Survival Of Colorectal Cancer Patients Research Articles

SAGL: A self-attention-based graph learning framework for predicting survival of colorectal cancer patients

Background and Objective: Colorectal cancer (CRC) is one of the most commonly diagnosed cancers worldwide. The accurate survival prediction for CRC patients plays a significant role in the formulation of treatment strategies. Recently, machine learning and deep learning approaches have been increasingly applied in cancer survival prediction. However, most existing methods inadequately represent and leverage the dependencies among features and fail to sufficiently mine and utilize the comorbidity patterns of CRC. To address these issues, we propose a self-attention-based graph learning (SAGL) framework to improve the postoperative cancer-specific survival prediction for CRC patients.Methods: We present a novel method for constructing dependency graph (DG) to reflect two types of dependencies including comorbidity-comorbidity dependencies and the dependencies between features related to patient characteristics and cancer treatments. This graph is subsequently refined by a disease comorbidity network, which offers a holistic view of comorbidity patterns of CRC. A DG-guided self-attention mechanism is proposed to unearth novel dependencies beyond what DG offers, thus augmenting CRC survival prediction. Finally, each patient will be represented, and these representations will be used for survival prediction.Results: The experimental results show that SAGL outperforms state-of-the-art methods on a real-world dataset, with the receiver operating characteristic curve for 3- and 5-year survival prediction achieving 0.849±0.002 and 0.895±0.005, respectively. In addition, the comparison results with different graph neural network-based variants demonstrate the advantages of our DG-guided self-attention graph learning framework.Conclusions: Our study reveals that the potential of the DG-guided self-attention in optimizing feature graph learning which can improve the performance of CRC survival prediction.

Long-Noncoding RNA (lncRNA) EGOT Prevents the Malignant Process of Colorectal Carcinoma by Regulating BTG3

This study investigates the role of the long non-coding RNA EGOT in colorectal cancer (CRC) by examining its expression in 40 pairs of CRC and adjacent normal tissues and assessing its impact on clinical outcomes. EGOT was found to be downregulated in CRC tissues, and low EGOT levels were associated with a higher likelihood of lymphatic and distant metastasis, as well as poorer overall and progression-free survival in CRC patients. Functional experiments revealed that overexpression of EGOT in SW480 cells reduced cell viability, migration, and wound closure, while knockdown of EGOT in LoVo cells had the opposite effect. In vivo experiments with nude mice confirmed that EGOT downregulation accelerated CRC growth, whereas its overexpression slowed tumor growth. The study identified BTG3 as the target gene of EGOT, and they exhibited a negative correlation in CRC tissues. Rescue experiments demonstrated that BTG3 could reverse the effects of EGOT on CRC cell phenotypes. In conclusion, EGOT is a downregulated molecule in CRC, closely associated with metastasis and patient prognosis. It exerts a suppressive influence on CRC cell proliferation, migration, and tumorigenesis by negatively regulating BTG3.

SDCBP modulates tumor microenvironment, tumor progression and anti-PD1 efficacy in colorectal cancer.

Anti-programmed cell death 1 (aPD1) therapy has yielded limited success in patients with colorectal cancer (CRC). Syndecan binding protein (SDCBP), encodes a PDZ domain-containing protein that is essential for cellular processes, including cell adhesion, migration, and signal transduction. Here, we investigated the effect of SDCBP on tumor progression, immunotherapy, and the tumor microenvironment (TME) in CRC. High expression of SDCBP is associated with non-response to immunotherapy and correlated with poorer disease-free survival (DFS) in CRC patients. Inhibiting SDCBP by transfecting shRNA or using its inhibitor zinc pyrithione (ZnPT) hindered proliferation and metastasis while enhancing the efficacy of aPD1 treatment in a mouse xenograft model and liver metastasis model. The TME of CRC was significantly altered following ZnPT treatment characterized by a reduced amount of M2 macrophages and a heightened percentage of M1 macrophages. The co-culture system of CRC cells and macrophages provided evidence that SDCBP silencing promoted the repolarisation of M2 macrophages into M1. SDCBP promotes the proliferation, metastasis, and immunotherapy resistance of CRC. Thus, ZnPT represents an effective SDCBP inhibitor and exhibits considerable potential for combination with aPD1 to enhance immunotherapy efficacy.

