Prognostic Indicator In Colorectal Cancer Research Articles

Integrated single-cell and bulk RNA sequencing analysis identifies a cancer associated fibroblast-related signature for predicting prognosis and therapeutic responses in colorectal cancer

BackgroundCancer-associated fibroblasts (CAFs) contribute notably to colorectal cancer (CRC) tumorigenesis, stiffness, angiogenesis, immunosuppression and metastasis, and could serve as a promising therapeutic target. Our purpose was to construct CAF-related prognostic signature for CRC.MethodsWe performed bioinformatics analysis on single-cell transcriptome data derived from Gene Expression Omnibus (GEO) and identified 208 differentially expressed cell markers from fibroblasts cluster. Bulk gene expression data of CRC was obtained from The Cancer Genome Atlas (TCGA) and GEO databases. Univariate Cox regression and least absolute shrinkage operator (LASSO) analyses were performed on TCGA training cohort (n = 308) for model construction, and was validated in TCGA validation (n = 133), TCGA total (n = 441), GSE39582 (n = 470) and GSE17536 (n = 177) datasets. Microenvironment Cell Populations-counter (MCP-counter) and Estimate the Proportion of Immune and Cancer cells (EPIC) methods were applied to evaluated CAFs infiltrations from bulk gene expression data. Real-time polymerase chain reaction (qPCR) was performed in tissue microarrays containing 80 colon cancer samples to further validate the prognostic value of the CAF model. pRRophetic and Tumor Immune Dysfunction and Exclusion (TIDE) algorithms were utilized to predict chemosensitivity and immunotherapy response. Human Protein Atlas (HPA) databases and immunohistochemistry were used to evaluate the protein expressions.ResultsA nine-gene prognostic CAF-related signature was established in training cohort. Kaplan–Meier survival analyses revealed patients with higher CAF risk scores were correlated with adverse prognosis in each cohort. MCP-counter and EPIC results consistently revealed CAFs infiltrations were significantly higher in high CAF risk group. Patients with higher CAF risk scores were more prone to not respond to immunotherapy, but were more sensitive to several conventional chemotherapeutics, suggesting a potential strategy of combining chemotherapy with anti-CAF therapy to improve the efficacy of current T-cell based immunotherapies. Univariate and multivariate Cox regression analyses verified the CAF model was as an independent prognostic indicator in predicting overall survival, and a CAF-based nomogram was then built for clinical utility in predicting prognosis of CRC.ConclusionTo conclude, the CAF-related signature could serve as a robust prognostic indicator in CRC, which provides novel genomics evidence for anti-CAF immunotherapeutic strategies.

Alcohol Consumption is associated with Increased CEA Levels in Male Patients with Stage IV Colorectal Cancer- A Single-Institution Retrospective Analysis

Introduction: Alcohol use is an independent risk factor for liver metastasis, a major cause of morbidity and mortality in colorectal cancer (CRC) patients. Serum CEA level is an established prognostic indicator in CRC, yet the correlation with behavioral factors such as alcohol use remains to be defined. In a single-center review, we evaluated alcohol use, gender, and CEA levels in predicting advanced disease in CRC patients. Methods: Retrospective analysis of UNMC patients diagnosed with CRC as the primary cancer between 2012-2019, stages I-IV, and age >19 with documentation of alcohol use. Univariable statistics were performed using Chi-Square and non-parametric tests. Associations between stage, gender, and alcohol use (some vs. none) and the log-transformed CEA outcome (either initial or rate of change) were assessed using linear regressions. Results: Alcohol use was found to be reported in 333 of 1243 CRC patients. The cohort was comprised of 192 male and 141 female subjects. Elevated CEA levels at CRC diagnosis were associated with increased all-cause mortality (33.0% for CEA > 3.4ng/ml vs 10.4% for CEA < 3.4ng/ml). Model analysis found that stage IV male alcohol users showed an increase in serial CEA levels compared to males who did not use alcohol, but this pattern was not observed among stage IV females. Conclusions: Males with a history of alcohol use may be at risk for advanced CRC disease suggesting the utility of serial serum CEA monitoring in these patients. A detailed alcohol use history should be obtained in all patients with CRC as it has prognostic value and may allow for early intervention. This analysis was limited by missing alcohol use data for the majority (73.2%) of CRC patients evaluated. A prospective study is warranted to define the implications of alcohol use and risk of CRC liver metastasis.

