Identification of hub gene associated with colorectal cancer: Integrating Mendelian randomization, transcriptome analysis and experimental verification

TL;DR

This study identifies FUT8 as a key gene linked to colorectal cancer and suggests VE-822 as a potential treatment based on genetic and experimental evidence.

Contribution

The study integrates Mendelian randomization, transcriptome analysis, and experimental validation to identify FUT8 as a CRC hub gene and VE-822 as a potential drug target.

Findings

FUT8 is overexpressed in CRC and linked to tumor immunity and metastasis.

VE-822 inhibits CRC cell proliferation and binds to FUT8, increasing its thermal stability.

Six eQTLs, including FUT8, are associated with increased CRC risk.

Abstract

Colorectal cancer (CRC) is a prevalent malignancy with significant mortality rates globally. Understanding the genetic and molecular mechanisms underlying CRC development is crucial for improving therapeutic strategies.

In this study, we utilized cis-eQTL summary data to identify genes potentially causally associated with CRC. The expression levels of candidate genes in tumor and normal tissues were compared using the GEPIA2 database. The correlations between FUT8 expression and cellular functions, tumor mutation burden, immune checkpoint genes, and immune infiltration were analyzed. Molecular docking was performed to identify potential drugs targeting FUT8, and the effects of the selected drug on cell proliferation were evaluated using the MTT assay. Additionally, the cellular thermal shift assay (CETSA) was employed to assess the interaction between the drug and the target protein.

We identified 19 genes with eQTLs potentially associated with CRC, among which six eQTLs were associated with increased CRC risk, including FUT8. FUT8 was significantly overexpressed in CRC tumor tissues and correlated with various cellular functions such as stemness, invasion, EMT, and metastasis. Higher FUT8 expression was associated with higher tumor mutation burden and significant correlations with multiple immune checkpoint genes. Molecular docking identified VE-822 as a promising drug candidate targeting FUT8, which demonstrated inhibitory effects on CRC cell proliferation. The CETSA results indicated that VE ‒ 822 could bind to FUT8 and improve its thermal stability.

FUT8 is a crucial gene that causes colon cancer and is linked to tumour immunity. VE-822 is a promising candidate for treating CRC by targeting FUT8.

This study utilized cis-eQTL data to identify genes associated with colorectal cancer (CRC). The FUT8 gene, identified via SMR analysis, was found to be overexpressed in tumor tissues and correlated with cellular functions and immune checkpoint genes, highlighting its potential as a therapeutic target. Furthermore, molecular docking identified VE-822 as a promising drug candidate targeting FUT8. It demonstrated inhibitory effects on CRC cell proliferation and could bind to FUT8 and affect its expression. Our findings highlight the importance of the FUT8 gene in the development of colorectal cancer and suggest the potential of VE-822 as a treatment for colon cancer.

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