Analysis of the Treatment for Advanced Microsatellite Stable Colorectal Cancer in Middle-Aged and Elderly People

Microsatellite stabilized (MSS) rectal cancer is a highly prevalent cancer in the middle-aged and elderly population. There exists some expertise in detecting and evaluating the chemotherapy effect in advanced colorectal cancer patients. Multiple studies have combined targeted therapy, chemotherapy, and immunotherapy as a breakthrough. Programmed cell death protein 1 (PD-1) inhibitors have certain therapeutic effects in the treatment of MSS rectal cancer patients. The combination of PD-1 inhibitors and furoquinib can improve the disease control rate (DCR) and progression- free survival (PFS) in colorectal cancer (CRC) patients with advanced MSS, and the adverse reactions are controllable. The combination of erlotinib hydrochloride and Xindilizumab was more effective in treating MSS-type colorectal cancer patients than clinical standard treatment. This study analyzes the various treatment methods for MSS-type CRC in middle- aged and elderly people to provide a reference basis in clinical practice.

GSTM1 and GSTP1 Polymorphisms Affect Outcome in Colorectal Adenocarcinoma.

Background and Objectives: Despite improvements in screening programs, a large number of patients with colorectal cancer (CRC) are diagnosed in an advanced disease stage. Previous investigations imply that glutathione transferases (GSTs) might be associated with the development and progression of CRC. Moreover, the detoxification mechanism of oxaliplatin, which represents the first line of treatment for advanced CRC, is mediated via certain GSTs. The aim of this study was to evaluate the significance of certain GST genetic variants on CRC prognosis and the efficacy of oxaliplatin-based treatment. Materials and Methods: This prospective study included 523 patients diagnosed with CRC in the period between 2014 and 2016, at the Digestive Surgery Clinic, University Clinical Center of Serbia, Belgrade. Patients were followed for a median of 43.47 ± 17.01 months (minimum 1-63 months). Additionally, 109 patients with advanced disease, after surgical treatment, received FOLFOX6 treatment as a first-line therapy between 2014 and 2020. The Kaplan-Meier method was used to analyze cumulative survival, and the Cox proportional hazard regression model was used to study the effects of different GST genotypes on overall survival. Results: Individuals with the GSTM1-null genotype and the GSTP1 IleVal+ValVal (variant) genotype had significantly shorter survival when compared to referent genotypes (GSTM1-active and GSTP1 IleIle) (log-rank: p = 0.001). Moreover, individuals with the GSTM1-null genotype who received 5-FU-based treatment had statistically significantly shorter survival when compared to individuals with the GSTM1-active genotype (log-rank: p = 0.05). Conclusions: Both GSTM1-null and GSTP1 IleVal+ValVal (variant) genotypes are associated with significantly shorter survival in CRC patients. What is more, the GSTM1-null genotype is associated with shorter survival in patients receiving FOLOFOX6 treatment.

Sulforaphane Inhibits IL-1β-Induced IL-6 by Suppressing ROS Production, AP-1, and STAT3 in Colorectal Cancer HT-29 Cells.

Colorectal cancer (CRC) stands as a major cause of cancer-related mortality globally, accounting for approximately 881,000 deaths each year. Traditional approaches such as chemotherapy and surgery have been the primary treatment modalities, yet the outcomes for patients with metastatic CRC are often unsatisfactory. Recent research has focused on targeting the pathways involved in oxidative stress, inflammation, and metastasis to enhance the survival of CRC patients. Within this context, sulforaphane (SFN), a notable phytochemical found predominantly in cruciferous vegetables, has been recognized as a potential anticancer agent. However, the specific mechanisms through which SFN may exert its chemopreventive effects in CRC remain unclear. This study explores the impact of SFN on IL-1β-induced IL-6 activation and MAPK and AP-1 signaling in HT-29 cells. Our findings reveal that SFN treatment not only diminishes IL-1β-stimulated IL-6 expression but also reduces oxidative stress by curtailing reactive oxygen species (ROS) production. Furthermore, it hinders the proliferation and invasiveness of HT-29 cells through the modulation of MAPK/AP-1 and STAT3 signaling pathways. These results indicate that SFN mitigates IL-1β-induced IL-6 expression in CRC cells by attenuating ROS production and disrupting MAPK/AP-1 signaling. This suggests that SFN holds significant potential as a chemotherapeutic agent for both treating and preventing CRC.