Tumor Infiltrating Lymphocytes Target HLA-I Phosphopeptides Derived From Cancer Signaling in Colorectal Cancer.

There is a pressing need for novel immunotherapeutic targets in colorectal cancer (CRC). Cytotoxic T cell infiltration is well established as a key prognostic indicator in CRC, and it is known that these tumor infiltrating lymphocytes (TILs) target and kill tumor cells. However, the specific antigens that drive these CD8+ T cell responses have not been well characterized. Recently, phosphopeptides have emerged as strong candidates for tumor-specific antigens, as dysregulated signaling in cancer leads to increased and aberrant protein phosphorylation. Here, we identify 120 HLA-I phosphopeptides from primary CRC tumors, CRC liver metastases and CRC cell lines using mass spectrometry and assess the tumor-resident immunity against these posttranslationally modified tumor antigens. Several CRC tumor-specific phosphopeptides were presented by multiple patients’ tumors in our cohort (21% to 40%), and many have previously been identified on other malignancies (58% of HLA-A*02 CRC phosphopeptides). These shared antigens derived from mitogenic signaling pathways, including p53, Wnt and MAPK, and are therefore markers of malignancy. The identification of public tumor antigens will allow for the development of broadly applicable targeted therapeutics. Through analysis of TIL cytokine responses to these phosphopeptides, we have established that they are already playing a key role in tumor-resident immunity. Multifunctional CD8+ TILs from primary and metastatic tumors recognized the HLA-I phosphopeptides presented by their originating tumor. Furthermore, TILs taken from other CRC patients’ tumors targeted two of these phosphopeptides. In another cohort of CRC patients, the same HLA-I phosphopeptides induced higher peripheral T cell responses than they did in healthy donors, suggesting that these immune responses are specifically activated in CRC patients. Collectively, these results establish HLA-I phosphopeptides as targets of the tumor-resident immunity in CRC, and highlight their potential as candidates for future immunotherapeutic strategies.

Abstract 835: T-cell abundance, clonality and disease specific survival in colorectal cancer

Abstract Immune responses to colorectal cancer (CRC) are important prognostic factors as measured by either tumor infiltrating lymphocytes per high powered field or the presence of Crohn's like lymphoid reaction. New technologies to quantify specific features of immune responses include immunoSeq (Adaptive Biotechnologies), which accurately quantifies T-cell receptor (TCR) abundance and T-cell receptor clonality. Here we measured the independent contributions of TCR abundance and TCR clonality to 5-year CRC-specific survival in the Molecular Epidemiology of Colorectal Cancer (MECC) study. The MECC study consented, interviewed, and followed 6,006 incident cases of CRC diagnosed between March 31, 1998 and July 1, 2017 (median follow-up time = 6.9 years). Archived paraffin blocks were retrieved, and 2,750 cases had sufficient tissue and adequate DNA extraction to perform the immunoSeq assay. Analyses were restricted to 1,625 samples with more than 100 T-cells to permit accurate quantification of TCR abundance and TCR clonality as measured by Simpson Clonality Index. TCR abundance was log2 transformed for analyses, and Simpson Clonality Index was log2-transformed and z-scale normalized separately by assay version. In unadjusted models, dichotomized log2 transformed TCR abundance (Hazard Ratio (HR) = 0.57, 95% confidence interval (CI) 0.47-0.71, p=9.77E-08) and dichotomized TCR clonality (HR = 0.77, 95% CI 0.63-0.94, p=0.01) were each statistically significantly associated with 5-year CRC-specific survival. In a model with adjustment for age, sex, microsatellite instability, stage and assay version, both dichotomized log2 transformed TCR abundance (HR = 0.61, 95% CI, 0.49-0.75, p=3.03E-06), and dichotomized TCR clonality (HR = 0.81, 95% CI, 0.66-0.99, p=0.048) were associated with improved 5-year disease-specific survival. Conclusion: TCR abundance and TCR clonality are independent prognostic indicators in CRC. Citation Format: Joseph Bonner, Sephanie L. Schmit, Sidney S. Lindsey, Ya-Yu Tsai, Rebeca Sanz-Pamplona, M. Henar Alonso, Marilena Melas, Hedy S. Rennert, Kevin J. McDonnell, Gregory Idos, Christopher P. Walker, W. Martin Kast, Diane Da Silva, Harlan S. Robins, Joel K. Greenson, Victor Moreno, Gad Rennert, Stephen B. Gruber. T-cell abundance, clonality and disease specific survival in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 835.

