancer.

Colorectal cancer (CRC) is one of the most frequent gastrointestinal malignancies with high morbidity and mortality rates. Several biological markers for the prognostication of patient outcome of CRCs are available. Recently, our group identified two favorable factors for the survival of CRC patients: PDZ-binding kinase (PBK) and phospho-histone H3 (PHH3). Both showed a significant inverse association to pT stage. The aim of this study was to uncover the mechanism through which these cellular proliferation–associated protein expressions lead to favorable clinical outcome in CRC patients. We first confirmed co-expression of PBK and PHH3 in CRC cells. Further investigation showed that aberrantly expressed PBK up-regulated the cellular proliferation of CRC cells with accumulation of PHH3. The PBK inhibitor OTS514 suppressed cellular proliferation of CRC cells through down-regulation of PHH3 and induction of apoptosis. In vitro studies revealed that PBK suppressed the migration and invasion of CRC cells with suppression of Wnt/β-catenin signaling and CDH1 stabilization. Exogeneous PBK up-regulated the phosphorylated CDH1 at S840, S846, and S847 residues in cultured cells. Recombinant PBK directly phosphorylated HH3; however, it failed to phosphorylate CDH1 directly in vitro. The present study demonstrated the association of two markers PBK and PHH3 in CRC. We further identified one of the potential mechanisms by which higher expression of these cellular proliferation–associated proteins leads to the better survival of CRC patients, which likely involves PBK-mediated suppression of the migration and invasion of CRC cells. Our findings suggest that PBK-targeting therapeutics may be useful for the treatment of CRC patients with PBK-expressing tumors.

CARMA3 Promotes Colorectal Cancer Cell Motility and Cancer Stemness via YAP-Mediated NF-κB Activation.

Simple SummaryCARMA3 is overexpressed in most cancers, and its expression is positively associated with poor prognosis. In this study, we evaluated the detailed mechanisms of CARMA3-mediated CRC metastasis. We found that overexpression of CARMA3 induced the expression of YAP and NF-κB activation, then elicited EMT induction to enhance cell migration and invasion. We demonstrate for the first time that YAP is a critical downstream regulator of CARMA3 in CRC. Our findings reveal a regulation axis between CARMA3 and Hippo oncoprotein YAP and further support the potential role of CARMA3 in the metastasis and cancer stemness of CRC.CARD-recruited membrane-associated protein 3 (CARMA3) is overexpressed in various cancers and is associated with cancer cell proliferation, metastasis, and tumor progression; however, the underlying mechanisms of CARMA3 in colorectal cancer (CRC) metastasis remain unclear. Here, we found that higher CARMA3 expression was correlated with poor overall survival and metastasis in CRC patients from the TNMplot database and Human Tissue Microarray staining. Elevating CARMA3 expression promoted cell proliferation, epithelial-mesenchymal transition (EMT) induction, migration/invasion abilities, sphere formation, and cancer stem cell markers expression. Knockdown of CARMA3 decreased these processes via the EMT-related transcription factor Slug. Moreover, CARMA3 depletion significantly reduced tumor growth in mice that were consistent with the in vitro results. CRC migration/invasion could be regulated by CARMA3/YAP/Slug signaling axis using genetic inhibition of Yes-associated protein (YAP). Interestingly, CARMA3 induced activation of nuclear factor (NF)-κB through YAP expression, contributing to upregulation of Slug. YAP expression positively correlated with CARMA3, NF-κB, and Slug gene expression and poor clinical outcomes in CRC patients. Our findings demonstrate for the first time that CARMA3 plays an important role in CRC progression, which may serve as a potential diagnostic biomarker and candidate therapeutic target for CRC treatment.