Abstract 7496: The piritramide-based perioperative analgesia can affect the cancer dissemination in colorectal cancer patients

Abstract Introduction: Colorectal cancer (CRC) stands as a prominent contributor to global cancer-related mortality. Post-surgical management of CRC patients often involves the administration of opioid analgesics. These analgesics operate through opioid and cannabinoid receptors, pathways implicated in tumor progression and metastasis, potentially impacting patient survival adversely. This investigation delves into the influence of piritramide and morphine on cancer dissemination, encompassing in vitro and in vivo assessments, cytotoxicity analyses, and elucidation of their mode of action. Methods: The presence of circulating tumor cells (CTCs) in the blood of 131 CRC patients was quantitatively assessed using the real-time polymerase chain reaction (qPCR) method. Cytotoxic effects of morphine and piritramide were evaluated via colony-forming assays (CFA) utilizing HCT116 and HT29 cell lines. The impact of piritramide and morphine on opioid receptor activity was gauged through transfected reporter cell lines and fluorescence imaging plater reader (FLIPR) calcium assays. In vivo models involving subcutaneous and intrasplenic administration in SCID and BALB mice, respectively, utilizing HCT116 and HT29 cell lines, were conducted. Morphological profiling, employing the cell painting assay, facilitated high-content image-based analysis on both cell lines. Results: Perioperative analgesia with piritramide exhibited a tendency towards longer time to recurrence (TTR) survival in CRC patients (HR=1.8, p=0.104). Conversely, morphine-treated patients demonstrated a twofold increase in TTR events (HR=4.7, p=0.011). Piritramide, but not morphine, significantly inhibited colony growth in HCT116 and HT-29 cell lines in the CFA, consistent with cytotoxicity test results. Functional assays revealed agonistic effects of both piritramide and morphine on opioid receptor kappa 1 (OPRK1) and mu 1 (OPRM1), with piritramide exhibiting greater potency as an OPRK1 agonist. In the SCID mice model, subcutaneous application of HT29 cell lines resulted in significantly reduced tumor growth in piritramide-treated mice. In the intrasplenic model utilizing BALB mice, mice treated with piritramide exhibited diminished tumor growth and a reduction in both the number and size of metastases. Comparative analysis with reference compounds revealed a distinct phenotypic profile of piritramide affecting the endoplasmic reticulum. Conclusion: Piritramide, as opposed to morphine, demonstrated cytotoxic effects on both in vitro and in vivo CRC cell lines, resulting in reduced tumor growth and dissemination. Perioperative analgesia with piritramide exhibited potential in improving time to recurrence survival in CRC patients. Acknowledgement: This study received support from the European Union - Next Generation EU (LX22NPO5102) and Palacky University Olomouc (LF 2023_006). Citation Format: Josef Srovnal, Emil Berta, Monika Vidlarova, Alona Rehulkova, Katerina Jecmenova, Miroslav Popper, Alzbeta Srovnalova, Petr Prasil, Pavel Skalicky, Tomas Gabrhelik, Jan Maca, Pavel Michalek, Marian Hajduch. The piritramide-based perioperative analgesia can affect the cancer dissemination in colorectal cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7496.

Overexpression of circular RNA hsa_circ_0008621 facilitates colorectal cancer progression and predicts poor prognosis.

