Prognosis Of Colon Adenocarcinoma Research Articles

High MICAL-L2 expression and its role in the prognosis of colon adenocarcinoma

BackgroundMICAL-like protein 2 (MICAL-L2), a member of the molecules interacting with CasL (MICAL) family of proteins, is strongly associated with the malignancy of multiple types of cancer. However, the role of MICAL-L2 in colon adenocarcinoma (COAD) has not been well characterized.MethodsIn this study, we analyzed the role of MICAL-L2 in COAD using datasets available from public databases. The mRNA and protein expression of MICAL-L2 was investigated using TCGA, UALCAN, and independent immunohistochemical assays. Overall survival (OS) and disease-specific survival (DSS) of COAD patients were assessed based on the MICAL-L2 expression level using the Kaplan–Meier method. Univariate and multivariate analysis was employed to determine whether MICAL-L2 could serve as an independent prognostic indicator of OS. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and gene set enrichment analysis (GSEA) were further utilized to explore the possible cellular mechanism underlying the role of MICAL-L2 in COAD. In addition, the correlation between MICAL-L2 expression and immune cell infiltration levels was investigated via single-sample gene set enrichment analysis (ssGSEA).ResultsData from TCGA, HPA, and UALCAN datasets indicated that MICAL-L2 expression was significantly higher in COAD tissue than in adjacent normal tissues, and this was confirmed by immunohistochemical assays. Kaplan–Meier survival analysis revealed that patients with MICAL-L2 had shorter OS and DSS. Furthermore, multivariate Cox analysis indicated that MICAL-L2 was an independent risk factor for OS in COAD patients. ROC analysis confirmed the diagnostic value of MICAL-L2, and a prognostic nomogram involving age, M stage, and MICAL-L2 expression was constructed for OS. Functional enrichment analyses revealed that transport-related activity was closely associated with the role of MICAL-L2 in COAD. Regarding immune infiltration levels, MICAL-L2 was found to be positively associated with CD56bright NK cells.ConclusionsOur results suggested that MICAL-L2 is a promising biomarker for determining prognosis and correlated with immune infiltration levels in COAD.

Exploration of Potential Roles of m5C-Related Regulators in Colon Adenocarcinoma Prognosis.

Objectives: The purpose of this study was to investigate the role of 13 m5C-related regulators in colon adenocarcinoma (COAD) and determine their prognostic value. Methods: Gene expression and clinicopathological data were obtained from The Cancer Genome Atlas (TCGA) datasets. The expression of m5C-related regulators was analyzed with clinicopathological characteristics and alterations within m5C-related regulators. Subsequently, different subtypes of patients with COAD were identified. Then, the prognostic value of m5C-related regulators in COAD was confirmed via univariate Cox regression and least absolute shrinkage and selection operator (LASSO) Cox regression analyses. The prognostic value of risk scores was evaluated using the Kaplan-Meier method, receiver operating characteristic (ROC) curve. The correlation between the two m5C-related regulators, risk score, and clinicopathological characteristics were explored. Additionally, Gene Set Enrichment Analysis (GSEA), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, and Gene Ontology (GO) analysis were performed for biological functional analysis. Finally, the expression level of two m5C-related regulators in clinical samples and cell lines was detected by quantitative reverse transcription-polymerase chain reaction and through the Human Protein Atlas database. Results: m5C-related regulators were found to be differentially expressed in COAD with different clinicopathological features. We observed a high alteration frequency in these genes, which were significantly correlated with their mRNA expression levels. Two clusters with different prognostic features were identified. Based on two independent prognostic m5C-related regulators (NSUN6 and ALYREF), a risk signature with good predictive significance was constructed. Univariate and multivariate Cox regression analyses suggested that the risk score was an independent prognostic factor. Furthermore, this risk signature could serve as a prognostic indicator for overall survival in subgroups of patients with different clinical characteristics. Biological processes and pathways associated with cancer, immune response, and RNA processing were identified. Conclusion: We revealed the genetic signatures and prognostic values of m5C-related regulators in COAD. Together, this has improved our understanding of m5C RNA modification and provided novel insights to identify predictive biomarkers and develop molecular targeted therapy for COAD.

