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  • Identification of HRH1-Associated Candidate Genes Potentially Involved in 5-Fluorouracil Resistance in Colon Cancer: A Bioinformatic Analysis

  • Mehrnaz Asayesh,1,* Melika Asayesh,2
    1. Student Research Committee, Department of Medical Immunology, Medical Sciences Faculty, Golestan University of Medical Science, Gorgan, Iran.
    2. Student Research Committee, Hamadan University of Medical Science, Hamadan, Iran.


  • Introduction: Colorectal cancer (CRC) is a major global health burden, with nearly 1.9 million new cases reported worldwide in 2022. Despite advances in diagnosis and treatment, the prognosis of patients with advanced CRC remains poor, partly due to therapeutic resistance. 5-Fluorouracil (5-FU) remains a cornerstone of CRC chemotherapy and is widely used in treatment regimens such as FOLFOX and FOLFIRI, particularly for advanced and metastatic disease. However, resistance to 5-FU substantially limits treatment efficacy and represents a complex and multifactorial process involving diverse molecular and cellular mechanisms. The histaminergic system has emerged as a potential regulator of tumor progression and therapeutic response. In the tumor microenvironment of CRC, histamine can be released by immune cells, including mast cells and eosinophils. Histamine exerts its biological effects through four G protein-coupled receptors (H1R–H4R), which activate distinct intracellular signaling pathways. Among these receptors, H1R has been implicated in cancer-related processes, including cellular proliferation, migration, epithelial–mesenchymal transition, and angiogenesis. However, the relationship between HRH1-associated genes and 5-FU resistance in CRC remains poorly understood. Therefore, in this study, we applied an integrative bioinformatic approach to identify HRH1-associated candidate genes potentially involved in 5-FU resistance in CRC, with the aim of providing potential molecular targets for further investigation.
  • Methods: First, Differential gene expression between colon cancer and normal tissues was evaluated using Gene Expression Profiling Interactive Analysis 2 (GEPIA2). Then, a protein–protein interaction (PPI) network centered on histamine receptor 1 (HRH1) was constructed using the STRING database to identify HRH1-interacting hub genes. In parallel, differentially expressed genes (DEGs) were identified from two Gene Expression Omnibus (GEO) datasets, GSE232211 and GSE58058, based on colorectal cancer cell-line models. The HRH1-associated hub genes were subsequently intersected with the DEGs identified from the GEO datasets, and genes with consistent expression directions based on log₂ fold change (log₂FC) were retained for further analysis. We performed functional enrichment analysis using Enrichr, followed by Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis of the identified candidate genes.
  • Results: The STRING-based PPI analysis identified 21 hub genes. The intersection of these genes and GEO datasets resulted in four candidate genes, GNG2, AGT, AOC1, and GNAQ, which showed significant and consistent expression changes and were prioritized as potential genes associated with 5-FU resistance in colon cancer. Enrichr functional enrichment and KEGG pathway analysis further highlighted their involvement in histamine-related signaling pathways.
  • Conclusion: The identified genes appear to participate in biological processes relevant to colorectal cancer progression and therapeutic response. GNG2 has been implicated in the regulation of colorectal cancer cell proliferation and metastasis through the PI3K/AKT/mTOR signaling pathway, with its overexpression inducing G0/G1 cell-cycle arrest and suppressing tumor growth. AGT is overexpressed in colorectal cancer and has been associated with autophagy-related pathways and chemotherapy resistance, with higher AGT expression positively associated with 5-FU resistance. AOC1 has been linked to aggressive colorectal cancer phenotypes, including increased proliferation, migration, and liver metastasis, whereas its suppression reduces tumor growth; importantly, AOC1 also contributes to histamine degradation, suggesting a potential role in modulating histamine availability and signaling. GNAQ has been reported to regulate tumor cell proliferation and apoptosis through the ARHGEF25–RHOA signaling axis, while loss of GNAQ has been associated with increased aggressive behavior and drug resistance; additionally, GNAQ provides a mechanistic link to HRH1 signaling as the Gq protein mediating downstream H1 receptor activation. Collectively, our findings identify GNG2, AGT, AOC1, and GNAQ as HRH1-associated candidate genes potentially involved in 5-FU resistance in colorectal cancer, providing potential molecular biomarkers and therapeutic targets for further investigation.
  • Keywords: Colorectal cancer, histamine signaling, histamine receptor 1, 5-Fluorouracil resistance

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