To evaluate the potential role of serum and tissue hsa_circ_0008621 as a prognostic biomarker for CRC patients. Focused on the functional role of hsa_circ_0008621 in colorectal cancer (CRC). Serum and tissue hsa_circ_0008621 expression were quantified by qRT-PCR in 157 CRC patients, as well as 100 serums from healthy controls. Serum and tissue hsa_circ_0008621 expression was evaluated for their prognostic role in CRC patients using Kaplan-Meier curves and Multivariate Cox proportional hazards analysis. To further characterize the biological role of hsa_circ_0008621 expression in CRC, invitro hsa_circ_0008621 inhibition was performed and the effects on cellular growth, migration, invasion, apoptosis, and glycolysis were explored. Next, the downstream molecules for hsa_circ_0008621 were predicted. Hsa_circ_0008621 expression was significantly upregulated in CRC tissues and serums. Serum hsa_circ_0008621 levels were significantly up-regulated in advanced-staged samples. High serum hsa_circ_0008621 expression was associated with shorter overall survival and recurrence-free survival in CRC patients. Multivariate Cox regression analysis identified a high level of serum hsa_circ_0008621 expression as an independent prognostic factor with respect to overall survival and recurrence-free survival. Loss of function assays for hsa_circ_0008621 invitro led to a significant decrease in cell proliferation, migration, invasion, and glycolysis, but an increase in cell apoptosis. Hsa_circ_0008621 can sponge miR-532-5p, which targets SLC16A3. High level of serum hsa_circ_0008621 is associated with poor survival in CRC and promotes CRC progression, suggesting it to be a promising non-invasive prognostic biomarker and novel therapeutic target in CRC patients.

Abstract 6430: Gene expression signature quantifies the cellular contribution of the tumor vs. the microenvironment in determining colorectal cancer prognosis and therapeutic outcome

Abstract Accumulating evidence has suggested that cancer progression and therapeutic response may depend on not only tumor cells but also their tumor microenvironment (TME). However, their contributory roles are complex and not well understood. Here we report an analysis of 2373 human colorectal cancer (CRC) tumors representing all stages, leading to identification of a 20-gene signature capable of quantifying the cellular contribution of the tumor vs. the TME in determining colorectal cancer prognosis and therapeutic outcome. We classified these tumors into the consensus molecular subtypes (CMS1-4) with distinct, variable TME cellular features defined by CIBERSORT deconvolution analysis of bulk gene expression data. Surprisingly, all the 10 positive signature genes (portending worse survival) were strongly correlated with the TME-rich CMS1 and CMS4 tumors. By contrast, all the 10 negative signature genes (portending better survival) were highly related to the TME-poor CMS2 and CMS3 tumors. A single cell expression analysis from an independent database further revealed that strikingly, all the 10 positive genes were principally expressed by the immune/stromal TME whereas all the 10 negative genes were predominantly expressed in epithelial tumor cells. These data suggest that the TME has an equally important role as do tumor cells in determining CRC prognosis and support targeting the TME to improve survival. Moreover, distinct gene expression from tumor cells versus the TME also showed a differential impact on therapeutic outcome. Retrospective analyses on two independent clinical trial datasets show that the 20-gene signature score significantly predicted progression free survival in metastatic CRC patients treated with cetuximab, an FDA-approved EGFR inhibitor therapy. These data suggest a potential for the 20-gene signature as a predictive biomarker to identify “sensitive” versus “resistant” subpopulations of CRC patients to improve outcome of EGFR-targeted therapy. Citation Format: Mingli Yang, Timothy J. Yeatman, Michael V. Nebozhyn, Michael J. Schell, Lance Pflieger, Andrey Loboda, Warren J. Pledger, Ramani Soundararajan, Michelle Maurin, Heiman Wang, Jetsen Rodriguez Silva, Ashley Alden. Gene expression signature quantifies the cellular contribution of the tumor vs. the microenvironment in determining colorectal cancer prognosis and therapeutic outcome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6430.