Aberrant expression of WNK lysine deficient protein kinase 1 is associated with poor prognosis of colon adenocarcinoma.

WNK1 (WNK lysine deficient protein kinase 1) is a kind of protein kinase and participates in angiogenesis, having a potent tumor promoting role. WNK1 is ubiquitously expressed, and its upregulated expression has been reported in several tumor types. Here, we aimed to investigate the correlation between WNK1 expression and colon adenocarcinoma (COAD) progression. In the current study, WNK1 expression was evaluated by immunohistochemically in adjacent normal colonic mucosae and primary adenocarcinomas. The effect of WNK1 on overall survival (OS) and its associations with the clinicopathological parameters were analyzed in a retrospective cohort of COAD patients (n = 185). The tumor-related effects of WNK1 in COAD were further tested via cellular and mice experiments. According to our cohort, higher WNK1 expression was significantly associated with unfavorable prognostic factors, such as high pT stage, pN stage, as well as shorter OS. Moreover, WNK1 exhibited tumor promoting role in COAD cancer cell lines as well as in nude mice. Silencing WNK1 can significantly inhibit the proliferation of COAD both in vitro and in vivo. In all, WNK1 acts as a tumor promoter and may be used as a COAD prognostic biomarker.

5mC-Related lncRNAs as Potential Prognostic Biomarkers in Colon Adenocarcinoma.

Simple SummaryTo identify the prognostic significance of 5mC-related lncRNAs in colon adenocarcinoma (COAD), we examined the expression levels and mutations of 21 5mC-regulated genes of COAD in TCGA. We also identified lncRNAs associated with 5mC regulatory genes using Pearson correlation analysis. After the least absolute shrinkage and selection operator (Lasso) Cox regression, the risk signature of 4 5mC-related lncRNAs was selected. Next, the risk signature’s predictive efficacy was proven. Moreover, the biological mechanism and potential immunotherapeutic response of this risk signature were identified. Collectively, we constructed the 5mC-related lncRNA risk signature, which could provide a novel prognostic prediction of COAD patients.Globally, colon adenocarcinoma (COAD) is one of the most frequent types of malignant tumors. About 40~50% of patients with advanced colon adenocarcinoma die from recurrence and metastasis. Long non-coding RNAs (lncRNAs) and 5-methylcytosine (5mC) regulatory genes have been demonstrated to involve in the progression and prognosis of COAD. The goal of this study was to explore the biological characteristics and potential predictive value of 5mC-related lncRNA signature in COAD. In this research, The Cancer Genome Atlas (TCGA) was utilized to obtain the expression of genes and somatic mutations in COAD, and Pearson correlation analysis was used to select lncRNAs involved in 5mC-regulated genes. Furthermore, we applied univariate Cox regression and Lasso Cox regression to construct 5mC-related lncRNA signature. Then Kaplan–Meier survival analysis, principal components analysis (PCA), receiver operating characteristic (ROC) curve, and a nomogram were performed to estimate the prognostic effect of the risk signature. GSEA was utilized to predict downstream access of the risk signature. Finally, the immune characteristics and immunotherapeutic signatures targeting this risk signature were analyzed. In the results, we obtained 1652 5mC-related lncRNAs by Pearson correlation analysis in the TCGA database. Next, we selected a risk signature that comprised 4 5mC-related lncRNAs by univariate and Lasso Cox regression. The prognostic value of the risk signature was proven. Finally, the biological mechanism and potential immunotherapeutic response of the risk signature were identified. Collectively, we constructed the 5mC-related lncRNA risk signature, which could provide a novel prognostic prediction of COAD patients.