Prognostic value of tumor budding in gallbladder cancer: application of the International Tumor Budding Consensus Conference scoring system.

Tumor budding (TB), a histopathological manifestation of epithelial-mesenchymal transition, is an important step in cancer invasion and metastasis development. TB has been considered a strong prognostic indicator in colorectal cancer. The International Tumor Budding Consensus Conference (ITBCC) scoring system is the standardized method used for patient outcome prediction in several human tumors. We investigated the clinicopathological implications and applicability of TB measured using the ITBCC scoring system in gallbladder cancer (GBC). The TB grades assigned to the 78 GBC patients were as follows: Bd1 (low TB), 41 (52.6%) patients; Bd2 (intermediate TB), 22 (28.2%) patients; and Bd3 (high TB), 15 (19.2%) patients. A higher TB grade correlated with a poorer histological differentiation (P< 0.000), higher pT category (P< 0.000), the involvement of surgical resection margin (P= 0.005), presence of nodal metastasis (P< 0.000), lymphatic and venous invasion (P< 0.000), and perineural invasion (P= 0.004). Univariate Cox regression analysis revealed that a poor histological grade, high pT category, lymphatic invasion, perineural invasion, and intermediate to high TB grades were associated with worse 5-year overall survival and disease-free survival. TB was not significantly associated with death or recurrence risk in multivariate Cox analysis. The interobserver agreement of TB grading was substantial. This study is the first to apply the ITBCC scoring system and suggest the prognostic value of TB in GBC.

Biochemical study of Cancer Antigen CEA and CA 19-9 as prognostic markers in colorectal cancer (CRC)

Colorectal cancer is one of the most common types of cancer in the world. Several factors have been shown to put individuals at risk to CRC and these include age, the presence of polyps, inflammatory bowel disease, lifestyle, genetic background and family medical history. In the present study, we were related to the cancer antigen CEA and CA19-9 as prognostic markers in colorectal cancer. This may be helping us to detect colorectal cancer in an early stage. In this study, we have included 60 patients diagnosed with colorectal cancer. These patients were categorized as 10 patients between stage I-IV with disease dissemination and recurrence; 50 patients in between stage I- IV without dissemination and recurrence; 60 healthy controls. The cancer antigen CEA and Ca 19-9 were analyzed as prognostic markers in colorectal cancer. The statistical analysis was done by using SPSS software and expressed in terms of mean ± standard deviation. The p values (p˂0.005) were considered as statistically significant value. Person correlation between the cancer antigen CEA and CA-19-9 were analyzed. The cancer antigen CEA and Ca19-9 level were significantly increased in colorectal cancer patients as compared to the healthy controls group (p˂0.005). The significant Person correlation was observed in between CEA and CA19-9. The level of CEA and CA19-9 were significantly prognostic indicator in colorectal cancer. CEA and CA19-9 can be used as a diagnostic and prognostic marker for the screening of both colon and rectum cancer.

Syntenin-1 promotes colorectal cancer stem cell expansion and chemoresistance by regulating prostaglandin E2 receptor