Prognosis Analysis of Additional Surgical Treatment for High-Risk T1 Colorectal Cancer Patients After Endoscopic Resection

To analyze the effect of additional surgery on the survival and prognosis of high-risk T1 colorectal cancer patients who have undergone endoscopic resection. The clinical data of patients with high-risk T1 colorectal cancer were retrospectively collected. The patients were divided into the endoscopic resection (ER) plus additional surgical resection (SR) group, or the ER+SR group, and the ER group according to whether additional SR were performed after ER. Baseline data of the patients and information on the location, size, and postoperative pathology of the lesions were collected. Patient survival-related information was obtained through the medical record system and patient follow-up. The primary outcome indicators were the overall survival and the colorectal cancer-specific survival. Univariate Cox regression analysis was used to screen survival-related risk factors and hazard ratio (HR) was calculated. Multivariate Cox regression analysis was used to analyze the independent influencing factors. The data of 109 patients with T1 high-risk colorectal cancer were collected, with 52 patients in the ER group and 57 patients in the ER+SR group. The mean age of patients in the ER group was higher than that in the ER+SR group (65.21 years old vs. 60.54 years old, P=0.035), and the median endoscopic measurement of the size of lesions in the ER group was slightly lower than that in the ER+SR group (2.00 cm vs. 2.50 cm, P=0.026). The median follow-up time was 30.00 months, with the maximum follow-up time being 119 months, in the ER+SR group and there were 4 patients deaths, including one colorectal cancer-related death. Whereas the median follow-up time in the ER group was 28.50 months, with the maximum follow-up time being 78.00 months, and there were 4 patient deaths, including one caused by colorectal cancer. The overall 5-year cumulative survival rates in the ER+SR group and the ER group were 94.44% and 81.65%, respectively, and the cancer-specific 5-year cumulative survival rates in the ER+SR group and the ER group were 97.18% and 98.06%, respectively. The Kaplan-Meier analysis showed no significant difference in the overall cumulative survival or cancer-specific cumulative survival between the ER+SR and the ER groups. Univariate Cox regression analysis showed that age and the number of reviews were the risk factors of overall survival (HR=1.16 and HR=0.27, respectively), with age identified as an independent risk factor of overall survival in the multivariate Cox regression analysis (HR=1.10, P=0.045). For T1 colorectal cancer patients with high risk factors after ER, factors such as patient age and their personal treatment decisions should not be overlooked. In clinical practice, additional caution should be exercised in decision-making concerning additional surgery.

Relationship Between Tim-3 and Galectin-9 Expression Levels, Clinical Pathological Characteristics, and Prognosis in Patients After Radical Resection of Colorectal Cancer