SSR4 as a prognostic biomarker and related with immune infiltration cells in colon adenocarcinoma

Background Signal sequence receptor subunit delta (SSR4) gene is reported to encode the translocon-associated protein δ, and related with the human immune regulation. However, the expression of SSR4 in colon adenocarcinoma (COAD) and its correlation with clinical treatment remains unclear. Research design and methods SSR4 mRNA expression level and its relationship with tumor infiltrating lymphocytes (TILs) in COAD were evaluated through several databases. Furthermore, the study collected 238 cases of COAD tissue samples to detect the association of SSR4 protein expression level in TILs with clinical pathological information, and the prognosis of COAD. Results SSR4 mRNA was significantly high expressed in COAD tissues, and significantly correlated with several types of TILs in COAD. Moreover, SSR4 highly expressed in many types of TILs, especially highly expressed in plasma cell from COAD patients with advanced TNM stage. High SSR4 protein expression in TILs was associated with lymph node metastasis, distant metastasis, American Joint Committee on Cancer (AJCC) staging, and Response Evaluation Criteria in Solid Tumors (RECIST) efficacy. COAD patients with high SSR4 expression in TILs had better overall survival. Conclusions In conclusion, high SSR4 mRNA and protein expression in TILs can be used as a prognostic biomarker for predicting better overall survival and treatment efficacy in COAD patients.

Down-regulated C4orf19 confers poor prognosis in colon adenocarcinoma identified by gene co-expression network.

Colon adenocarcinoma (COAD) is the most common histologic subtype of colorectal cancer (CRC), and its prognosis is poor. Unlike traditional research in molecular biology, which is limited to analyzing the function of a single gene or protein in malignant tumors. The Weighted gene correlation network analysis (WGCNA) technique is used to describe the gene association model among different samples in order to identify highly collaborative genes. In this study, a computational strategy was used to conduct a systematic study of prognosis-related genes (PRGs) of COAD from the TCGA database. PRGs were subsequently used for WGCNA, which included 379 COAD patient expression profiles and 39 controls. As a consequence, nine gene modules were built. Among these, the brown module had not only a negative relationship with COAD, but also simultaneously in inverse relationship with the clinical stage, stage T, stage M and stage N. C4orf19, which was identified as one of the DEG and hub genes in the brown module by calculating modular connectivity, has a negative correlation with the clinical stage and TMN stage. In addition, the downward-regulated C4orf19 protein was detected in COAD clinical specimens. Finally, in vitro experiments have confirmed that regulated C4orf19 can promote COAD cell proliferation, invasion and migration, and the biological mechanism of C4orf19 perhaps by influencing the nitrogen metabolic pathway.

The expression of LRRN4 was correlated with the progression and prognosis of colon adenocarcinoma (COAD) patients.

Our present study aims to investigate the value of LRRN4 in the progression and prognosis of COAD patients. All COAD and adjacent sample data was downloaded from TCGA database. Survival analysis was performed according to Kaplan-Meier method. The real-time quantitative PCR and immunohistochemistry analysis were conducted for validation in cell lines and tissues. The GSEA was conducted to find functional KEGG pathways. Multivariate Cox regression proportional hazard mode was used to determine whether LRRN4 expression was an independent prognostic factor. The LRRN4 expression in COAD samples were significantly higher than that in adjacent samples, which was consistent with our experiments in cell lines and tissues. Along with the increase of TNM Stage, LRRN4 expression had an increasing tendency. The COAD patients with high LRRN4 expression showed undesirable prognoses. Additionally, the TGF-β signaling pathway, WNT signaling pathway and other 25 pathways were significantly activated in the high LRRN4 expression group. In conclusion, high LRRN4 expression was closely related to the onset of COAD and it was a poor prognostic factor for COAD patients.