BackgroundThe protein syntenin-1 is expressed by a variety of cell types, and is upregulated in various malignancies, including melanoma, breast cancer and glioma. Although the mechanism by which elevated syntenin-1 expression contributes to cancer has been described, the exact pathway has not been elucidated.MethodsTo investigate the involvement of syntenin-1 in colorectal cancer (CRC), we performed immunohistochemical analysis of 139 CRC surgical specimens. We also examined syntenin-1 knockdown in CRC cell lines.ResultsHigh syntenin-1 expression was associated with less differentiated histologic grade and poor prognosis, and was an independent prognostic indicator in CRC. Syntenin-1 knockdown in CRC cells reduced the presence of cancer stem cells (CSCs), oxaliplatin chemoresistance and migration. DNA microarray analysis and quantitative real-time polymerase chain reaction showed decreased prostaglandin E2 receptor 2 (PTGER2) expression in syntenin-1-knockdown cells. PTGER2 knockdown in CRC cells yielded the same phenotype as syntenin-1 knockdown. Celecoxib, which has anti-inflammatory effects by targeting cyclooxygenase-2, reduced CSCs and decreased chemoresistance, while prostaglandin E2 (PGE2) had the opposite effect.ConclusionsOur findings suggested that syntenin-1 enhanced CSC expansion, oxaliplatin chemoresistance and migration capability through regulation of PTGER2 expression. Syntenin-1 may be a promising new prognostic factor and target for anti-cancer therapies.

Characterising the prognostic potential of HLA-DR during colorectal cancer development

HLA-DR, an MHC class II molecule that mediates antigen presentation, is a favourable prognostic indicator in colorectal cancer (CRC). However, the dynamics and location of HLA-DR expression during CRC development are unclear. We aimed to define HLA-DR expression by immunohistochemistry in colorectal epithelium and stromal tissue at different stages of cancer development, assessing non-neoplastic colorectal adenocarcinoma–adjacent tissue, adenomas and carcinoma tissues, and to associate HLA-DR levels with clinical outcomes. Patients with higher than median HLA-DR expression survived at least twice as long as patients with lower expression. This association was significant for HLA-DR staining in the colorectal carcinoma epithelium (n = 152, p = 0.011, HR 1.9, 95% CI 1.15–3.15) and adjacent non-neoplastic epithelium (n = 152, p < 0.001, HR 2.7, 95% CI 1.59–4.66), but not stroma. In stage II cases, however, the prognostic value of HLA-DR expression was significant only in adjacent non-neoplastic tissues, for both epithelium (n = 63, p = 0.015, HR 3.6, 95% CI 1.279–10.25) and stroma (n = 63, p = 0.018, HR 5.07, 95% CI 1.32–19.49). HLA-DR was lower in carcinoma tissue compared to matched adenomas (n = 35), in epithelium (p < 0.01) and stroma (p < 0.001). HLA-DR was further reduced in late-stage carcinoma (n = 101) compared to early stage (n = 105), in epithelium (p < 0.001) and stroma (p < 0.01). HLA-DR expression was lower (p < 0.05) in the adjacent non-neoplastic epithelium of patients with cancer recurrence. We demonstrate a progressive loss of HLA-DR in epithelial and stromal tissue compartments during CRC development and show prognostic ability in carcinoma–adjacent non-neoplastic tissues, highlighting the importance of this molecule in the anti-cancer immune response. These findings may have wider implications for immunotherapeutic interventions.

The impact of lymph node ratio on overall survival in patients with colorectal cancer.

Lymph node metastasis is a predominant prognostic indicator in colorectal cancer. Number of lymph nodes removed surgically was demonstrated to correlate with staging accuracy and oncological outcomes. However, number of lymph nodes removed depends on uncontrolled variables. Therefore, a more reliable prognostic indicator is needed. Calculation of ratio of positive lymph nodes to total number of removed lymph nodes may be an appealing solution. We retrospectively analyzed data of 156 Stage III colorectal cancer patients whom underwent surgery between 2008 and 2015. Patients' demographic characteristics, tumor grade, location, vascular-perineural invasion status, number of removed lymph nodes, and ratio of positive lymph nodes to number of removed lymph nodes were recorded. Spearman correlation analysis was used to determine the correlation coefficient while Kaplan-Meier method and Cox proportional hazard regression model were performed for the prediction of survival and multivariate analysis, respectively. Number of removed lymph nodes did not correlate with survival, but it was inversely correlated with number of positive lymph nodes. Multivariate analysis showed that ratio of removed positive lymph nodes to the total number of lymph nodes was a significant prognostic factor for survival for a ratio equal or above 0.31 was a poor prognostic indicator (108 months vs. 34 months, hazard ratio: 4.24 [95% confidence interval: 2.15-8.34]; P < 0.019). Tumor characteristics failed to demonstrate any prognostic value. This study showed that positive lymph node ratio (PLNR) is an important prognostic factor for Stage III colorectal cancer. Although 0.31 can be taken as threshold for "PLNR," prospective trials including larger patient groups are needed to validate its role as a prognostic indicator.

