scholarly journals Potential Mechanism of Immune Evasion Associated with the Master Regulator ASCL2 in Microsatellite Stability in Colorectal Cancer

2021 ◽  
Vol 2021 ◽  
pp. 1-12
Author(s):  
Qian Yang ◽  
Guowei Huang ◽  
Liyan Li ◽  
Enmin Li ◽  
Liyan Xu
Keyword(s):  
Colorectal Cancer ◽  
Immune Evasion ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
Novel Treatments ◽  
T Cell Infiltration ◽  
Immune Resistance ◽  
Unbiased Gene ◽  
Ifn Γ ◽  
Microsatellite Stability

Colorectal cancer (CRC) has two major subtypes, microsatellite instability (MSI) and microsatellite stability (MSS) based on the genomic instability. In this study, using computational programs, we identified 9 master transcription factors (TFs) based on epigenomic profiling in MSS CRC samples. Notably, unbiased gene set enrichment analysis (GSEA) showed that several master TFs were strongly associated with immune-related functions in TCGA MSS CRC tissues, such as interferon gamma (IFN-γ) and interferon alpha (IFN-α) responses. Focusing to the top candidate, ASCL2, we found that CD8+ T cell infiltration was low in ASCL2 overexpressed MSS CRC samples. Compared with other gastrointestinal (GI) cancers (gastric cancer, MSI CRC, and esophageal cancer), ASCL2 is specifically upregulated in MSS CRC. Moreover, we identified 28 candidate genes in IFN-γ and IFN-α response pathways which were negatively correlated with ASCL2. Together, these results link transcriptional dysregulation with the immune evasion in MSS CRC, which may advance the understanding of immune resistance and contribute to developing novel treatments of MSS CRC.

scholarly journals Tumor ferroptosis status demonstrated vulnerability to chemotherapy and reflected immune-activation in colorectal cancer

2020 ◽  
Author(s):  
Yang Lv ◽  
QingYang Feng ◽  
ZhiYuan Zhang ◽  
Peng Zheng ◽  
DeXiang Zhu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
T Cells ◽  
Enrichment Analysis ◽  
Progression Free Survival ◽  
Gene Set Enrichment Analysis ◽  
The Cancer Genome Atlas ◽  
M1 Macrophage ◽  
Central Molecule ◽  
Ifn Γ ◽  
Cox Analysis

Abstract Background: Existing studies for ferroptosis and prognosis in colorectal cancer (CRC) were limited. In this study, we aim to investigate the prognostic role of ferroptosis markers in patients with CRC and exploration of its micro-environmental distributions. Methods: A total of 911 patients from 2008 to 2013 with CRC were enrolled. Immunohistochemical staining was performed for CRC patients’ tissue microarray. Selection and prognostic validation of markers were based on mRNA data from the cancer genome atlas (TCGA) database. Gene Set Enrichment Analysis (GSEA) was performed to indicate relative immune landmarks and hallmarks. Ferroptosis and immune contexture were examined by CIBERSORT. Survival outcomes were analyzed by Kaplan-meier analysis and cox analysis.Results: A panel of 42 genes was selected. Through mRNA expression difference and prognosis analysis, GPX4, NOX1 and ACSL4 were selected as candidate markers. By IHC, increased GPX4, decreased NOX1 and decreased FACL4 indicate poor prognosis and worse clinical characteristics. Ferroptosis score based on GPX4, NOX1 and ACSL4 was constructed and validated with high C-index. Low ferroptosis score can also demonstrate the better progression free survival and better adjuvant chemotherapy (ACT) responsiveness. Moreover, tumor with low ferroptosis score tend to be infiltrated with more CD4+ T cells, CD8+ T cells and less M1 macrophage. Finally, we found that IFN-γ was potentially the central molecule at the crossroad between ferroptosis and onco-immune response. Conclusion: Ferroptosis plays important role on CRC tumor progression, ACT response and prognosis. Ferroptosis contributes to immune-supportive responses and IFN-γ was the central molecule for this process.

scholarly journals Gene set enrichment analysis for genome-wide DNA methylation data

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Jovana Maksimovic ◽  
Alicia Oshlack ◽  
Belinda Phipson
Keyword(s):  
Dna Methylation ◽  
Enrichment Analysis ◽  
R Package ◽  
Gene Set Enrichment Analysis ◽  
Methylation Array ◽  
Gene Set ◽  
Genome Wide ◽  
Genome Methylation ◽  
Unbiased Gene ◽  
Gene Set Testing