Significance of long non-coding RNA IFNG-AS1 in the progression and clinical prognosis in colon adenocarcinoma

ABSTRACT Colon adenocarcinoma originates from adenoma and triggers serious healthy burdensome. lncRNAs develop a crucial role in the progression of colorectal carcinoma. In this study, we aimed to investigate the clinical value and potential role of lncRNA interferon (IFN) gamma antisense RNA 1 (IFNG-AS1) in colon adenocarcinoma. This study enrolled 95 colorectal adenoma patients, 128 colorectal adenocarcinoma patients, and 88 healthy individuals. The serum, tissue IFNG-AS1 expression levels were explored by real-time quantitative reverse transcription-PCR (RT-qPCR) assay. The receiver operator characteristic curve and Kaplan-Meier method were used to assess the clinical significance of IFNG-AS1. The chi-square test was used to analyze the association between tissue IFNG-AS1 and clinical characteristics. Functional experiments were conducted to delve into the effects of IFNG-AS1 on cellular activities (cell viability/migration/invasion). The target miRNA of IFNG-AS1 was also explored. IFNG-AS1 expression in both serum and tissue samples was elevated in patients. Serum IFNG-AS1 could diagnose colon adenoma and adenocarcinoma patients from the healthy control. High tissue IFNG-AS1 was correlated with several clinical characteristics and a shorter overall survival time. Silence of IFNG-AS1 could be available for repressing cellular capacities via the sponge to miR-627-3p. IFNG-AS1 was rised in colon adenocarcinoma and it was relevant to tumor size, TNM stage, and poor prognosis of patients. Beyond that, downregulated expression of IFNG-AS1 may repress malignant progression of colon adenocarcinoma by regulating miR-627-3p. IFNG-AS1 might be a potential diagnosis or prognosis predictor for colon adenocarcinoma patients.

Loss of ATP5A1 enhances proliferation and predicts poor prognosis of colon adenocarcinoma

BackgroundATP Synthase F1 Subunit Alpha (ATP5F1A), also named as ATP5A1, is a subunit of mitochondrial ATP synthase. Dysregulated expression of ATP5A1 has been reported in several malignancies, nevertheless it showed either oncogenic or tumor-suppressing roles in different cancer types. Here we aimed to initially investigate the expression and role of ATP5A1 in colon adenocarcinoma. MethodsWe firstly evaluated the transcription and mRNA levels of ATP5A1 using data from The Cancer Genome Atlas (TCGA). Besides, we tested its mRNA and protein expression in our enrolled retrospective cohort (n = 115). Univariate and multivariate analyzes were conducted to assess its prognostic value. Cellular experiments and xenografts in mice model were performed to validate the role of ATP5A1 in colon cancer. ResultsATP5A1 showed a significant lower level in colon adenocarcinoma than in adjacent nontumorous tissue. Advanced tumor stage was characterized with lower ATP5A1 level. Lower ATP5A1 was associated with poor prognosis in both TCGA dataset (P = 0.041) and our cohort (P = 0.001). Furthermore, Cox regression analysis demonstrated that ATP5A1 was a novel independent prognostic factor for colon cancer patients (HR=0.43, P = 0.018). Finally, cellular and xenografts data confirmed that overexpressing ATP5A1 can remarkably attenuate colon cancer growth. ConclusionLow expression of ATP5A1 may be a potential molecular marker for poor prognosis in colon cancer. Data availabilityData will be available upon request.

Prognostic implications of ferroptosis-associated gene signature in colon adenocarcinoma.