ADAMTS4 is upregulated in colorectal cancer and could be a useful prognostic indicator of colorectal cancer.

ADAMTS4 is a member of the ADAMTS4 family, which secretes proteinases. The mechanism of tumor metastasis may be correlated to its promotion of angiogenesis. It was determined whether ADAMTS4 participates in colorectal cancer progression. The expression in clinical samples and CRC cell lines was investigated. Using immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), and RT-PCR, the expression of ADAMTS4 was determined in colorectal tumors of different cancer stages and anatomic sites, and in three cell lines of different aggressiveness. The overexpression of ADAMTS4 was observed in tissue samples by IHC, and this was mainly located in the cytoplasm, as detected by FISH. The qRT-PCR and western blot analyses further supported the clinical sample findings. The present data support the notion that the overexpression of ADAMTS4 in CRC might be useful as a non-invasive biomarker for detecting CRC in patients.

Combination of C-reactive Protein and Monocyte Count Is a Useful Prognostic Indicator for Patients With Colorectal Cancer.

Several studies have demonstrated the usefulness of C-reactive protein (CRP) or cellular components obtained from complete blood count as prognostic indicators in colorectal cancer (CRC) patients. The aim of this study was to investigate the prognostic significance of the combination of CRP and blood cellular components in CRC patients. A total of 463 patients who underwent curative surgery for CRC were enrolled in this study. ROC analysis revealed that the values of area under the curve of neutrophil, lymphocyte, platelet, and monocyte counts (MC) for overall survival (OS) were 0.594, 0.513, 0.553, and 0.625, respectively. Using cut-off values derived from ROC analysis, patients were divided into the following groups, CRPHigh, CRPLow, MCHigh, and MCLow The 5-year OS rates of CRPHigh and MCHigh, CRPHigh and MCLow, CRPLow and MCHigh, and CRPLow and MCLow patients were 60.2%, 75.7%, 82.1%, and 88.3%, respectively (p<0.0001). Multivariate analysis revealed that the combination of serum CRP levels and MC was an independent prognostic indicator. With regard to the cause of death, the combination of CRP and MC was significantly associated with both cancer-related and unrelated death. The combination of CRP and MC is useful in predicting the prognosis in CRC patients.

A prognostic index based on an eleven gene signature to predict systemic recurrences in colorectal cancer

Approximately half of colorectal cancer (CRC) patients experience disease recurrence and metastasis, and these individuals frequently fail to respond to treatment due to their clinical and biological diversity. Here, we aimed to identify a prognostic signature consisting of a small gene group for precisely predicting CRC heterogeneity. We performed transcriptomic profiling using RNA-seq data generated from the primary tissue samples of 130 CRC patients. A prognostic index (PI) based on recurrence-associated genes was developed and validated in two larger independent CRC patient cohorts (n = 795). The association between the PI and prognosis of CRC patients was evaluated using Kaplan–Meier plots, log-rank tests, a Cox regression analysis and a RT-PCR analysis. Transcriptomic profiling in 130 CRC patients identified two distinct subtypes associated with systemic recurrence. Pathway enrichment and RT-PCR analyses revealed an eleven gene signature incorporated into the PI system, which was a significant prognostic indicator of CRC. Multivariate and subset analyses showed that PI was an independent risk factor (HR = 1.812, 95% CI = 1.342–2.448, P < 0.001) with predictive value to identify low-risk stage II patients who responded the worst to adjuvant chemotherapy. Finally, a comparative analysis with previously reported Consensus Molecular Subgroup (CMS), high-risk patients classified by the PI revealed a distinct molecular property similar to CMS4, associated with a poor prognosis. This novel PI predictor based on an eleven gene signature likely represents a surrogate diagnostic tool for identifying high-risk CRC patients and for predicting the worst responding patients for adjuvant chemotherapy.

