scholarly journals Identification of Gene Co-Expression Networks Associated with Consensus Molecular Subtype-1 of Colorectal Cancer

Cancers ◽  
2021 ◽  
Vol 13 (22) ◽  
pp. 5824
Author(s):  
Sha’Kayla K. Nunez ◽  
Corey D. Young ◽  
Ti’ara L. Griffen ◽  
Adaugo Q. Ohandjo ◽  
Lawrence P. McKinney ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Immune Responses ◽  
Signaling Pathways ◽  
Gene Networks ◽  
Cell Activation ◽  
Molecular Subtype ◽  
Akt Signaling ◽  
The Cancer Genome Atlas ◽  
Oncogenic Signaling ◽  
Promote Cell Proliferation

Colorectal cancer (CRC) is driven in part by dysregulated Wnt, Ras-Raf-MAPK, TGF-β, and PI3K-Akt signaling. The progression of CRC is also promoted by molecular alterations and heterogeneous—yet interconnected—gene mutations, chromosomal instability, transcriptomic subtypes, and immune signatures. Genomic alterations of CRC progression lead to changes in RNA expression, which support CRC metastasis. An RNA-based classification system used for CRC, known as consensus molecular subtyping (CMS), has four classes. CMS1 has the lowest survival after relapse of the four CRC CMS phenotypes. Here, we identify gene signatures and associated coding mRNAs that are co-expressed during CMS1 CRC progression. Using RNA-seq data from CRC primary tumor samples, acquired from The Cancer Genome Atlas (TCGA), we identified co-expression gene networks significantly correlated with CMS1 CRC progression. CXCL13, CXCR5, IL10, PIK3R5, PIK3AP1, CCL19, and other co-expressed genes were identified to be positively correlated with CMS1. The co-expressed eigengene networks for CMS1 were significantly and positively correlated with the TNF, WNT, and ERK1 and ERK2 signaling pathways, which together promote cell proliferation and survival. This network was also aligned with biological characteristics of CMS1 CRC, being positively correlated to right-sided tumors, microsatellite instability, chemokine-mediated signaling pathways, and immune responses. CMS1 also differentially expressed genes involved in PI3K-Akt signaling. Our findings reveal CRC gene networks related to oncogenic signaling cascades, cell activation, and positive regulation of immune responses distinguishing CMS1 from other CRC subtypes.

scholarly journals AP-1 Transcription Factors as Regulators of Immune Responses in Cancer

Cancers ◽  
2019 ◽  
Vol 11 (7) ◽  
pp. 1037 ◽  
Author(s):  
Vasileios Atsaves ◽  
Vasiliki Leventaki ◽  
George Z. Rassidakis ◽  
Francois X. Claret
Keyword(s):  
Immune Responses ◽  
T Cell Activation ◽  
Cell Activation ◽  
Clinical Success ◽  
Nuclear Gene ◽  
Mapk Signaling ◽  
Immune Checkpoint Blockade ◽  
Immune Checkpoints ◽  
Activator Protein 1 ◽  
Oncogenic Signaling

Immune check point blockade therapy has revolutionized the standard of cancer treatment and is credited with producing remarkable tumor remissions and increase in overall survival. This unprecedented clinical success however is feasible for a limited number of cancer patients due to resistance occurring before or during a course of immunotherapy, which is often associated with activation of oncogenic signaling pathways, co-inhibitory checkpoints upregulation or expansion of immunosuppressive regulatory T-cells (Tregs) in the tumor microenviroment (TME). Targeted therapy aiming to inactivate a signaling pathway such as the Mitogen Activated Protein Kinases (MAPKs) has recently received a lot of attention due to emerging data from preclinical studies indicating synergy with immune checkpoint blockade therapy. The dimeric transcription factor complex Activator Protein-1 (AP-1) is a group of proteins involved in a wide array of cell processes and a critical regulator of nuclear gene expression during T-cell activation. It is also one of the downstream targets of the MAPK signaling cascade. In this review, we will attempt to unravel the roles of AP-1 in the regulation of anti-tumor immune responses, with a focus on the regulation of immune checkpoints and Tregs, seeking to extract useful insights for more efficacious immunotherapy.