BACKGROUNDColon adenocarcinoma (COAD) is one of the most common and fatal malignant tumors, which increases the difficulty of prognostic predictions. Thus, new biomarkers for the diagnosis and prognosis of COAD should be explored. Ferroptosis is a recently identified programmed cell death process that has the characteristics of iron-dependent lipid peroxide accumulation. However, the predictive value of ferroptosis-related genes (FRGs) for COAD still needs to be further clarified. AIMTo identify some critical FRGs and construct a COAD patient prognostic signature for clinical utilization. METHODSThe Cancer Genome Atlas database (TCGA) and Gene Expression Omnibus databases were the data sources for mRNA expression and corresponding COAD patient clinical information. Differentially expressed FRGs were recognized using R and Perl software. We constructed a multi-FRG signature of the TCGA-COAD cohort by performing a univariate Cox regression and least absolute shrinkage and selection operator Cox regression analysis. COAD patients from the Gene Expression Omnibus cohort were utilized for verification. RESULTSOur research showed that most of the FRGs (85%) were differentially expressed between the corresponding adjacent normal tissues and cancer tissues in the TCGA-COAD cohort. Seven FRGs were related to overall survival (OS) in the univariate Cox analysis (all P < 0.05). A model with five FRGs (AKR1C1, AKR1C3, ALOX12, CRYAB, and FDFT1) was constructed to divide patients into high- and low-risk groups. The OS of patients in the high-risk group was significantly lower than that of the low-risk group (all P < 0.01 in the TCGA and Gene Expression Omnibus cohorts). The risk score was an independent prognosticator of OS in the multivariate Cox analysis (hazard ratio > 1, P < 0.01). The predictive capacity of the model was verified by a receiver operating characteristic curve analysis. In addition, a nomogram based on the expression of five hub FRGs and risk score can precisely predict the OS of individual COAD cancer patients. Immune correlation analysis and functional enrichment analysis results revealed that immunology-related pathways were abundant, and the immune states of the high-risk group and the low-risk group were different.CONCLUSIONIn conclusion, a novel five FRG model can be utilized for predicting prognosis in COAD. Targeting ferroptosis may be a treatment option for COAD.

Mutations Status of Chemokine Signaling Pathway Predict Prognosis of Immune Checkpoint Inhibitors in Colon Adenocarcinoma.

In recent years, tumor immunotherapy has become an important treatment program and popular research focus. However, the use of immune checkpoint inhibitors (ICI) in the treatment of colorectal cancer still has limitations due to the current markers only being able to predict the prognosis of a small number of patients. As the chemokine signaling pathway can promote the anti-tumor response of the immune system by recruiting immune cells, we explored the relationship between mutations in the chemokine signaling pathway and the prognosis of colon adenocarcinoma (COAD) patients receiving ICI treatment. To analyze the relationship between chemokine mutation status and the prognosis of patients receiving ICI treatment, clinical and mutation data, with immunotherapy, for a COAD cohort was obtained from “cbioportal.” Then, combining this with COAD cohort data from The Cancer Genome Atlas (TCGA) database, the panorama of gene mutation, immunogenicity, and difference in tumor microenvironment (TME) of chemokine pathways with different mutation statuses were analyzed. High-mut status has been proved to be a prognostic indicator of COAD patients receiving ICI treatment by Univariate and Multivariate Cox regression analysis. CIBERSORT analysis showed that the infiltration degree of M1 macrophages, neutrophils, and activated natural killer (NK) cells was higher in those with high-mut status. Immunogenicity of the high-mut group was also significantly increased, with the mutation number of tumor mutation burden (TMB), neoantigen load (NAL), DNA damage repair (DDR) pathway and microsatellite instability biomarker (MSI-H) being significantly higher. In this study, we found that the mutation state of chemokine pathways is closely associated with the prognosis of COAD patients undergoing ICI treatment. The higher number of TMB, NAL, and DDR mutations and inflammatory TME, may be the mechanism of behind a better prognosis. This discovery provides a possible idea for ICI therapy of COAD.

Identification of Transcription Factor-Related Gene Signature and Risk Score Model for Colon Adenocarcinoma.

The prognosis of colon adenocarcinoma (COAD) remains poor. However, the specific and sensitive biomarkers for diagnosis and prognosis of COAD are absent. Transcription factors (TFs) are involved in many biological processes in cells. As the molecule of the signal pathway of the terminal effectors, TFs play important roles in tumorigenesis and development. A growing body of research suggests that aberrant TFs contribute to the development of COAD, as well as to its clinicopathological features and prognosis. In consequence, a few studies have investigated the relationship between the TF-related risk model and the prognosis of COAD. Therefore, in this article, we hope to develop a prognostic risk model based on TFs to predict the prognosis of patients with COAD. The mRNA transcription data and corresponding clinical data were downloaded from TCGA and GEO. Then, 141 differentially expressed genes, validated by the GEPIA2 database, were identified by differential expression analysis between normal and tumor samples. Univariate, multivariate and Lasso Cox regression analysis were performed to identify seven prognostic genes (E2F3, ETS2, HLF, HSF4, KLF4, MEIS2, and TCF7L1). The Kaplan–Meier curve and the receiver operating characteristic curve (ROC, 1-year AUC: 0.723, 3-year AUC: 0.775, 5-year AUC: 0.786) showed that our model could be used to predict the prognosis of patients with COAD. Multivariate Cox analysis also reported that the risk model is an independent prognostic factor of COAD. The external cohort (GSE17536 and GSE39582) was used to validate our risk model, which indicated that our risk model may be a reliable predictive model for COAD patients. Finally, based on the model and the clinicopathological factors, we constructed a nomogram with a C-index of 0.802. In conclusion, we emphasize the clinical significance of TFs in COAD and construct a prognostic model of TFs, which could provide a novel and reliable model for the prognosis of COAD.