Downregulation of serum exosomal miR-150-5p is associated with poor prognosis in patients with colorectal cancer.

Growing evidence have revealed the serum exosomal miRNAs emerged as biomarkers for various cancer types, including colorectal cancer (CRC). Here, we sought to explore the potential clinical significance of serum exosomal miR-150-5p in CRC. A total of 133 CRC patients and 60 healthy volunteers as control group were recruited in this study. Exosomes were isolated from the serum of all the participants. The total RNA was isolated from the exosomes and the serum exosomal miR-150-5p levels were measured by quantitative reverse transcription-polymerase chain reaction. The findings showed that the serum exosomal miR-150-5p levels were significantly reduced in CRC cases compared with those in the control group. Serum exosomal miR-150-5p levels in post-operative blood samples were greatly upregulated one month after surgical treatment. In addition, decreased serum exosomal miR-150-5p expression was closely correlated with poorly differentiation, positive lymph node metastasis and advanced TNM stage. Moreover, receiver operating characteristic (ROC) curve analysis showed serum exosomal miR-150-5p level had good performance to identify CRC cases from healthy volunteers, and a combination of serum exosomal miR-150-5p and carcinoembryonic antigen (CEA) could improve the diagnostic accuracy with an increased the area under the ROC curve (AUC) value. Furthermore, the survival time of patients with higher serum exosomal miR-150-5p expression was significantly longer than those with lower expression. Serum exosomal miR-150-5p was confirmed as an independent prognostic indicator in CRC. Mechanistically, ZEB1 was identified as a direct downstream target of miR-150-5p. Collectively, serum exosomal miR-150-5p might be a novel noninvasive biomarker for CRC diagnosis and prognosis.

Combined Microsatellite Instability and Elevated Microsatellite Alterations at Selected Tetranucleotide Repeats (EMAST) Might Be a More Promising Immune Biomarker in Colorectal Cancer.

The form of microsatellite instability (MSI) affecting tetranucleotide repeats known as elevated microsatellite alterations at selected tetranucleotide repeats (EMAST) has emerged as a new potential biomarker in multiple cancers. In colorectal cancer (CRC), the correlation between EMAST and MSI mutations remain inconclusive. We evaluated 1,505 patients with CRC using five EMAST markers (D20S82, D20S85, D8S321, D9S242, and MYCL1) and the Bethesda panel of MSI markers. Most commonly, mutations involved in CRCs were identified by MassArray Assay, and DNA repair genes were analyzed by next-generation sequencing. Clinical characteristics and prognostic relevance were correlated with EMAST and MSI. Tumors that were EMAST positive and MSI high (MSI-H) were detected in 159 (10.6%) and 154 (10.2%) of 1,505 patients with CRC. Patients were divided into four groups according to EMAST and MSI status (EMAST-positive and MSI-H, EMAST-positive and microsatellite-stable [MSS], EMAST-negative and MSI-H, and EMAST-negative and MSS). The EMAST-positive and MSI-H group was associated with female predominance, higher prevalence of proximal colon tumors, early stage tumors, poorly differentiated tumors, mucinous histology, and higher incidence of mutations in PI3KCA, BRAF, TGFBR, PTEN, and AKT1 compared with other groups. Furthermore, compared with only EMAST-positive tumors or only MSI-H tumors, tumors that were both EMAST-positive and MSI-H had a higher frequency of MLH1, MSH3, MSH6, PMS2, and EXO1 gene mutations. Finally, the presence of EMAST-positive and MSI-H tumors was a good prognostic indicator in CRC. High mutations in several DNA repair genes in EMAST-positive and MSI-H tumors suggest that this subtype of CRC might be more suitable for treatment with immune therapy. Elevated microsatellite alterations at selected tetranucleotide repeats (EMAST) is a unique molecular subtype of colorectal cancer (CRC). The current study demonstrated that the EMAST-positive and MSI-high (MSI-H) group was associated with female predominance, higher prevalence of proximal colon tumors, early stage tumors, poorly differentiated tumors, mucinous histology, and higher incidence of mutations in PI3KCA, BRAF, TGFBR, PTEN, and AKT1 compared with other groups. Most importantly, high mutations in DNA repair genes and MSI-related genes in EMAST-positive and MSI-H tumors suggest that this subtype of CRC might be more suitable for treatment with immune therapy compared with MSI-H tumors alone.