A lipid metabolism-related genes prognosis biomarker associated with the tumor immune microenvironment in colorectal carcinoma

Background and aimLipid metabolic reprogramming is considered to be a new hallmark of malignant tumors. The purpose of this study was to explore the expression profiles of lipid metabolism-related genes (LMRG) in colorectal cancer (CRC).MethodsThe lipid metabolism statuses of 500 CRC patients from the Cancer Genome Atlas (TCGA) and 523 from the Gene Expression Omnibus (GEO GSE39582) database were analyzed. The risk signature was constructed by univariate Cox regression and least absolute shrinkage and selection operator (LASSO) Cox regression.ResultsA novel four-LMRG signature (PROCA1, CCKBR, CPT2, and FDFT1) was constructed to predict clinical outcomes in CRC patients. The risk signature was shown to be an independent prognostic factor for CRC and was associated with tumour malignancy. Principal components analysis demonstrated that the risk signature could distinguish between low- and high-risk patients. There were significantly differences in abundances of tumor-infiltrating immune cells and mutational landscape between the two risk groups. Patients in the low-risk group were more likely to have higher tumor mutational burden, stem cell characteristics, and higher PD-L1 expression levels. Furthermore, a genomic-clinicopathologic nomogram was established and shown to be a more effective risk stratification tool than any clinical parameter alone.ConclusionsThis study demonstrated the prognostic value of LMRG and showed that they may be partially involved in the suppressive immune microenvironment formation.

The Chemokine CXCL7 Is Related to Angiogenesis and Associated With Poor Prognosis in Colorectal Cancer Patients.

ObjectiveThe present study was designed to investigate the role of the chemokine CXCL7 in angiogenesis and explore its prognostic value in colorectal cancer (CRC).MethodsA total of 160 CRC patients who had undergone surgery were included in this study, and staged according to the guidelines of the AJCC, 7th Edition. Expression of CXCL7 and VEGF was detected by immunohistochemical (IHC) staining and divided into high and low expression subgroups. The correlation between CXCL7 and VEGF expression was evaluated by Spearman’s rank-correlation coefficient. Prognosis based on CXCL7 and VEGF was evaluated using the Cox proportional hazards regression model and a nomogram of 5-year overall survival (OS) time.ResultsCXCL7 was highly expressed in tumor tissues (65.63% vs 25.00% in paracancerous tissue, P < 0.001), as was VEGF. CXCL7 and VEGF expression correlated well with N and TNM stage cancers (all P < 0.001). Importantly, CXCL7 was positively correlated with VEGF expression in CRC tissues. CXCL7 was an independent predictor of poor OS of CRC patients (HR = 2.216, 95% CI: 1.069-4.593, P = 0.032), and co-expression of CXCL7 and VEGF of predicted poor OS of 56.96 months.ConclusionExpression of CXCL7 correlated with VEGF and was associated with poor clinical outcomes in CRC patients.

Prognostic Impact and Functional Annotations of KIF11 and KIF14 Expression in Patients with Colorectal Cancer

Genomic instability (GIN) has an important contribution to the pathology of colorectal cancer (CRC). Therefore, we selected mitosis and cytokinesis kinesins, KIF11 and KIF14, as factors of potential clinical and functional value in CRC, as their aberrant expression has been suspected to underlie GIN. We examined the expression and the prognostic and biological significance of KIF11 and KIF14 in CRC via in-house immunohistochemistry on tissue microarrays, public mRNA expression datasets, as well as bioinformatics tools. We found that KIF11 and KIF14 expression, at both the protein and mRNA level, was markedly altered in cancer tissues compared to respective controls, which was reflected in the clinical outcome of CRC patients. Specifically, we provide the first evidence that KIF11 protein and mRNA, KIF14 mRNA, as well as both proteins together, can significantly discriminate between CRC patients with better and worse overall survival independently of other relevant clinical risk factors. The negative prognostic factors for OS were high KIF11 protein, high KIF11 protein + low KIF14 protein, low KIF11 mRNA and low KIF14 mRNA. Functional enrichment analysis revealed that the gene sets related to the cell cycle, DNA replication, DNA repair and recombination, among others, were positively associated with KIF11 or KIF14 expression in CRC tissues. In TCGA cohort, the positive correlations between several measures related to GIN and the expression of KIFs were also demonstrated. In conclusion, our results suggest that CRC patients can be stratified into distinct risk categories by biological and molecular determinants, such as KIF11 and KIF14 expression and, mechanistically, this is likely attributable to their role in maintaining genome integrity.