HOXC11 positively regulates the long non-coding RNA HOTAIR and is associated with poor prognosis in colon adenocarcinoma.

Colorectal cancer ranks third in terms of incidence and second in terms of mortality worldwide. The homeobox transcript antisense intergenic RNA (HOTAIR), which was found to be located on the antisense chain of the homeobox C (HOXC) gene cluster, is a long non-coding RNA involved in multiple types of tumors. The role of HOXC11 in tumors remains unclear. Reverse transcription-quantitative PCR was performed to detect the expression level of HOXC11 in colon adenocarcinoma. Cell proliferation and invasion were assessed. RNase protection assay was used to test the possibility of RNA duplex formation. The increased expression and co-expression trend of HOXC11 and HOTAIR were identified in multiple types of cancer from The Cancer Genome Atlas and the results were validated in 12 colon adenocarcinoma and paired non-tumor tissue samples. The expression of HOXC11 and HOTAIR was found to be associated with poor prognosis in colon adenocarcinoma and kidney renal clear cell carcinoma. Furthermore, HOXC11 was found to positively regulate HOTAIR by RNA duplex formation and promoted the proliferation and invasion of colon adenocarcinoma cells.

483P The correlation analysis between MUC16 mutation and immunotherapy predictive biomarkers in colon adenocarcinoma

The prognosis of colon adenocarcinoma (COAD) remains unsatisfactory, but the efficacy of immune checkpoint inhibitors (ICIs) therapy was limited. Microsatellite instability (MSI), Tumor mutation burden (TMB) and Tumor immune microenvironment (TME) of ICIs have been confirmed to be promising predictive biomarkers of ICIs in pan-cancer. The function of MUC16 gene and the correlation with ICIs therapy efficacy have not been revealed.

HOXC11 Expression Is Associated with the Progression of Colon Adenocarcinoma and Is a Prognostic Biomarker.

This study aimed to evaluate the role of HOXC11 in progression and prognosis in colon adenocarcinoma (COAD) patients. The COAD patient data were downloaded from "The Cancer Genome Atlas (TCGA)" database. The Wilcoxon rank-sum test or Kruskal-Wallis test was used to analyze the correlation between HOXC11 expression and clinicopathologic characteristics. The significance of difference in overall survival between different groups was determined by log-rank test. The HOXC11 expression was verified from mRNA and protein level by conducting real-time quantitative PCR, Western blot, and immunohistochemistry analysis. Significantly enriched Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were screened after gene set enrichment analysis. As a result, high HOXC11 expression was closely related to the occurrence of COAD based on the data in TCGA, which was then successfully validated in cell lines and clinical tissues. Enhanced HOXC11 expression was significantly associated with tumor-node-metastasis (TNM) and M stage. Prognosis of highly expressed HOXC11 COAD patients was significantly worse than those with low HOXC11 expression. GRAFT_VERSUS_HOST_DISEASE and other signaling pathways were significantly activated in high HOXC11 expression COAD patients. In conclusion, high expression of HOXC11 was closely associated with the progression of COAD, and HOXC11 was a promising prognostic biomarker in COAD patients.