AbstractDNA methylation is one of the most commonly studied epigenetic marks, due to its role in disease and development. Illumina methylation arrays have been extensively used to measure methylation across the human genome. Methylation array analysis has primarily focused on preprocessing, normalization, and identification of differentially methylated CpGs and regions. GOmeth and GOregion are new methods for performing unbiased gene set testing following differential methylation analysis. Benchmarking analyses demonstrate GOmeth outperforms other approaches, and GOregion is the first method for gene set testing of differentially methylated regions. Both methods are publicly available in the missMethyl Bioconductor R package.

scholarly journals Transcriptomic Profiling for the Autophagy Pathway in Colorectal Cancer

2020 ◽  
Vol 21 (19) ◽  
pp. 7101
Author(s):  
Justyna Gil ◽  
Paweł Karpiński ◽  
Maria M. Sąsiadek
Keyword(s):  
Colorectal Cancer ◽  
Cell Lines ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
Field Cancerization ◽  
Cancer Tissue ◽  
Mrna Levels ◽  
Targeting Therapy ◽  
Autophagy Pathway ◽  
Using Data

The role of autophagy in colorectal cancer (CRC) pathogenesis appears to be crucial. Autophagy acts both as a tumor suppressor, by removing redundant cellular material, and a tumor-promoting factor, by providing access to components necessary for growth, metabolism, and proliferation. To date, little is known about the expression of genes that play a basal role in the autophagy in CRC. In this study, we aimed to compare the expression levels of 46 genes involved in the autophagy pathway between tumor-adjacent and tumor tissue, employing large RNA sequencing (RNA-seq) and microarray datasets. Additionally, we verified our results using data on 38 CRC cell lines. Gene set enrichment analysis revealed a significant deregulation of autophagy-related gene sets in CRC. The unsupervised clustering of tumors using the mRNA levels of autophagy-related genes revealed the existence of two major clusters: microsatellite instability (MSI)-enriched and -depleted. In cluster 1 (MSI-depleted), ATG9B and LAMP1 genes were the most prominently expressed, whereas cluster 2 (MSI-enriched) was characterized by DRAM1 upregulation. CRC cell lines were also clustered according to MSI-enriched/-depleted subgroups. The moderate deregulation of autophagy-related genes in cancer tissue, as compared to adjacent tissue, suggests a prominent field cancerization or early disruption of autophagy. Genes differentiating these clusters are promising candidates for CRC targeting therapy worthy of further investigation.

scholarly journals Deficiency of 15-LOX-1 Induces Radioresistance through Downregulation of MacroH2A2 in Colorectal Cancer

Cancers ◽  
2019 ◽  
Vol 11 (11) ◽  
pp. 1776 ◽  
Author(s):  
Yoo Jin Na ◽  
Bo Ram Kim ◽  
Jung Lim Kim ◽  
Sanghee Kang ◽  
Yoon A. Jeong ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Dna Damage ◽  
Specific Treatment ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
Patient Specific ◽  
Histone H2a ◽  
Gene Set Enrichment ◽  
Damage Response ◽  
Radiation Induced

Despite the importance of radiation therapy, there are few radiation-related markers available for use in clinical practice. A larger catalog of such biomarkers is required to help clinicians decide when radiotherapy should be replaced with a patient-specific treatment. Arachidonate 15-lipoxygenase (15-LOX-1) enzyme is involved in polyunsaturated fatty acid metabolism. When colorectal cancer (CRC) cells were exposed to radiation, 15-LOX-1 was upregulated. To verify whether 15-LOX-1 protects against or induces DNA damage, we irradiated sh15-LOX-1 stable cells. We found that low 15-LOX-1 is correlated with radioresistance in CRC cells. These data suggest that the presence of 15-LOX-1 can be used as a marker for radiation-induced DNA damage. Consistent with this observation, gene-set-enrichment analysis based on microarray experiments showed that UV_RESPONSE was decreased in sh15-LOX-1 cells compared to shCon cells. Moreover, we discovered that the expression of the histone H2A variant macroH2A2 was sevenfold lower in sh15-LOX-1 cells. Overall, our findings present mechanistic evidence that macroH2A2 is transcriptionally regulated by 15-LOX-1 and suppresses the DNA damage response in irradiated cells by delaying H2AX activation.

scholarly journals UBQLN4 is activated by C/EBPβ and exerts oncogenic effects on colorectal cancer via the Wnt/β-catenin signaling pathway