Expression of septin 2 and association with clinicopathological parameters in colorectal cancer.

Septin 2 (SEPT2) is a tumor-related gene belonging to the SEPT family that affects the cellular processes of hepatoma carcinoma cells, glioblastoma cells and mesangial cells and is highly expressed in breast cancer, biliary tract cancer and acute myeloid leukemia. Colorectal cancer (CRC) is the third most common type of malignancy in humans. In the present study, Oncomine database was used to compare the expression pattern of SEPT2 mRNA between CRC and normal tissues. Additionally, protein expression in 90 pairs of CRC and paracancerous tissues was analyzed by western blotting and immunohistochemistry (IHC). The results showed that SEPT2 was highly expressed in CRC tissues at the mRNA and protein levels. SEPT2 expression quantified by IHC was associated with lymph node metastasis, the degree of differentiation and TNM staging. Increased SEPT2 wass associated with reduced overall survival (OS) according to Kaplan-Meier analysis. COX proportional hazard analysis indicated that SEPT2 was an independent factor that influenced the OS of patients with CRC. Therefore, SEPT2 was associated with the occurrence, progression and prognosis of CRC and thus, may be a marker and prognostic indicator of CRC.

Angiotensin I-converting enzyme gene plays a crucial role in the pathology of carcinomas in colorectal cancer

Angiotensin I-Converting Enzyme (ACE, CD143) Gene plays a crucial role in the pathology of carcinomas in many cancers including colorectal cancer (CRC). However, the methylation of ACE was rarely reported. In this study, our purpose was to investigate the methylation status of ACE and explored its prognostic value in CRC. The expression of ACE was detected by quantitative real-time polymerase chain reaction (qRT-PCR) analysis while the methylation status of ACE was measured via methylation-specific polymerase chain reaction (MSP). The result demonstrated that ACE expression was up-regulated in tumour tissues and HT-29 cells compared with the controls. ACE was also confirmed to be hypomethylated in CRC. Next, we evaluated the influence of ACE hypomethylation on cell growth. It was proved to be a favourable factor for the cell proliferation, cell colony forming, but an inhibitor for the cell apoptosis of CRC cells according to MST assay, colony forming assay and flow cytometry assay. ACE hypomethylation was also considered to be related to the prognosis of CRC through Cox regression analysis. Taken together, the over-expression of ACE was regulated by its hypomethylation and the ACE hypomethylation might be an independent prognostic indicator in CRC.

Fusobacterium nucleatum-positive colorectal cancer.

Colorectal cancer (CRC) is an important threat to human health and the fourth leading cause of mortality worldwide. Accumulating evidence indicates that the composition of the intestinal flora is associated with the occurrence of CRC. Fusobacterium nucleatum (Fn), one of the highly enriched bacteria in CRC tissues, invades the mucosa with adhesion factors and virulence proteins, interacts with the host immune system and promotes the occurrence and development of CRC and chemoresistance. Fn infection is prevalent in human colorectal carcinoma, although the infection rate varies in different regions. Fn may be used as a prognostic indicator of CRC. It is important to understand the multi-pathway carcinogenic mechanisms associated with CRC in order to develop novel antibacterial drugs against Fn. The current review summarizes the role of Fn and relevant research concerning CRC published in recent years, focusing on Fn infection in CRC, pathogenesis of Fn, Fn-positive CRC treatment, screening and prevention strategies against Fn-positive CRC.

The Significance of MicroRNA-449a and Its Potential Target HDAC1 in Patients With Colorectal Cancer.