Analysis of Interleukin-1 Signaling Alterations of Colon Adenocarcinoma Identified Implications for Immunotherapy.

Immune checkpoint inhibitors (ICIs) have made breakthrough progress in the treatment of various malignant tumors. However, only some patients receiving ICIs obtain long-lasting clinical effects, and some patients still do not achieve remission. Improving the treatment benefits of this part of the population has become a concern of clinicians. IL-1 signaling plays an important role in the tumor microenvironment (TME). However, the relationship between the IL-1 signaling mutation status and the prognosis of colon adenocarcinoma (COAD) patients receiving ICIs has not been reported. We downloaded the data of a COAD cohort receiving ICIs, including prognostic data and mutation data. Additionally, we downloaded the data of a COAD cohort from The Cancer Genome Atlas (TCGA) database, including clinical data, expression data and mutation data. Gene set enrichment analysis (GSEA) was used to assess differences in the activity of some key physiological pathways between the IL-1 signaling mutated-type (IL-1-MT) and IL-1 signaling wild-type (IL-1-WT) groups. The CIBERSORT algorithm was used to evaluate the contents of immune cells in the TME of COAD patients. The multivariate Cox regression model results suggested that IL-1-MT can be used as an independent predictor of a better prognosis in COAD patients receiving ICIs (P = 0.03, HR = 0.269, 95% CI: 0.082-0.883). Additionally, IL-1-MT COAD patients had significantly longer overall survival (OS) (log-rank P = 0.015). CIBERSORT analysis showed that the IL-1-MT group had high infiltration levels of activated dendritic cells (DCs), M1 macrophages, neutrophils, activated natural killer (NK) cells, activated CD4+ memory T cells and CD8+ T cells. Similarly, the IL-1-MT group had significantly upregulated immunogenicity, including in terms of the tumor mutation burden (TMB), neoantigen load (NAL) and number of mutations in DNA damage repair (DDR) signaling. GSEA showed that the IL-1-MT group was highly enriched in the immune response and proinflammatory mediators. Additionally, the expression levels of immune-related genes, immune checkpoint molecules and immune-related signatures were significantly higher in the IL-1-MT group than in the IL-1-WT group. IL-1-MT may be an independent predictor of a good prognosis in COAD patients receiving ICIs, with significantly longer OS in IL-1-MT COAD patients. Additionally, IL-1-MT was associated with significantly increased immunogenicity, activated immune cell and inflammatory mediator levels and immune response-related scores.

Nomograms to predict cancer-specific mortality in colon adenocarcinoma with different types of villous architecture.

The role of villous architecture in the prognosis of colon adenocarcinoma remains unclear. This study aimed to investigate the prognostic factors of colon adenocarcinoma with different types of villous architecture and to establish nomograms for predicting cancer-specific mortality. This retrospective study included 10,427 patients with colon adenocarcinoma arising in adenomas with villous architectures. The patients were stratified into the tubulovillous adenocarcinoma cohort and villous adenocarcinoma cohort. The prognostic risk factors, which were incorporated into nomograms for survival prediction, were determined by the log-rank test and Cox hazard models. The Harrell's Concordance Index (C-index) and calibration curve were utilized to evaluate the prediction accuracy. The pathological type of villous architecture was independently associated with the mortality of the entire population. Age, race, tumor size, T/N/M stage, and chemotherapy were independent risk factors of mortality in both cohorts. Interestingly, tumor differentiation was a prognostic factor for tubulovillous adenocarcinoma rather than villous adenocarcinoma, while the retrieved lymph node number was a prognostic factor for villous adenocarcinoma rather than tubulovillous adenocarcinoma. Survival analysis showed that the mortality rate of villous adenocarcinoma was higher than that of tubulovillous adenocarcinoma (HR 1.361, P < 0.001). We then established nomograms to predict the mortality of both cohorts and found excellent discrimination and predictive accuracy (C-index 0.842 and 0.821). Villous architecture is a determinant of colon adenocarcinoma outcomes, which might prompt reports of villous architecture in colon adenocarcinoma specimens by pathologists. Our population-based nomograms could be useful for predicting the survival of patients with colon adenocarcinoma and guiding individualized treatments.

