Abstract

Objective

   To analyze and validate differential genes in the cytokine-cytokine
   receptor interaction CCRI pathway in laryngeal squamous cell carcinoma
   (LSCC) using bioinformatics and Mendelian randomization (MR) to find
   potential biomarkers for LSCC.

Methods

   Five sets of LSCC-related gene chips were downloaded from the GEO
   database, and four sets of combined datasets were randomly selected as
   the test set and one set as the validation set to screen for
   differential genes in the CCRI pathway; two-way Mendelian randomization
   was performed to analyze the causal relationship between cytokine
   receptor as the exposure factor and LSCC as the outcome variable; and
   the causal relationship was analyzed by DGIdb, Miranda, miRDB, miRWalk,
   TargetScan, spongeScan, and TISIDB databases to analyze the
   relationship between differential genes and drugs, immune cell
   infiltration, and mRNA-miNA-lncRNA interactions.

Results

   A total of 7 differentially expressed genes CD27, CXCL2, CXCL9, INHBA,
   IL6, CXCL11, and TNFRSF17 were screened for enrichment in the CCRI
   signaling pathway; MR analysis showed that the CCRI receptor was a risk
   factor for LSCC (IVW: OR = 1.629, 95 % CI:1.060–2.504, P = 0.026);
   Seven differential genes were correlated with drugs, immune cells and
   mRNA-miNA-lncRNA, respectively; the CCRI differential gene expression
   analysis in the validation set was consistent with the test set
   results.

Conclusion

   This study provided CCRI differential gene expression by
   bioinformatics, and MR analysis demonstrated that cytokine receptors
   are risk factors for LSCC, providing new ideas for the pathogenesis and
   therapeutic targets of LSCC.

   Keywords: Mendelian randomization analysis, Laryngeal squamous cell
   carcinoma, Cytokine-cytokine receptor interaction pathway,
   Bioinformatics, Gene-drug interactions, CeRNA regulatory network,
   Immune infiltration

1. Introduction

   Laryngeal cancer is one of the most common malignancies in
   otolaryngology-head and neck surgery, with an incidence rate second
   only to nasopharyngeal carcinoma and nasal cavity cancer [[37]1].
   Laryngeal squamous cell carcinoma (LSCC) is the most common
   histological subtype of laryngeal cancer, accounting for about
   85 % ∼ 95 % of cases [[38]2].It is closely associated with smoking and
   alcohol consumption, and its pathogenesis is not yet fully elucidated
   [[39]3].Due to the anatomical complexity and specificity of the
   laryngeal region, tumor growth is concealed and difficult to detect in
   early stages, with approximately 60 % of patients diagnosed at an
   advanced stage of cancer [[40]4].Current treatment options for
   laryngeal cancer primarily involve multidisciplinary approaches,
   including surgery, radiation therapy, chemotherapy, biological therapy,
   and immunotherapy; however, the 5-year survival rate and prognosis
   remain suboptimal [[41]5].Postoperative patients often suffer from
   impaired swallowing, respiratory, and phonatory functions,
   significantly affecting their quality of life [[42]6].Therefore,
   identifying new potential target genes in laryngeal cancer to explore
   the pathogenesis and guide treatment is of great importance.

   Cytokines are a group of biologically active signaling molecules
   synthesized and secreted by immune cells and some non-immune cells,
   including interleukins, tumor necrosis factors, colony-stimulating
   factors, interferons, chemokines, and growth factors [[43]7]. Cytokines
   exert their biological effects by binding to specific cytokine
   receptors. Through cytokine-receptor interactions, they induce cell
   apoptosis, regulate cell development and differentiation, modulate the
   immune response, mediate inflammatory reactions, and promote tissue
   repair [[44]8]. Studies have found that there may be common signaling
   pathways between cytokine receptor systems and oncogenes that stimulate
   tissue cells to proliferate, differentiate, and even transform into
   cancer cells [[45]9]. With advances in understanding the biology of
   cytokines and receptors, cytokine therapy and anti-cytokine therapy are
   increasingly being successfully applied in clinical settings
   [[46]10].Mendelian randomization is a causal inference method that has
   been widely used in recent years, It takes advantage of the randomness
   of alleles at meiosis and the irreversibility of genetic variations
   before the onset of a disease and uses the genetic variation as an
   instrumental variable to infer the causal relationship between the
   exposure factor and the outcome of the study (disease), which largely
   reduces the bias and confounding by confounding factors.With the
   development of bioinformatics technologies and Mendelian randomization
   analysis methods, analyzing key genes in tumor development and
   exploring their causal relationships to unravel the mechanisms of tumor
   pathogenesis and therapeutic targets has become one of the current
   research hotspots.

   This study utilizes bioinformatics combined with multiple relevant
   databases to screen for differentially expressed genes in the CCRI
   signaling pathway. Through Mendelian randomization analysis, the causal
   relationship between cytokine receptor pathways and LSCC is
   investigated. Based on the pathway genes, potential drugs, miRNAs, and
   immune cells related to LSCC are predicted, providing new theoretical
   references for the pathogenesis and targeted therapy of LSCC.