In a previous study, we demonstrated that deficiency of microRNA-449a (miR-449a) promoted colorectal tumorigenesis. In this study, the significance of miR-449a in the prognosis and relationship with HDAC1 in colorectal cancer was examined. Seventy-two patients with colorectal cancer and 16 patients with colorectal liver metastasis who underwent surgery were included. miR-449a expression in tumor tissue of resected specimen was investigated by real-time polymerase chain reaction and histone deacetylase 1 (HDAC1) expression was examined by immunohistochemistry. Lymphovascular invasion and increased serum carcinoembryonic antigen levels were seen more frequent in patients with low miR-449a expression. Patients with low miR-449a expression were found to have a poorer prognosis than those with high expression. Vascular invasion, increased serum carbohydrate antigen 19-9 level and low miR-449a were associated with poorer disease-free survival. miR-449a expression was lower in metastatic liver tumor compared to primary tumor. HDAC1 positivity was higher in patients with low miR-449a. miR-449a level might be a prognostic indicator for colorectal cancer and miR-449a might regulate HDAC1 expression.

Monoamine Oxidase B Predicts Poor Prognosis in Colorectal Cancer Patients, and Its Expression Is Significantly Associated with Epithelial to Mesenchymal Transition

Background: Monoamine oxidases (MAOs) are enzymes located on the outer membrane of mitochondria that catalyze monoamine oxidation. Recently, increased expression levels of MAOs have been shown in several cancer types. However, the possible roles of MAOs in the progression and prognosis of colorectal cancer have not yet been elucidated. Methods: We analyzed the role and importance of MAOs in colorectal cancer via an online database analysis and by using tumor tissue microarray. Findings: Several independent colorectal cancer cohorts indicated that high expression of monoamine oxidase B (MAOB) but not of MAOA correlated with worse disease stage and poorer survival. A tissue microarray of 203 cases of colorectal cancer underwent immunohistochemical staining for MAOs and the results were evaluated for the associations with clinicopathological parameters and patient outcomes. High expression of MAOB in primary tumor tissue was observed in 114 samples and was significantly correlated with poor prognosis in colorectal cancer patients (p = 0.002). Moreover, via multivariate analyses, overexpression of MAOB remained an independent prognostic factor for overall survival (p = 0.006) and disease-free survival (p = 0.009). However, the correlation between MAOA expression and these parameters was not significant in colorectal cancer patients. Interpretation: In this study, a significant positive correlation between MAOB and mesenchymal-type gene expression was also found. According to the highlighted characteristics of MAOB in colorectal cancer, MAOB can be used as an independent poor prognostic indicator for colorectal cancer. Funding: This study was supported by the Ministry of Science and Technology, Taiwan, R.O.C. Declaration of Interest: The authors have declared no conflicts of interest. Ethical Approval: The study was carried out with the approval of the Institutional Review Board of WanFang Hospital (Approval No. 99047) and permission from the ethics committees of the institution involved.

Prognostic Value of Combined Tumor Marker and Controlling Nutritional Status (CONUT) Score in Colorectal Cancer Patients

Nutritional status is strongly associated with prognosis in cancer patients. Controlling Nutritional Status (CONUT) score is a nutritional marker based on serum albumin, cholesterol, and total lymphocyte count. We investigated the prognostic significance of a combination of the tumor marker carcinoembryonic antigen (CEA) and CONUT score (T-CONUT) in colorectal cancer (CRC) patients. A total of 522 patients who underwent surgery for CRC at our hospital were retrospectively enrolled in this study. Patients were divided into groups based on the results of receiver operating characteristic (ROC) curve analysis as follows: CONUThigh (CONUT score ≥ 3) and CONUTlow (CONUT score < 3), and CEAlow (< 5 ng/mL) and CEAhigh (≥ 5 ng/mL). The 5-year overall survival (OS) rates of patients in the CONUTlow and CONUThigh groups were 76.0% and 53.9%, respectively (P < 0.0001), and in the CEAlow and CEAhigh groups were 80.7% and 47.6%, respectively (P < 0.0001). Regarding T-CONUT, the 5-year OS rates of patients with CEAlow/CONUTlow, CEAlow/CONUThigh, CEAhigh/CONUTlow, and CEAhigh/CONUThigh were 84.7%, 69%, 55.3%, and 36.1%, respectively (P < 0.0001). Multivariate analysis identified T-CONUT score as an independent prognostic indicator in CRC patients. T-CONUT may be a useful tool for predicting prognosis in CRC patients.