Association of gene and protein expression and genetic polymorphism of CC chemokine ligand 4 in colorectal cancer.

BACKGROUNDLeukocytes, such as T cells and macrophages, play an important role in tumorigenesis. CC chemokine ligand (CCL) 4, which is produced by lymphocytes and macrophages, has been found to be expressed in the mucosa of the gastrointestinal tract and is a potent chemoattractant for various leukocytes. AIMTo examine CCL4 expression and its genetic polymorphism rs10491121 in patients with colorectal cancer (CRC) and evaluate their prognostic significance.METHODSLuminex technology was used to determine CCL4 Levels in CRC tissue (n = 98), compared with paired normal tissue, and in plasma from patients with CRC (n = 103), compared with healthy controls (n = 97). Included patients had undergone surgical resection for primary colorectal adenocarcinomas between 1996 and 2019 at the Department of Surgery, Ryhov County Hospital, Jönköping, Sweden. Reverse transcription quantitative PCR was used to investigate the CCL4 gene expression in CRC tissue (n = 101). Paired normal tissue and TaqMan single nucleotide polymorphism assays were used for the CCL4 rs10491121 polymorphism in 610 CRC patients and 409 healthy controls. RESULTSThe CCL4 protein and messenger RNA expression levels were higher in CRC tissue than in normal paired tissue (90%, P < 0.001 and 45%, P < 0.05, respectively). CRC tissue from patients with localized disease had 2.8-fold higher protein expression levels than that from patients with disseminated disease. Low CCL4 protein expression levels in CRC tissue were associated with a 30% lower cancer-specific survival rate in patients (P < 0.01). The level of plasma CCL4 was 11% higher in CRC patients than in healthy controls (P < 0.05) and was positively correlated (r = 0.56, P < 0.01) with the CCL4 protein level in CRC tissue. The analysis of CCL4 gene polymorphism rs10491121 showed a difference (P < 0.05) between localized disease and disseminated disease in the right colon, with a dominance of allele A in localized disease. Moreover, the rate of the A allele was higher among CRC patients with mucinous cancer than among those with non-mucinous cancer.CONCLUSIONThe present study indicates that the CRC tissue levels of CCL4 and CCL4 gene polymorphism rs10491121, particularly in the right colon, are associated with clinical outcome in CRC patients.

Comprehensive analysis of the prognosis and immune infiltration for CXC chemokines in colorectal cancer.

The C-X-C motif (CXC) chemokines are a family of chemotactic molecules that have been identified as potential prognostic markers and prospective therapeutic targets for many kinds of cancer types. Increasing evidence shows that CXC chemokines are associated with the progression of colorectal cancer (CRC); however, the correlations of CXC chemokines with prognostic and immune infiltrates in CRC remain to be clarified. In this study, we analyzed the mRNA expression level, prognostic data and immune infiltrates of CXC chemokines in CRC patients from the Gene Expression Profiling Interactive Analysis, Oncomine, cBioPortal and databases using GeneMANIA, STRING, DAVID 6.8, and TIMER. Our results showed that CXCL1/2/3/4/5/8/9/10/11/13/14/16 were significantly overexpressed in CRC tissues. Furthermore, expression of CXCL1/2/3/9/10/11 was associated with tumor stage in CRC. A significant association was also identified between the co-expression of CXCL16 with EGFR, KRAS and NRAS. In addition, the survival analysis suggested that high CXCL2/3/8/9/10/11/14 expression is correlated with clinical outcomes of CRC patients. Moreover, a significant association was observed between the CXCL8/9/10/11 expression and immune infiltration in colonic and rectal adenocarcinoma. Overall, CXC chemokines are not only implicated as prognostic biomarkers for CRC patients, but may also influence the immune status of CRC tissues.