Expression and Clinical Significance of Lactate Dehydrogenase A in Colon Adenocarcinoma

Lactate dehydrogenase A (LDHA) is an important glycolytic enzyme that promotes glycolysis and plays a crucial role in cancer cell invasion and immune infiltration. However, the relevance of LDHA in colon adenocarcinoma (COAD) remains unclear. In this study, we analyzed the correlation between the expression of LDHA and clinicopathological characteristics in COAD using immunohistochemistry analysis, and then used integrative bioinformatics analyses to further study the function and role of LDHA in COAD. We found that LDHA was highly expressed in COAD tissues compared with adjacent normal tissues, and that COAD patients with high LDHA expression levels showed poor survival. In addition, LDHA expression was closely associated with the immune infiltrating levels of CD8+ T cells, neutrophils, and dendritic cells. Our findings highlight the potential role of LDHA in the tumorigenesis and prognosis of COAD. Furthermore, our results indicate that COAD is a novel immune checkpoint in the diagnosis and treatment of COAD.

Network analysis identifies DAPK3 as a potential biomarker for lymphatic invasion and colon adenocarcinoma prognosis

SummaryColon adenocarcinoma is a prevalent malignancy with significant mortality. Hence, the identification of molecular biomarkers with prognostic significance is important for improved treatment and patient outcomes. Clinical traits and RNA-Seq of 551 patient samples in the UCSC Toil Recompute Compendium of The Cancer Genome Atlas TARGET and Genotype Tissue Expression project datasets (primary_site = colon) were used for weighted gene co-expression network analysis to reveal the association between gene networks and cancer cell invasion. One module, containing 151 genes, was significantly correlated with lymphatic invasion, a histopathological feature of higher risk colon cancer. DAPK3 (death-associated protein kinase 3) was identified as the pseudohub of the module. Gene ontology identified gene enrichment related to cytoskeletal organization and apoptotic signaling processes, suggesting modular involvement in tumor cell survival, migration, and epithelial-mesenchymal transformation. Although DAPK3 expression was reduced in patients with colon cancer, high expression of DAPK3 was significantly correlated with greater lymphatic invasion and poor overall survival.

Integrative analysis of ceRNA network reveals functional lncRNAs associated with independent recurrent prognosis in colon adenocarcinoma

BackgroundLong non-coding RNAs (lncRNAs), acting as competing endogenous RNA (ceRNA) have been reported to regulate the expression of targeted genes by sponging miRNA in colon adenocarcinoma (COAD).MethodsHowever, their potential implications for recurrence free survival prognosis and functional roles remains largely unclear in COAD. In this study, we downloaded the TCGA dataset (training dataset) and GSE39582 (validation dataset) of COAD patients with prognostic information.ResultsA total of 411 differentially expressed genes (DElncRNAs: 12 downregulated and 43 upregulated), 18 DE miRNAs (9 downregulated and 9 upregulated) and 338 DEmRNAs (113 downregulated and 225 upregulated) were identified in recurrence samples compared with non-recurrence samples with the thresholds of FDR < 0.05 and |log2FC|> 0.263. Based on six signature lncRNAs (LINC00899, LINC01503, PRKAG2-AS1, RAD21-AS1, SRRM2-AS1 and USP30-AS1), the risk score (RS) system was constructed. Two prognostic clinical features, including pathologic stage and RS model status were screened for building the nomogram survival model. Moreover, a recurrent-specific ceRNA network was successfully constructed with 2 signature lncRNAs, 4 miRNAs and 113 mRNAs. Furthermore, we further manifested that SRRM2-AS1 predicted a poor prognosis in COAD patients. Furthermore, knockdown of SRRM2-AS1 significantly suppressed cell proliferation, migration, invasion and EMT markers in HT-29 and SW1116 cells.ConclusionThese identified novel lncRNA signature and ceRNA network associated with recurrence prognosis might provide promising therapeutic targets for COAD patients.