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Xiaolong Tang ◽  
Yahang Liang ◽  
Guorui Sun ◽  
Qingsi He ◽  
Hui Qu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Western Blot ◽  
Signaling Pathway ◽  
Lymphatic Metastasis ◽  
Core Promoter ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
Luciferase Reporter ◽  
Migration And Invasion

AbstractUbiquilin 4 (UBQLN4) is an important member of the ubiquitin-like protein family. An increasing number of studies have shown that UBQLN4 is an important regulator of tumorigenesis. Nevertheless, the biological function and detailed mechanisms of UBQLN4 in colorectal cancer (CRC) development and progression remain unclear. Here, we identified UBQLN4 upregulation in CRC tissues and it is positively associated with CRC size, TNM stage, and lymphatic metastasis. Patients with high UBQLN4 expression had a poor prognosis. Functionally, overexpression of UBQLN4 significantly promoted CRC cell proliferation, migration, and invasion, while UBQLN4 silencing elicited the opposite effect. This result was consistent with the conclusion that UBQLN4 expression correlated positively with the CRC size and lymphatic metastasis. In vivo, UBQLN4 silencing also inhibited tumor growth. Mechanistically, using gene set enrichment analysis (GSEA) and western blot experiments, we identified that UBQLN4 activated the Wnt/β-catenin signaling pathway to upregulate β-catenin and c-Myc expression, thereby promoting CRC proliferation, migration and invasion. A rescue experiment further verified this conclusion. Dual luciferase reporter, real-time quantitative PCR (RT-qPCR), western blot and chromatin immunoprecipitation (ChIP) assays indicated that the transcription factor CCAAT/enhancer-binding protein beta (C/EBPβ) directly bound to the UBQLN4 core promoter region and activated its transcription, upregulating β-catenin and c-Myc expression to promote CRC progression. Thus, our findings suggest that UBQLN4 is a key oncogene in CRC and may be a promising target for the diagnosis and treatment of patients with CRC.

scholarly journals DDX10 Promotes the Proliferation and Metastasis of Colorectal Cancer Cells via Splicing RPL35

2021 ◽  
Author(s):  
Xin Zhou ◽  
Zhihong Liu ◽  
Cuifeng Zhang ◽  
Manman Jiang ◽  
Yuxiao Jin ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Molecular Mechanisms ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
Migration And Invasion ◽  
Ppi Network ◽  
Interacting Protein ◽  
Network Analyses ◽  
Potential Biomarker

Abstract Background: Colorectal cancer (CRC) has become the second deadliest cancer in the world and severely threatens human health. An increasing number of studies have focused on the role of the RNA helicase DEAD-box (DDX) family in CRC. However, the mechanism of DDX10 in CRC has not been elucidated.Methods: In our study, we analysed the expression data of CRC samples from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases. Subsequently, we performed cytological experiments and animal experiments to explore the role of DDX10 in CRC cells. Furthermore, we performed Gene Ontology (GO)/ Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis and protein-protein interaction (PPI) network analyses. Finally, we predicted the interacting protein of DDX10 by LC-MS/MS and verified it by coimmunoprecipitation (Co-IP) and qPCR.Results: In the present study, we identified that DDX10 mRNA was extremely highly expressed in CRC tissues compared with normal colon tissues in the TCGA and GEO databases. The protein expression of DDX10 was measured by immunochemistry (IHC) in 17 CRC patients. The biological roles of DDX10 were explored via cell and molecular biology experiments in vitro and in vivo and cell cycle assays. We found that DDX10 knockdown markedly reduced CRC cell proliferation, migration and invasion. Then, we constructed a PPI network with the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING). GO and KEGG enrichment analysis and gene set enrichment analysis (GSEA) showed that DDX10 was closely related to RNA splicing and E2F targets. Using LC-MS/MS and Co-IP assays, we discovered that RPL35 is the interacting protein of DDX10. In addition, we hypothesize that RPL35 is related to the E2F pathway and the immune response in CRC.Conclusions: In conclusion, provides a better understanding of the molecular mechanisms of DDX10 in CRC and provides a potential biomarker for the diagnosis and treatment of CRC.

scholarly journals Identification of a Hypoxia - Related lncRNA Signature For The Prognosis of Colorectal Cancer

2021 ◽  
Author(s):  
HUA HUANG ◽  
Shanshan Xu ◽  
Youran Li ◽  
Yunfei Gu ◽  
Lijiang Ji
Keyword(s):  
Colorectal Cancer ◽  
Roc Analysis ◽  
Cox Regression ◽  
Differential Expression Analysis ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
Receptor Interaction ◽  
Prognostic Signature ◽  
Gene Set Enrichment ◽  
Gene Set

