Dataset Information

Expression Profile and Prognostic Value of Wnt Signaling Pathway Molecules in Colorectal Cancer.

ABSTRACT: Colorectal cancer (CRC) is a heterogeneous disease with changes in the genetic and epigenetic levels of various genes. The molecular assessment of CRC is gaining increasing attention, and furthermore, there is an increase in biomarker use for disease prognostication. Therefore, the identification of different gene biomarkers through messenger RNA (mRNA) abundance levels may be useful for capturing the complex effects of CRC. In this study, we demonstrate that the high mRNA levels of 10 upregulated genes (DPEP1, KRT80, FABP6, NKD2, FOXQ1, CEMIP, ETV4, TESC, FUT1, and GAS2) are observed in CRC cell lines and public CRC datasets. Moreover, we find that a high mRNA expression of DPEP1, NKD2, CEMIP, ETV4, TESC, or FUT1 is significantly correlated with a worse prognosis in CRC patients. Further investigation reveals that CTNNB1 is the key factor in the interaction of the canonical Wnt signaling pathway with 10 upregulated CRC-associated genes. In particular, we identify NKD2, FOXQ1, and CEMIP as three CTNNB1-regulated genes. Moreover, individual inhibition of the expression of three CTNNB1-regulated genes can cause the growth inhibition of CRC cells. This study reveals efficient biomarkers for the prognosis of CRC and provides a new molecular interaction network for CRC.

SUBMITTER: Wu YF

PROVIDER: S-EPMC8533439 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

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Expression Profile and Prognostic Value of Wnt Signaling Pathway Molecules in Colorectal Cancer.

Wu Yung-Fu YF Wang Chih-Yang CY Tang Wan-Chun WC Lee Yu-Cheng YC Ta Hoang Dang Khoa HDK Lin Li-Chia LC Pan Syu-Ruei SR Ni Yi-Chun YC Anuraga Gangga G Lee Kuen-Haur KH

Biomedicines 20210927 10

Colorectal cancer (CRC) is a heterogeneous disease with changes in the genetic and epigenetic levels of various genes. The molecular assessment of CRC is gaining increasing attention, and furthermore, there is an increase in biomarker use for disease prognostication. Therefore, the identification of different gene biomarkers through messenger RNA (mRNA) abundance levels may be useful for capturing the complex effects of CRC. In this study, we demonstrate that the high mRNA levels of 10 upregulat ...[more]

PMID: 34680448

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Project description:Integrin beta5 (ITGB5) expression levels are dysregulated in a variety of cancers. However, the mechanism and clinical value of ITGB5 in colorectal cancer (CRC) remain unclear. The Gene Expression Omnibus (GEO) database, real-time PCR, Western blotting and immunohistochemistry were utilized to evaluate ITGB5 expression levels in CRC tissue. Clinical data from the GEO database were obtained to further explore the associations of ITGB5 with clinical features and patient survival. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis and gene set enrichment analysis (GSEA) were performed to explore the functions and signaling pathways of ITGB5. In addition, ITGB5 expression was inhibited by siRNA, and the roles of ITGB5 in SW480 and RKO cell growth, migration and invasion, as well as in the Wnt/β-catenin signaling pathway, were investigated. Pancancer studies have shown that ITGB5 is highly expressed in a variety of cancers. Moreover, ITGB5 expression is significantly increased in CRC tissues and is correlated with TNM stage, invasion depth, lymph node metastasis and distant metastasis stage. Kaplan-Meier analysis and meta-analysis of the GSE39582 and GSE17538 datasets indicated that a high level of ITGB5 is a high risk factor for overall survival (OS) and disease-free survival (DFS). In addition, receiver operating characteristic (ROC) curve analysis revealed the value of ITGB5 in predicting DFS, and univariate and multivariate analyses showed that ITGB5 may be an independent prognostic factor for DFS. GO and KEGG analyses indicated that many GO terms related to the extracellular matrix (ECM), focal adhesion and ECM-receptor interaction pathways were enriched. GSEA revealed focal adhesion, cancer pathways, ECM-receptor interactions and Wnt signaling pathways in the samples with high ITGB5 expression. Correlation analysis revealed that high ITGB5 expression is significantly correlated with the TGF-β/EMT pathway and WNT targets. Silencing of ITGB5 inhibited SW480 and RKO cell proliferation, invasion and migration. Mechanistically, downregulated ITGB5 expression blocked the Wnt/β-catenin signaling pathway and epithelial-mesenchymal transition (EMT) in CRC cells. Moreover, ITGB5 expression was related to M0 macrophages, M2 macrophages, neutrophils and plasma cell fractions. ITGB5 may be associated with poor prognosis and metastasis in patients with CRC. ITGB5 may hold promise as a prognostic biomarker and a new potential therapeutic target for CRC.

Project description:Colorectal cancer (CRC) ranks as the second leading cause of cancer-related mortality globally and is the third most prevalent cancer. The effective treatment of CRC is challenged by tumor drug resistance, underscoring the urgent need for novel therapeutic strategies. It is well recognized that epigenetic modifications, particularly DNA methylation, significantly contribute to the initiation and advancement of CRC. Tumors frequently exhibit hypermethylation of specific gene promoters alongside a general hypomethylation of genomic DNA. In normal tissues, gene promoters, particularly those of tumor suppressor genes, are typically unmethylated, whereas they are often hypermethylated in cancerous tissues. Previous studies have identified the methylation status of the CpG island within the SLC30A10 gene as a reliable biomarker for CRC. Notably, a hypermethylated phenotype is inversely correlated with SLC30A10 expression. However, the precise functional implications of SLC30A10 suppression in the context of CRC progression remain to be elucidated.). The investigation of molecular pathways involved in metal metabolism in CRC has not been conducted previously at the transcriptomic level. Furthermore, the relationship between the mutational characteristics of tumors—such as individual mutations, mutational burden, and microsatellite instability—and the activity of genes related to metal metabolic pathways has not been explored. This project aims to be the first to examine the antitumor potential of modulating the transport systems for manganese and zinc ions in CRC. The molecular function of SLC30A10 is to export zinc (Zn) and manganese (Mn) ions from the cell. Additionally, SLC30A10 plays a crucial role in mitigating Mn-induced cytotoxicity and facilitates Zn transport to early endosomes while promoting endosomal recirculation to avert Zn toxicity. Our findings indicate that overexpression of SLC30A10 is correlated with the knockout of its functional antagonist, SLC39A14 in the HuTu80 and HCT-15 cell lines.

Dataset Information

Expression Profile and Prognostic Value of Wnt Signaling Pathway Molecules in Colorectal Cancer.

Publications

Expression Profile and Prognostic Value of Wnt Signaling Pathway Molecules in Colorectal Cancer.

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