EGFR signalling and oncogenic pathway signature in colorectal cancer

Şahin, Ibrahim Halil; Oktay, Ahmet Afsin

doi:10.1136/gutjnl-2013-304781

Cited by 3 publications

(2 citation statements)

References 6 publications

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“…In oxidative stress conditions, an important cellular response is the activation of the PIK3CA—AKT pathway that involves the oxidation and subsequent inactivation of PTEN , a tumour suppressor gene [ 76 ]. Both molecular pathways are connected by EGFR that has improved colorectal cancer classification and treatment [ 77 ].…”

Section: Biologic Performances Of Obesitymentioning

confidence: 99%

Obesity and colorectal cancer: molecular features of adipose tissue

2016

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The huge part of population in developed countries is overweight or obese. Obesity is often determined by body mass index (BMI) but new accurate methods and ratios have recently appeared to measure body fat or fat located in the intestines. Early diagnosis of obesity is crucial since it is considered an increasing colorectal cancer risk factor. On the one hand, colorectal cancer has been strongly associated with lifestyle factors. A diet rich in red and processed meats may increase colorectal cancer risk; however, high-fiber diets (grains, cereals and fruits) have been associated with a decreased risk of colorectal cancer. Other life-style factors associated with obesity that also increase colorectal cancer risk are physical inactivity, smoking and high alcohol intake. Cutting-edge studies reported that high-risk transformation ability of adipose tissue is due to production of different pro-inflammatory cytokines like IL-8, IL-6 or IL-2 and other enzymes like lactate dehydrogenase (LDH) and tumour necrosis factor alpha (TNFα). Furthermore, oxidative stress produces fatty-acid peroxidation whose metabolites possess very high toxicities and mutagenic properties. 4-hydroxy-2-nonenal (4-HNE) is an active compounds that upregulates prostaglandin E2 which is directly associated with high proliferative colorectal cancer. Moreover, 4-HNE deregulates cell proliferation, cell survival, differentiation, autophagy, senescence, apoptosis and necrosis via mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase (PIK3CA)—AKT and protein kinase C pathways. Other product of lipid peroxidation is malondialdehyde (MDA) being able to regulate insulin through WNT-pathway as well as having demonstrated its mutagenic capability. Accumulation of point mutation enables genomic evolution of colorectal cancer described in the model of Fearon and Vogelstein. In this review, we will summarize different determination methods and techniques to assess a truthfully diagnosis and we will explain some of the capabilities that performs adipocytes as the largest endocrine organ.

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Section: Biologic Performances Of Obesitymentioning

confidence: 99%

Obesity and colorectal cancer: molecular features of adipose tissue

2016

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“…Mutations in the RAS family suggest continuous activation of EGFR downstream signaling [11][12][13][14][15] and RAS genes (KRAS, NRAS) are used as biomarkers to predict poor response to anti-EGFR therapy [16,17]. However, tumor microenvironment re-plasticity, characterized by tumor immune cell infiltration and upregulation of immune checkpoint-related proteins, has recently been recognized as a novel explanation for drug resistance and treatment failure [18][19][20].…”

Section: Introductionmentioning

confidence: 99%

Identification of key genes involved in tumor immune cell infiltration and cetuximab resistance in colorectal cancer

et al. 2021

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Background The anti-epidermal growth factor receptor (EGFR) antibody introduces adaptable variations to the transcriptome and triggers tumor immune infiltration, resulting in colorectal cancer (CRC) treatment resistance. We intended to identify genes that play essential roles in cetuximab resistance and tumor immune cell infiltration. Methods A cetuximab-resistant CACO2 cellular model was established, and its transcriptome variations were detected by microarray. Meanwhile, public data from the Gene Expression Omnibus and The Cancer Genome Atlas (TCGA) database were downloaded. Integrated bioinformatics analysis was applied to detect differentially expressed genes (DEGs) between the cetuximab-resistant and the cetuximab-sensitive groups. Then, we investigated correlations between DEGs and immune cell infiltration. The DEGs from bioinformatics analysis were further validated in vitro and in clinical samples. Results We identified 732 upregulated and 1259 downregulated DEGs in the induced cellular model. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses, along with Gene Set Enrichment Analysis and Gene Set Variation Analysis, indicated the functions of the DEGs. Together with GSE59857 and GSE5841, 12 common DEGs (SATB-2, AKR1B10, ADH1A, ADH1C, MYB, ATP10B, CDX-2, FAR2, EPHB2, SLC26A3, ORP-1, VAV3) were identified and their predictive values of cetuximab treatment were validated in GSE56386. In online Genomics of Drug Sensitivity in Cancer (GDSC) database, nine of twelve DEGs were recognized in the protein-protein (PPI) network. Based on the transcriptome profiles of CRC samples in TCGA and using Tumor Immune Estimation Resource Version 2.0, we bioinformatically determined that SATB-2, ORP-1, MYB, and CDX-2 expressions were associated with intensive infiltration of B cell, CD4+ T cell, CD8+ T cell and macrophage, which was then validated the correlation in clinical samples by immunohistochemistry. We found that SATB-2, ORP-1, MYB, and CDX-2 were downregulated in vitro with cetuximab treatment. Clinically, patients with advanced CRC and high ORP-1 expression exhibited a longer progression-free survival time when they were treated with anti-EGFR therapy than those with low ORP-1 expression. Conclusions SATB-2, ORP-1, MYB, and CDX-2 were related to cetuximab sensitivity as well as enhanced tumor immune cell infiltration in patients with CRC.

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