The TIM-3 Rs10053538 Polymorphism Is Associated with Clinical Prognosis of Colorectal Cancer

ABSTRACT Background: Genetic variants in the T cell immunoglobulin and mucin domain-containing molecule 3 (TIM-3) gene have been reported to be associated with the risk of cancers and patients’ outcomes. The aims of this study were to explore the role of TIM-3 polymorphisms in the risk of colorectal cancer (CRC) and the prognosis of CRC patients in a northern Chinese population. Methods: Two polymorphisms of TIM-3 were genotyped using polymerase chain reaction and ligase detection reaction in 364 CRC patients and 372 healthy control subjects. The levels of TIM-3 mRNA were investigated in 65 CRC tissues by quantitative real-time PCR. Results: The results showed that neither rs10053538 nor rs10515746 was associated with susceptibility to CRC. However, the CA+AA genotypes of rs10053538 were related to an advanced clinical stage and increased risk of lymph nodemetastasis (P = .046 and 0.024, respectively). Multivariate analyses performed after adjusting for clinical variables showed that patients with the CA+AA genotypes of rs10053538 exhibited a significantly shorter disease-free survival (DFS) and overall survival (OS) time compared with those carrying the CC genotype (HR = 1.91, 95% CI = 1.04–3.51; HR = 2.61, 95% CI = 1.35–5.03). In addition, the expression of TIM-3 mRNA was significantly increased in the CRC tissues of patients carrying the rs10053538 CA+AA genotypes compared with patients carrying the CC genotype (P = .019). Conclusion: The rs10053538 may serve as an independent molecular marker for predicting the clinical outcome of CRC patients in the study population.

Oncogenic long intervening noncoding RNA Linc00284 promotes c-Met expression by sponging miR-27a in colorectal cancer

Emerging evidences suggest that long noncoding RNA (lncRNA) plays a vital role in tumorigenesis and cancer progression. Here, the aim of this study is to investigate the biological function of long intervening noncoding RNA Linc00284 in colorectal cancer (CRC). The expression levels of Linc00284, miR-27a and c-Met were evaluated by qPCR and/or Western blotting. Immunohistochemistry was used to detect the expression of Ki67 and Phh3 in tumor tissues. The interaction between Linc00284, miR-27a and c-Met was validated by luciferase reporter assay and RNA immunoprecipitation (RIP) assay. Cell function experiments, including CCK-8, wound-healing and transwell invasion assays, were conducted. The in vivo studies were performed with the subcutaneous tumor xenograft mouse models. Our findings reveal that Linc00284 is upregulated in CRC tissues and colorectal cancer cell lines HCT116 and SW480 in comparison with corresponding para-carcinoma tissues and human fetal colonic mucosa cells FHC. High expression of Linc00284 in tumor tissues is associated with tumor metastasis and predicts a poor clinical outcome in CRC patients. Serum Linc00284 is increased, while miR-27a is decreased in CRC patients compared to healthy controls. ROC curve analysis indicates that serum Linc00284 and miR-27a produce the area under the curve (AUC) value of at 0.8151 and 0.7316 in patients with colorectal cancer compared to healthy individuals, respectively. Additionally, results in vitro and in vivo experiments suggest that Linc00284 silencing significantly suppresses CRC cell proliferation and/or invasion. Mechanistically, Linc00284 promotes c-Met expression by acting as miR-27a sponge, leading to the activation of downstream signaling pathways, thereby causing malignant phenotypes of CRC cells. Taken together, Linc00284 exhibits oncogenic function and the disturbance of Linc00284/miR-27a/c-Met regulatory axis contributes to CRC progression, providing new insight into the pathogenesis of colorectal cancer. Importantly, the expression levels of serum Linc00284 and miR-27a may serve as clinical biomarkers for CRC diagnosis.

Identification and Validation of a Novel DNA Damage and DNA Repair Related Genes Based Signature for Colon Cancer Prognosis.