Abstract Background: Colorectal cancer (CRC), the commonly seen malignancy, ranks the 3rd place among the causes of cancer-associated mortality. As suggested by more and more studies, long coding RNAs (lncRNAs) have been considered as prognostic biomarkers for CRC. But the significance of hypoxic lncRNAs in predicting CRC prognosis remains unclear.Methods: The gene expressed profiles for CRC cases were obtained based on the Cancer Genome Atlas (TCGA) and applied to estimate the hypoxia score using a single-sample gene set enrichment analysis (ssGSEA) algorithm. Overall survival (OS) of high- and low-hypoxia score group was analyzed by the Kaplan–Meier (KM) plot. To identify differentially expressed lncRNAs (DELs) between two hypoxia score groups, this study carried out differential expression analysis, and then further integrated with the DELs between controls and CRC patients to generate the hypoxia-related lncRNAs for CRC. Besides, prognostic lncRNAs were screened by the univariate Cox regression, which were later utilized for constructing the prognosis nomogram for CRC by adopting the least absolute shrinkage and selection operator (LASSO) algorithm. In addition, both accuracy and specificity of the constructed prognostic signature were detected through the receiver operating characteristic (ROC) analysis. Moreover, our constructed prognosis signature also was validated in the internal testing test. This study operated gene set enrichment analysis (GSEA) for exploring potential biological functions associated with the prognostic signature. Finally, the ceRNA network of the prognostic lncRNAs was constructed.Results: Among 2299 hypoxia-related lncRNAs of CRC in total, LINC00327, LINC00163, LINC00174, SYNPR-AS1, and MIR31HG were identified as prognostic lncRNAs by the univariate Cox regression, and adopted for constructing the prognosis signature for CRC. ROC analysis showed the predictive power and accuracy of the prognostic signature. Additionally, the GSEA revealed that ECM-receptor interaction, PI3K-Akt pathway, phagosome, and Hippo pathway were mostly associated with the high-risk group. 352 miRNAs-mRNAs pairs and 177 lncRNAs-miRNAs were predicted.Conclusion: To conclude , we identified 5 hypoxia-related lncRNAs to establish an accurate prognostic signature for CRC, providing important prognostic markers and therapeutic target.

scholarly journals Identification of Potential Diagnostic and Prognostic Biomarkers for Colorectal Cancer Based on GEO and TCGA Databases

2021 ◽  
Vol 11 ◽  
Author(s):  
Zhenjiang Wang ◽  
Mingyi Guo ◽  
Xinbo Ai ◽  
Jianbin Cheng ◽  
Zaiwei Huang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Interaction Network ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
Prognostic Biomarkers ◽  
High Recurrence Rate ◽  
Mortality And Morbidity ◽  
Invasive Test ◽  
Underlying Mechanisms

Colorectal cancer (CRC) is one of the most common neoplastic diseases worldwide. With a high recurrence rate among all cancers, treatment of CRC only improved a little over the last two decades. The mortality and morbidity rates can be significantly lessened by earlier diagnosis and prompt treatment. Available biomarkers are not sensitive enough for the diagnosis of CRC, whereas the standard diagnostic method, endoscopy, is an invasive test and expensive. Hence, seeking the diagnostic and prognostic biomarkers of CRC is urgent and challenging. With that order, we screened the overlapped differentially expressed genes (DEGs) of GEO (GSE110223, GSE110224, GSE113513) and TCGA datasets. Subsequent protein–protein interaction network analysis recognized the hub genes among these DEGs. Further functional analyses including Gene Ontology and KEGG pathway analysis and gene set enrichment analysis were processed to investigate the role of these genes and potential underlying mechanisms in CRC. Kaplan–Meier analysis and Cox hazard ratio analysis were carried out to clarify the diagnostic and prognostic role of these genes. In conclusion, our present study demonstrated that CCNA2, MAD2L1, DLGAP5, AURKA, and RRM2 are all potential diagnostic biomarkers for CRC and may also be potential treatment targets for clinical implication in the future.

scholarly journals Comprehensive analysis of ceRNA networks reveals prognostic lncRNAs related to immune infiltration in colorectal cancer