Some colorectal cancer patients still face high recurrence rates and poor prognoses even after they have undergone the surgical treatment of radical resection. Identifying potential biochemical markers and therapeutic targets for the prognostic evaluation of patients undergoing radical resection of colorectal cancer is crucial for improving their clinical outcomes. Recently, it has been reported that the T cell immunoglobulin and mucin domain protein 3 (Tim-3) and its ligand galactose lectin 9 (galectin-9) play crucial roles in immune dysfunction caused by various tumors, such as colorectal cancer. However, their expressions, biological functions, and prognostic value in colorectal cancer are still unclear. This study aims to investigate the relationship between Tim-3 and galectin-9 expression levels and the clinicopathological characteristics and prognosis of patients undergoing radical resection of colorectal cancer. A total of 171 patients who underwent radical resection of colorectal cancer at Chengdu Fifth People's Hospital between February 2018 and March 2019 were selected. Immunohistochemistry was performed to assess the expression levels of Tim-3 and galectin-9 in the cancer tissue samples and the paracancerous tissue samples of the patients. The relationship between Tim-3 and galectin-9 expression levels and the baseline clinical parameters of the patients was analyzed accordingly. Kaplan-Meier analysis was performed to assess the association between Tim-3 and galectin-9 expression levels and the relapse-free survival (RFS) and the overall survival (OS) of colorectal cancer patients. Cox regression analysis was conducted to identify factors associated with adverse prognosis in the patients. The immunohistochemical results showed that the high expression levels of Tim-3 and galectin-9 were observed in 70.18% (120/171) and 32.16% (55/171), respectively, of the colorectal cancer tissues, whereas the low expression levels were 29.82% (51/171) and 67.84% (116/171), respectively. Furthermore, the expression score of Tim-3 was significantly higher in colorectal cancer tissues than that in the paracancerous tissues, while the expression score of galectin-9 was lower than that in the paracancerous tissues (P<0.05). Further analysis revealed that the expression of Tim-3 and galectin-9 was associated with the depth of tumor infiltration, vascular infiltration, and clinical staging (P<0.05). During the follow-up period of 14-63 months, 7 out of 171 patients were lost to follow-up. Among the remaining patients, 49 and 112 cases presented abnormally low expression of Tim-3 and galectin-9, respectively, whereas 115 and 52 cases presented high expression of Tim-3 and galectin-9, respectively. Kaplan-Meier survival analysis demonstrated that patients with high Tim-3 expression in colorectal cancer tissues had significantly lower RFS and OS than those with low expression did (RFS: log-rank=22.66, P<0.001; OS: log-rank=19.71, P<0.001). Conversely, patients with low galectin-9 expression had significantly lower RFS and OS than those with high expression did (RFS: log-rank=19.45, P<0.001; OS: log-rank=22.24, P<0.001). Cox multivariate analysis indicated that TNM stage Ⅲ (HR=2.26, 95% CI: 1.20-5.68), high expression of Tim-3 (HR=0.80, 95% CI: 0.33-0.91), and low expression of galectin-9 (HR=1.80, 95% CI: 1.33-4.70) were independent risk factors affecting RFS and OS in patients (P<0.05). Aberrant expression of Tim-3 and galectin-9 is observed in colorectal cancer tissues. High expression of Tim-3 and low expression of galectin-9 are closely associated with adverse clinico-pathological characteristics and prognosis. They are identified as independent influencing factors that may trigger adverse prognostic events in patients. These findings suggest that Tim-3 and galectin-9 have potential as new therapeutic targets and clinical indicators.

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

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

DR6 Augments Colorectal Cancer Cell Growth, Invasion, and Stemness by Activating AKT/NF-κB Pathway.

This study aims to elucidate the role and mechanisms of Death Receptor 6 (DR6), a member of the tumor necrosis factor receptor superfamily, in the malignant progression of colorectal cancer (CRC). The association of DR6 expression levels and CRC patient survival was examined using the CRC cohort data from GEPIA database. The functional role of DR6 in CRC cells was investigated by performing loss-of-function and gain-of-function experiments based on CCK-8 proliferation assay, transwell migration and invasion assay, and sphere-forming assays. Xenograft model of CRC cells in nude mouse was established to evaluate the impact of DR6 knockdown on CRC tumorigenesis. Elevated expression of DR6 was correlated with an unfavorable prognosis in CRC patients. In vitro functional assays demonstrated that silencing DR6 considerably suppressed the proliferation, migration, invasion, and stemness of CRC cells, whereas its overexpression showed an opposite effect. DR6 knockdown also attenuated tumor formation of CRC cells in the nude mice. Mechanistically, silencing DR6 reduced the phosphorylation of AKT and NF-κB in CRC cells, and the treatment with an AKT activator (SC79) abrogated the inhibitory effects of DR6 knockdown on the malignant features of CRC cells. Our data suggest that DR6 contributes to the malignant progression of CRC by activating AKT/NF-κB pathway, indicating its clinical potential as a prognostic marker and therapeutic target for CRC.

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

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

EVA1A, a novel and promising prognostic biomarker in colorectal cancer.