Backgrounds: Colorectal cancer (CRC) with high incidence, has the third highest mortality of tumors. DNA damage and repair influence a variety of tumors. However, the role of these genes in colon cancer prognosis has been less systematically investigated. Here, we aim to establish a corresponding prognostic signature providing new therapeutic opportunities for CRC. Method: After related genes were collected from GSEA, univariate Cox regression was performed to evaluate each gene’s prognostic relevance through the TCGA-COAD dataset. Stepwise COX regression was used to establish a risk prediction model through the training sets randomly separated from the TCGA cohort and validated in the remaining testing sets and two GEO datasets (GSE17538 and GSE38832). A 12-DNA-damage-and-repair-related gene-based signature able to classify COAD patients into high and low-risk groups was developed. The predictive ability of the risk model or nomogram were evaluated by different bioinformatics‐ methods. Gene functional enrichment analysis was performed to analyze the co-expressed genes of the risk-based genes. Result: A 12-gene based prognostic signature established within 160 significant survival-related genes from DNA damage and repair related gene sets performed well with an AUC of ROC 0.80 for 5 years in the TCGA-CODA dataset. The signature includes CCNB3, ISY1, CDC25C, SMC1B, MC1R, LSP1P4, RIN2, TPM1, ELL3, POLG, CD36, and NEK4. Kaplan-Meier survival curves showed that the prognosis of the risk status owns more significant differences than T, M, N, and stage prognostic parameters. A nomogram was constructed by LASSO regression analysis with T, M, N, age, and risk as prognostic parameters. ROC curve, C-index, Calibration analysis, and Decision Curve Analysis showed the risk module and nomogram performed best in years 1, 3, and 5. KEGG, GO, and GSEA enrichment analyses suggest the risk involved in a variety of important biological processes and well-known cancer-related pathways. These differences may be the key factors affecting the final prognosis. Conclusion: The established gene signature for CRC prognosis provides a new molecular tool for clinical evaluation of prognosis, individualized diagnosis, and treatment. Therapies based on targeted DNA damage and repair mechanisms may formulate more sensitive and potential chemotherapy regimens, thereby expanding treatment options and potentially improving the clinical outcome of CRC patients.

The Change of Systemic Immune-Inflammation Index Independently Predicts Survival of Colorectal Cancer Patients after Curative Resection.

Background The systemic immune-inflammation index (SII) has an important role in predicting survival in some solid tumors. However, little information is available concerning the change of the SII (∆SII) in colorectal cancer (CRC) after curative resection. This study was designed to evaluate the role of ∆SII in CRC patients who received surgery. Methods A total 206 patients were enrolled in this study. Clinicopathologic characteristics and survival were assessed. The relationships between overall survival (OS), disease-free survival (DFS), and ∆SII were analyzed with both univariate Kaplan-Meier and multivariate Cox regression methods. Results Based on the patient data, the receiver operating characteristic (ROC) optimal cutoff value of ∆SII was 127.7 for OS prediction. The 3-year and 5-year OS rates, respectively, were 60.4% and 36.7% in the high-∆SII group (>127.7) and 87.6% and 79.8% in the low-∆SII group (≤127.7). The 3-year and 5-year DFS rates, respectively, were 54.1% and 34.1% in the high-∆SII group and 80.3% and 78.5% in the low-∆SII group. In the univariate analysis, smoking, pathological stages III-IV, high-middle degree of differentiation, lymphatic invasion, vascular invasion, and the high-ΔSII group were associated with poor OS. Adjuvant therapy, pathological stages III-IV, vascular invasion, and ΔSII were able to predict DFS. Multivariate analysis revealed that pathological stages III-IV (HR = 0.442, 95% CI = 0.236-0.827, p = 0.011), vascular invasion (HR = 2.182, 95% CI = 1.243-3.829, p = 0.007), and the high-ΔSII group (HR = 4.301, 95% CI = 2.517-7.350, p < 0.001) were independent predictors for OS. Adjuvant therapy (HR = 0.415, 95% CI = 0.250-0.687, p = 0.001), vascular invasion (HR = 3.305, 95% CI = 1.944-5.620, p < 0.001), and the high-ΔSII group (HR = 4.924, 95% CI = 2.992-8.102, p < 0.001) were significant prognostic factors for DFS. Conclusions The present study demonstrated that ∆SII was associated with the clinical outcome in CRC patients undergoing curative resection, supporting the role of ∆SII as a prognostic biomarker.