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Jingyi Chen ◽  
Yuxuan Song ◽  
Mei Li ◽  
Yu Zhang ◽  
Tingru Lin ◽  
...  
Keyword(s):  
Gene Expression ◽  
Colorectal Cancer ◽  
Target Genes ◽  
Immune Cell ◽  
Pearson Correlation ◽  
Enrichment Analysis ◽  
Cell Types ◽  
Gene Set Enrichment Analysis ◽  
The Cancer Genome Atlas ◽  
Cerna Network

Abstract Background Competing endogenous RNA (ceRNA) represents a class of RNAs (e.g., long noncoding RNAs [lncRNAs]) with microRNA (miRNA) binding sites, which can competitively bind miRNA and inhibit its regulation of target genes. Increasing evidence has underscored the involvement of dysregulated ceRNA networks in the occurrence and progression of colorectal cancer (CRC). The purpose of this study was to construct a ceRNA network related to the prognosis of CRC and further explore the potential mechanisms that affect this prognosis. Methods RNA-Seq and miRNA-Seq data from The Cancer Genome Atlas (TCGA) were used to identify differentially expressed lncRNAs (DElncRNAs), microRNAs (DEmiRNAs), and mRNAs (DEmRNAs), and a prognosis-related ceRNA network was constructed based on DElncRNA survival analysis. Subsequently, pathway enrichment, Pearson correlation, and Gene Set Enrichment Analysis (GSEA) were performed to determine the function of the genes in the ceRNA network. Gene Expression Profiling Interactive Analysis (GEPIA) and immunohistochemistry (IHC) were also used to validate differential gene expression. Finally, the correlation between lncRNA and immune cell infiltration in the tumor microenvironment was evaluated based on the CIBERSORT algorithm. Results A prognostic ceRNA network was constructed with eleven key survival-related DElncRNAs (MIR4435-2HG, NKILA, AFAP1-AS1, ELFN1-AS1, AC005520.2, AC245884.8, AL354836.1, AL355987.4, AL591845.1, LINC02038, and AC104823.1), 54 DEmiRNAs, and 308 DEmRNAs. The MIR4435-2HG- and ELFN1-AS1-associated ceRNA subnetworks affected and regulated the expression of the COL5A2, LOX, OSBPL3, PLAU, VCAN, SRM, and E2F1 target genes and were found to be related to prognosis and tumor-infiltrating immune cell types. Conclusions MIR4435-2HG and ELFN1-AS1 are associated with prognosis and tumor-infiltrating immune cell types and could represent potential prognostic biomarkers or therapeutic targets in colorectal carcinoma.

scholarly journals Modeling Intestinal Epithelial Response to Interferon-γ in Induced Pluripotent Stem Cell-Derived Human Intestinal Organoids

2020 ◽  
Vol 22 (1) ◽  
pp. 288
Author(s):  
Michael J. Workman ◽  
Elissa Troisi ◽  
Stephan R. Targan ◽  
Clive N. Svendsen ◽  
Robert J. Barrett
Keyword(s):  
Interferon Gamma ◽  
Adherens Junction ◽  
Induced Pluripotent Stem Cell ◽  
Enrichment Analysis ◽  
Cell Types ◽  
Gene Set Enrichment Analysis ◽  
Intestinal Organoids ◽  
Ifn Γ ◽  
Induced Pluripotent

Human intestinal organoids (HIOs) are increasingly being used to model intestinal responses to various stimuli, yet few studies have confirmed the fidelity of this modeling system. Given that the interferon-gamma (IFN-γ) response has been well characterized in various other cell types, our goal was to characterize the response to IFN-γ in HIOs derived from induced pluripotent stem cells (iPSCs). To achieve this, iPSCs were directed to form HIOs and subsequently treated with IFN-γ. Our results demonstrate that IFN-γ phosphorylates STAT1 but has little effect on the expression or localization of tight and adherens junction proteins in HIOs. However, transcriptomic profiling by microarray revealed numerous upregulated genes such as IDO1, GBP1, CXCL9, CXCL10 and CXCL11, which have previously been shown to be upregulated in other cell types in response to IFN-γ. Notably, “Response to Interferon Gamma” was determined to be one of the most significantly upregulated gene sets in IFN-γ-treated HIOs using gene set enrichment analysis. Interestingly, similar genes and pathways were upregulated in publicly available datasets contrasting the gene expression of in vivo biopsy tissue from patients with IBD against healthy controls. These data confirm that the iPSC-derived HIO modeling system represents an appropriate platform to evaluate the effects of various stimuli and specific environmental factors responsible for the alterations in the intestinal epithelium seen in various gastrointestinal conditions such as inflammatory bowel disease.

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