scholarly journals INHBB Is a Novel Prognostic Biomarker Associated with Cancer-Promoting Pathways in Colorectal Cancer

2020 ◽  
Vol 2020 ◽  
pp. 1-14
Author(s):  
Jinpeng Yuan ◽  
Aosi Xie ◽  
Qiangjian Cao ◽  
Xinxin Li ◽  
Juntian Chen
Keyword(s):  
Colorectal Cancer ◽  
Signaling Pathways ◽  
Signaling Pathway ◽  
Transforming Growth Factor ◽  
Cox Regression ◽  
Prognostic Biomarker ◽  
Disease Free Survival ◽  
Gene Set Enrichment Analysis ◽  
The Cancer Genome Atlas ◽  
Receptor Interaction

Background. Inhibin subunit beta B (INHBB) is a protein-coding gene that participated in the synthesis of the transforming growth factor-β (TGF-β) family members. The study is aimed at exploring the clinical significance of INHBB in patients with colorectal cancer (CRC) by bioinformatics analysis. Methods. Real-time PCR and analyses of Oncomine, Gene Expression Omnibus (GEO), and The Cancer Genome Atlas (TCGA) databases were utilized to evaluate the INHBB gene transcription level of colorectal cancer (CRC) tissue. We evaluated the INHBB methylation level and the relationship between expression and methylation levels of CpG islands in CRC tissue. The corresponding clinical data were obtained to further explore the association of INHBB with clinical and survival features. In addition, Gene Set Enrichment Analysis (GSEA) was performed to explore the gene ontology and signaling pathways of INHBB involved. Results. INHBB expression was elevated in CRC tissue. Although the promoter of INHBB was hypermethylated in CRC, methylation did not ultimately correlate with the expression of INHBB. Overexpression of INHBB was significantly and positively associated with invasion depth, distant metastasis, and TNM stage. Cox regression analyses and Kaplan-Meier survival analysis indicated that high expression of INHBB was correlated with worse overall survival (OS) and disease-free survival (DFS). GSEA showed that INHBB was closely correlated with 5 cancer-promoting signaling pathways including the Hedgehog signaling pathway, ECM receptor interaction, TGF-β signaling pathway, focal adhesion, and pathway in cancer. INHBB expression significantly promoted macrophage infiltration and inhibited memory T cell, mast cell, and dendritic cell infiltration. INHBB expression was positively correlated with stromal and immune scores of CRC samples. Conclusion. INHBB might be a potential prognostic biomarker and a novel therapeutic target for CRC.

Identification of distinctive patterns in cell signaling pathways in glioblastoma multiforme subtypes using gene expression TCGA data sets.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e23162-e23162
Author(s):  
Konstantin Volyanskyy ◽  
Minghao Zhong ◽  
Payal Keswarpu ◽  
John T Fallon ◽  
Michael Paul Fanucchi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Signaling ◽  
Signaling Pathways ◽  
Normal Tissue ◽  
Gene Selection ◽  
Molecular Subtype ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
The Cancer Genome Atlas ◽  
Cell Signaling Pathways