The purpose of this study was to investigate the potential of EVA1A as a prognostic biomarker for Colorectal cancer (CRC). The study utilized public databases to analyze the difference in Evala mRNA expression between CRC tumor tissues and adjacent normal tissues. Additionallymunohistochemical staining was performed on 90 paired tissue samples to detect EVA1A expression. The relationship between EVA1A and clinicopathological features was examined, and a Kaplan-Meier survival analysis was conducted. Univariate and multivariate Cox analyses were employed to identify prognostic factors affecting the overall survival (OS) of CRC patients. The analysis revealed a significant increase in Evala mRNA expression in CRC tumor cells compared to normal controls from public databases (P< 0.05). Immunohistochemical staining further confirmed a significant upregulation of EVA1A expression in CRC tissues (P< 0.05). High EVA1A expression was associated with age, pathological M stage, total tumor stage, and Carbohydrate antigen CA19-9 (CA19-9). Kaplan-Meier analysis demonstrated a significant association between high EVA1A expression and poor OS. Univariate and multivariate analysis identified EVA1A as an independent risk factor for CRC prognosis. The study suggests that EVA1A is increased in CRC tumor tissues and may serve as a potential biomarker for poor prognosis in CRC.

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

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

Identification and validation of a novel six-gene signature based on mucinous adenocarcinoma-related gene molecular typing in colorectal cancer

Background and objectivesColorectal mucinous adenocarcinoma (MAC) is a particular pathological type that has yet to be thoroughly studied. This study aims to investigate the characteristics of colorectal MAC-related genes in colorectal cancer (CRC), explore the role of MAC-related genes in accurately classifying CRC, and further construct a prognostic signature.MethodsCRC samples were collected from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). MAC-related differentially expressed genes (DEGs) were analyzed in TCGA samples. Based on colorectal MAC-related genes, TCGA CRC samples were molecularly typed by the non-negative matrix factorization (NMF). According to the molecular subtype characteristics, the RiskScore signature was constructed through univariate Cox, the least absolute shrinkage and selection operator (LASSO), and multivariate Cox regression analyses. Clinical significance in CRC of the RiskScore signature was analyzed. A nomogram was further built based on the RiskScore signature.ResultsFrom the colorectal MAC-related genes, three distinct molecular subtypes were identified. A RiskScore signature composed of six CRC subtype-related genes (CALB1, MMP1, HOXC6, ZIC2, SFTA2, and HYAL1) was constructed. Patients with high-RiskScores had the worse prognoses. RiskScores led to differences in gene mutation characteristics, antitumor drug sensitivity, and tumor microenvironment of CRC. A nomogram based on the signature was developed to predict the one-, three-, and five-year survival of CRC patients.ConclusionMAC-related genes were able to classify CRC. A RiskScore signature based on the colorectal MAC-related molecular subtype was constructed, which had important clinical significance for guiding the accurate stratification of CRC patients.

Non-coding RNAs as Biomarkers for Survival in Colorectal Cancer Patients.

Colorectal cancer (CRC) has a high incidence and fatality rate worldwide. It ranks second concerning death worldwide. Cancer patients are diagnosed with the disease at a later stage due to the absence of early diagnostic methods, which leads to increased death. With the help of recent advancements in the fields of diagnosis and therapy, the development of novel methods using new targets could be helpful for the long-term survival of CRC patients when CRC is detected early. However, the prognosis for the advanced stage of CRC is abysmal. New biomarkers are emerging as promising alternatives since they can be utilized for early detection of CRC, are simple to use, and non-invasive. Non-coding RNAs (ncRNAs) have been seen to have an aberrant expression in the development of many malignancies, including CRC. In the past two decades, much research has been done on non-coding RNAs, which may be valuable as biomarkers and targets for antitumor therapy. Non-coding RNAs can be employed in detecting and treating CRC. Non-coding RNAs play an essential role in regulating gene expression. This article reviews ncRNAs and their expression levels in CRC patients that could be used as potential biomarkers. Various ncRNAs have been associated with CRC, such as microRNAs, long non-coding RNAs, circular RNAs, etc. The expression of these non-coding RNAs may provide insights into the stages of cancer and the prognosis of cancer patients and therefore proper precautionary measures can be taken to decrease cancer-related deaths.