5-FU promotes stemness of colorectal cancer via p53-mediated WNT/\u03b2-catenin pathway activation

5-Fluorouracil (5-FU) remains the first-line treatment for colorectal cancer (CRC). Although 5-FU initially de-bulks the tumor mass, recurrence after chemotherapy is the barrier to effective clinical outcomes for CRC patients. Here, we demonstrate that p53 promotes WNT3 transcription, leading to activation of the WNT/β-catenin pathway in ApcMin/+/Lgr5EGFP mice, CRC patient-derived tumor organoids (PDTOs) and patient-derived tumor cells (PDCs). Through this regulation, 5-FU induces activation and enrichment of cancer stem cells (CSCs) in the residual tumors, contributing to recurrence after treatment. Combinatorial treatment of a WNT inhibitor and 5-FU effectively suppresses the CSCs and reduces tumor regrowth after discontinuation of treatment. These findings indicate p53 as a critical mediator of 5-FU-induced CSC activation via the WNT/β-catenin signaling pathway and highlight the significance of combinatorial treatment of WNT inhibitor and 5-FU as a compelling therapeutic strategy to improve the poor outcomes of current 5-FU-based therapies for CRC patients.

NF-κB2 and RELB offer prognostic information in colorectal cancer and NFKB2 rs7897947 represents a genetic risk factor for disease development

The Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) family of transcription factors plays an important role in immune responses and cancer development and progression. We have focused on NF-κB2 and RELB of the alternative pathway of NF-κB, which remains largely underexplored in colorectal cancer (CRC). We found that NF-κB2 and RELB protein levels were upregulated in tumour and surrounding stromal tissue compared to distant non-neoplastic tissue (NN) and associated stroma (p<0.001 in all associations). Moreover, low RELB protein expression was associated with decreased overall survival (p = 0.032). Lower RELB gene expression levels were observed in tumour compared to NN tissue (p = 0.003) and were associated with shorter time to progression (TTP) (p = 0.025). NF-κB2 gene expression levels were similar in tumour and NN tissue, but higher tumour levels were prognostic for improved survival (p = 0.038) and TTP (p<0.001). We also assessed the significance of two NF-κB2 genetic polymorphisms, rs12769316 and rs7897947. Both polymorphisms were associated with lymph node infiltration (p = 0.045 and p = 0.009, respectively). In addition, rs12769316 AA homozygotes relapsed less often compared to G allele carriers (p = 0.029). Moreover, rs7897947 allele frequencies differed significantly between CRC patients and healthy controls (p<0.001) and the minor allele (G) was associated with reduced risk for developing CRC (p<0.001, OR: 0.527, 95% CI: 0.387–0.717). In conclusion, the alternative NF-κB pathway appears deregulated in CRC. Moreover, NF-κB2 and RELB expression levels seem to be significant for the clinical outcome of CRC patients and rs7897947 appears to be a risk factor for CRC development.

Peripheral monocyte counts predict the clinical outcome for patients with colorectal cancer: a systematic review and meta-analysis.