e23162 Background: Cancer is characterized by a variety of heterogeneous genomic and transcriptomic patterns involving highly complex signaling biological pathways. The problem of identification of the factors driving tumor progression becomes even more challenging due to intricate interaction mechanisms between these pathways. Using novel approaches in machine learning, we demonstrate the ability to quantitatively describe characteristic signaling patterns in cancer based on transcriptomic data Methods: We used RNASeq data from 20531 genes in 174 samples of GBM from The Cancer Genome Atlas including 5 major histological subtypes – Classical, G-CIMP, Mesenchymal, Neural, and Proneural, anddeveloped predictive computational framework for molecular subtype differentiation from normal tissue relying on variance based gene selection and random forest algorithm. Results: We obtained a few key findings – (1) genes from cell signaling pathways alone differentiate each subtype from normal tissue with 100% accuracy; (2) predictive genes are specific to each subtype; (3) inferred pathway interactions are also specific to each subtype; (4) typically most of the predictive genes involved in signaling are down-regulated in tumor compared to normal tissue (MAPT, PRKCG, PDE2A, RYR2, ATP1B1, GRN1, GNAO1), however, in each subtype we observed a smaller subset of predictive genes which are highly up-regulated in tumor (ID3, FN1, JAG1, F2R, COL4A1, EDAR, CDK2, CDK4, MFNG, BIRC5, CCNB2). We detected and quantitatively evaluated characteristic signaling pathway involvement across the GBM subtypes for MAPK, RAP1, RAS, Notch, PI3K-Akt, mTOR, FoxO, Jak-STAT, Wnt, cAMP, and Calcium Signaling, providing a unique approximation for each subtype signaling profile. Conclusions: In this study, we identified gene expression profiles and associated signaling pathways for distinguishing GBM Multiforme subtypes from normal tissue. We observed and described a dense complex picture of interacting signaling pathways. The detected interactions may provide clinical insights and could be used to identify potential therapeutic targets, however, more research is needed to confirm this.

eIF6 Promotes Colorectal Cancer Proliferation and Invasion by Regulating AKT-Related Signaling Pathways

2019 ◽  
Vol 15 (7) ◽  
pp. 1556-1567 ◽  
Author(s):  
Jinxin Lin ◽  
Xihu Yu ◽  
Liping Xie ◽  
Puning Wang ◽  
Tuoyang Li ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Signaling Pathways ◽  
Large Scale ◽  
Prognostic Indicator ◽  
The Cancer Genome Atlas ◽  
Initiation Factor ◽  
Cancer Proliferation ◽  
Functional Studies ◽  
Normal Tissues ◽  
Cancer Signaling

Although abnormal expression of eukaryotic initiation factor 6 (eIF6) has been found in several human solid tumors, the functions and underlying mechanisms of eIF6 in the progression of colorectal cancer (CRC) still needs further elucidation. In the present study, large-scale gene analysis based on Oncomine and The Cancer Genome Atlas (TCGA) database revealed significantly higher baseline expression of eIF6 in colorectal cancer than in normal tissues. Furthermore, our Chinese cohort study revealed that high expression of eIF6 was correlated with aggressive characteristics and poor survival in CRC patients. Functional studies using magnetic nanoparticle extraction indicated that eIF6 was an oncogene in CRC cells. Regarding its mechanism, through Gene ontology (GO) and KEGG pathway analysis based on TCGA RNAseq database, we found that eIF6 can activate multiple AKT-related cancer signaling pathways, such as p-AKT\MMP1\cyclinD1\Bcl2-related signaling, to regulate cell proliferation, invasion, cell cycle and apoptosis in CRC. Collectively, these findings suggested that eIF6 can positively regulate AKT-related cancer signaling and enhance tumorigenicity in CRC, and may serve as a potential prognostic indicator and therapeutic target in CRC.

scholarly journals miR-330 Regulates Colorectal Cancer Oncogenesis by Targeting BACH1

2020 ◽  
Vol 10 (3) ◽  
pp. 444-451
Author(s):  
Solmaz Shirjang ◽  
Behzad Mansoori ◽  
Ali Mohammadi ◽  
Neda Shajari ◽  
Pascal H.G. Duijf ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Rectal Adenocarcinoma ◽  
Growth Factor Receptor ◽  
Colon Adenocarcinoma ◽  
The Cancer Genome Atlas ◽  
Oncogenic Signaling ◽  
Patients With Cancer ◽  
Colon And Rectal Cancer ◽  
Cancer Genome Atlas ◽  
Endothelial Growth Factor