PPP2R1B abolishes colorectal cancer liver metastasis and sensitizes Oxaliplatin by inhibiting MAPK/ERK signaling pathway

BackgroundPatients with colorectal cancer (CRC) with liver metastasis or drug resistance have a poor prognosis. Previous research has demonstrated that PPP2R1B inactivation results in the development of CRC. However, the role of PPP2R1B in CRC metastasis and drug resistance is unclear.MethodsVenny 2.1 was used to determine the intersection between survival-related differentially expressed genes (DEGs) and liver metastasis-related DEGs according to RNA-seq data from The Cancer Genome Atlas (TCGA) and the GEO database (GSE179979). LC‒MS/MS and coimmunoprecipitation were performed to predict and verify the substrate protein of PPP2R1B. Gene Set Variation Analysis (GSVA) was subsequently utilized to assess pathway enrichment levels. The predictive performance of PPP2R1B was assessed by regression analysis, Kaplan–Meier (KM) survival analysis and drug sensitivity analysis. Immunohistochemistry (IHC), qRT-PCR and western blotting were performed to measure the expression levels of related mRNAs or proteins. Biological features were evaluated by wound healing, cell migration and invasion assays and CCK-8 assays. A mouse spleen infection liver metastasis model was generated to confirm the role of PPP2R1B in the progression of liver metastasis in vivo.ResultsAccording to bioinformatics analysis, PPP2R1B is significantly associated with liver metastasis and survival in CRC patients, and these findings were further verified via immunohistochemistry (IHC), qPCR and Western blotting. Pathway enrichment and LC‒MS/MS analysis revealed that PPP2R1B is negatively associated with the MAPK/ERK signalling pathway. Additionally, PD98059, a MAPK/ERK pathway inhibitor, inhibited EMT in vitro by reversing the changes in key proteins involved in EMT signalling (ZEB1, E-cadherin and Snail) and ERK/MAPK signalling (p-ERK) mediated by PPP2R1B. Oxaliplatin sensitivity prediction and validation revealed that PPP2R1B silencing decreased Oxaliplatin chemosensitivity, and these effects were reversed by PD98059 treatment. Moreover, PPP2R1B was coimmunoprecipitated with p-ERK in vitro. A negative correlation between PPP2R1B and p-ERK expression was also observed in clinical CRC samples, and the low PPP2R1B/high p-ERK coexpression pattern indicated a poor prognosis in CRC patients. In vivo, PPP2R1B silencing significantly promoted liver metastasis.ConclusionsThis study revealed that PPP2R1B induces dephosphorylation of the p-ERK protein, inhibits liver metastasis and increases Oxaliplatin sensitivity in CRC patients and could be a potential candidate for therapeutic application in CRC.

Efficacy and Safety of Maintenance Therapy Using Cetuximab in Patients with Metastatic Colorectal Cancer: Retrospective Study.

Cetuximab (CET) combined with chemotherapy significantly improved the survival in RAS and RAF wild-type metastatic colorectal cancer (mCRC) patients, while clinical evidence was lacking on the use of maintenance therapy (MT). The study aimed to explore the role of maintenance therapy following Cetuximab + chemotherapy and the optimal Cetuximab-based maintenance therapy regimen. We retrospectively reviewed data on the efficacy and safety of CET-based MT in patients with mCRC who achieved diseasecontrolafter induction therapy. Eighty-one patients with mCRC who achieved disease control after CET + chemotherapy induction were enrolled. Overall median progression-free survival (PFS) was 10.5 (95% CI = 8.8-12.2) months and median maintenance/observation PFS (mnPFS) was 6.0 (95% CI = 5.0-7.0) months. Among these 81 patients, 61 patients were prescribed MT (CET alone for 21 patients and CET + chemotherapy for 40 patients). Median PFS and mnPFS in the MT group were significantly longer than those for the non-MT group. Different MT regimens did not affect PFS and mnPFS significantly. Univariate and multivariate analysis demonstrated MT, complete response/partial response during induction therapy, and absence of peritoneal metastasis to be positively associated with longer PFS and mnPFS. Treatment-related adverse events (AEs) were tolerable during MT, and AE-related deaths were not observed. MT with CET or CET + chemotherapy was an appropriate option following initial induction chemotherapy for patients with RAS and RAF wild-type mCRC. This strategy endowed survival benefits and a tolerable safety profile.