Monocytes originating from bone marrow play a key role in the inflammatory response. Divergent findings regarding the prognostic value of inflammatory factors like absolute monocyte count (AMC) in colorectal cancer (CRC) exist in the current literature. Thus, we sought to perform a systemic meta-analysis to comprehensively estimate whether the peripheral AMC affects the clinical outcome of CRC patients. A comprehensive literature search was performed in PubMed, Web of Science and EMBASE last updated to 23 December 2018, to identify studies reporting the prognostic value of AMC in patients with CRC. Hazard ratios and corresponding 95% confidence intervals (CIs) or P values were used as the effect size estimates for clinical outcomes including overall survival (OS), disease-free survival (DFS), cancer-specific survival (CSS) and progression-free survival (PFS) with the random-effect inverse variance weighted method. The potential heterogeneity was assessed with Q test and I statistics. Subgroup analyses with respect to some clinicopathological parameters were conducted. A total of 16 clinical studies comprising 3826 patients were included for analysis. Pooled analyses revealed that CRC patients with elevated AMC were significantly associated with worse OS (hazard ratio = 1.708, 95% CI: 1.480-1.971, P < 0.001), DFS (hazard ratio = 1.817, 95% CI: 1.289-2.560, P = 0.001), CSS (hazard ratio = 1.551, 95% CI: 1.187-2.027, P = 0.001) and PFS (hazard ratio = 1.487, 95% CI: 1.259-1.756, P < 0.001). In addition, subgroup analyses provided more information and demonstrated the prognostic effect of elevated preoperative AMC in patients with CRC. There were no significant heterogeneity and publication bias. In conclusion, elevated AMC seems to be served as an unfavorable and robust predicative indicator in CRC patients.

Reduced serum miR-98 predicts unfavorable clinical outcome of colorectal cancer.

Circulating microRNAs (miRNAs) are considered to be promising biomarkers for the diagnosis and prognosis prediction of cancers. However, the potential clinical significance of the serum miR-98 in colorectal cancer (CRC) remained unclear. This study aimed to examine the serum miR-98 levels in CRC patients and explore its potential value for CRC. A total of 115 CRC cases and 50 healthy volunteers were enrolled in this study. Quantitative reverse-transcription PCR (qRT-PCR) was performed to detect serum miR-98 expression in all the participants. The results revealed that serum miR-98 levels were frequently downregulated in CRC patients compared with controls. In addition, low serum miR-98 levels were closely associated with aggressive clinical features and shorter survival. Receiver operating characteristic (ROC) curve analysis demonstrated that serum miR-98 could well differentiate CRC patients from healthy controls with relatively high accuracy. Multivariate analysis further demonstrated that serum miR-98 was an independent prognostic factor for both overall survival and disease-free survival. Mechanistically, MYC, IL-6, and HIST1H2BH were identified as direct downstream targets of miR-98 in CRC cells. Collectively, serum miR-98 might be useful as an indicator for predicting the clinical outcome of CRC patients.

Eukaryotic elongation factor-2 kinase expression is an independent prognostic factor in colorectal cancer

BackgroundPrognostication of patients with colorectal cancer (CRC) currently relies on tumor-node-metastasis (TNM) staging but clinical outcomes of patients of the same histoclinical stage are heterogeneous. It is therefore imperative to devise novel molecular tests to stratify CRC patients. Our previous work demonstrated that eukaryotic elongation factor-2 kinase (EEF2K) is a tumor suppressor in CRC. Herein, we investigated EEF2K expression in CRC and determined its relationship with clinicopathological parameters.MethodsQuantitative RT-PCR and Westerns blots were used to examine EEF2K expression in primary tumor and the adjacent non-tumor tissues of CRC patients (n = 20). Kaplan-Meier curves and Cox regression analysis were used to assess the association between clinical outcomes of CRC patients and EEF2K protein expression determined by immunohistochemistry on tissue microarray (n = 151).ResultsEEF2K was significantly downregulated at both mRNA and protein levels in tumors of CRC patients. Univariate Cox regression analysis revealed that CRC patients with high tumor grade, advanced TNM staging and low EEF2K expression were associated with worse overall survival. Multivariate analysis further demonstrated that low EEF2K expression was an independent factor for predicting poorer overall survival in CRC patients (p = 0.014; Hazard ratio = 2.951; 95% confidence interval: 1.240–7.024). The 5-year survival rate was 82.8% in the EEF2K-high-expression group versus 63.9% in the EEF2K-low-expression group (p = 0.0118). The association of overall survival with EEF2K expression in CRC patients was verified in The Cancer Genome Atlas (TCGA) cohort.ConclusionsEEF2K is downregulated in CRC and its expression can be employed as a prognostic marker for CRC patients independent of TNM staging.