Purpose : Based on WHO report, colorectal cancer (CRC) is the second cause of death among patients with cancer worldwide. Dysregulation of miRNAs expressions has been demonstrated in different human cancers, especially CRC. Studies have shown that miR-330 could act as both TS-miR and/or oncomiR in different types of cancers. BACH1 is also identified as a transcription factor, which is involved in ontogenesis. In this study, we evaluated the CRC suppression via silencing of BACH1 by small silencer molecule called miR-330. Methods: Firstly, we analyzed the BACH1, miR-330-3p and miR-330-5p expressions according to the colon adenocarcinoma (COAD) and rectal adenocarcinoma (READ) project established from a patient of the colon and rectal cancer patients in The Cancer Genome Atlas (TCGA) database. The targeting of BACH1 via miR-330 in human CRC cells was evaluated by Vejnar bioinformatics methods, and confirmed by qRT-PCR and western blot analysis. Proliferation was performed by MTT assay. The MMP9, CXCR4, and VEGFR proteins were measured by western blotting. Results: The analysis of BACH1, miR-330-3p, and miR-330-5p expressions according to the COAD and READ projects showed that BACH1 was overexpressed, but miR-330-3p and miR330-5p were reduced in CRC tumors compared to normal controls. The miR-330 induction prevented proliferation of CRC cell by targeting BACH1 mRNA, which represses MMP9, C-X-C chemokine receptor type 4 (CXCR4), and vascular endothelial growth factor receptor (VEGFR) proteins expressions. Conclusion: Our results suggested that BACH1 is a potential target for miR-330 in CRC cells. The miR-330 induction inhibits CRC cells proliferation by suppressing BACH1 expression in posttranscriptional level. It was suggested that targeting of BACH1 via miRNA such as miR-330 could be a valid strategy in the field of CRC targeted therapy via modulating the oncogenic signaling pathway.

scholarly journals CXCL8 Associated Dendritic Cell Activation Marker Expression and Recruitment as Indicators of Favorable Outcomes in Colorectal Cancer

2021 ◽  
Vol 12 ◽  
Author(s):  
Enhao Li ◽  
Xiaobao Yang ◽  
Yuzhang Du ◽  
Guanzheng Wang ◽  
David W. Chan ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Dendritic Cell ◽  
Cell Activation ◽  
Suppressor Cells ◽  
The Cancer Genome Atlas ◽  
Dendritic Cell Activation ◽  
Antitumor Effects ◽  
Activation Markers

Accumulating evidence suggests that tumor-infiltrating immune cells (TICs) in the tumor microenvironment (TME) serve as promising therapeutic targets. CXCL8 (IL-8) may also be a potential therapeutic target in cancer. CXCL8 is a potent chemotactic factor for neutrophils, myeloid-derived suppressor cells (MDSCs) and monocytes, which are considered immunosuppressive components in cancer-bearing hosts. Here, we identified the TME-related gene CXCL8 in a high-ImmuneScore population that contributed to better survival in colorectal cancer (CRC) patients from The Cancer Genome Atlas (TCGA) database. An integrated gene profile and functional analysis of TIC proportions revealed that the dendritic cell (DC) activation markers CD80, CD83, and CD86 were positively correlated with CXCL8 expression, suggesting that CXCL8 may be functional as antitumor immune response status in the TME. The gene signature was further validated in independent GSE14333 and GSE38832 cohorts from the Gene Expression Omnibus (GEO). To test the differential contributions of immune and tumor components to progression, three CRC cell lines, CT26, MC38 and HCT116, were used. In vitro results suggested no significant growth or survival changes following treatment with an inhibitor of the CXCL8 receptor (CXCR1/2) such as reparixin or danirixin. In vivo treatment with danirixin (antagonists of CXCR2) promoted tumor progression in animal models established with CT26 cells. CXCR2 antagonism may function via an immune component, with CXCR2 antagonist treatment in mice resulting in reduced activated DCs and correlating with decreased Interferon gamma (IFN-γ) or Granzyme B expressed CD8+ T cells. Furthermore, CXCL8 induced DC migration in transwell migration assays. Taken together, our data suggested that targeting the CXCL8-CXCR2 axis might impede DC activation or recruitment, and this axis could be considered a favorable factor rather than a target for critical antitumor effects on CRC.

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