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Association between Inter-α-trypsin inhibitor heavy chain 4 (ITIH4) mRNA expression and EGFR mutation status in lung adenocarcinoma: an exploratory, single-center study

genomics
molecular-biology
oncology
respiratory-medicine
translational-medicine

Abstract

Background. The inter-α-trypsin inhibitor heavy chain 4 (ITIH4) protein has been implicated in inflammation and tumor progression, yet its relationship with oncogenic signaling remains unclear. Epidermal growth factor receptor (EGFR) mutations drive a subset of lung adenocarcinomas, but whether these alterations influence ITIH4 expression has not been established. This study explored the association between ITIH4 mRNA expression, EGFR mutation status, and clinicopathological factors in lung adenocarcinoma.

Methods. A cross-sectional study was conducted using 186 lung adenocarcinoma samples. EGFR mutations were detected by real-time PCR, and ITIH4 mRNA expression was quantified using one-step RT-qPCR, normalized to GAPDH. Log₂-transformed values were analyzed with General Linear Models (GLM) with Bonferroni-adjusted pairwise comparisons. Because all male patients were smokers and all female patients were non-smokers, sex and smoking were analyzed as a combined categorical variable.

Results. ITIH4 mRNA expression was significantly lower in EGFR- mutated tumors than in wild-type tumors (mean difference = 2.446 log₂ units, P < 0.001), corresponding to a 5.45-fold decrease. Male/smoker samples showed higher ITIH4 expression than female/non-smokers (mean difference = 1.525 log₂ units, P < 0.001; ≈2.9-fold increase). The downregulation of ITIH4 in EGFR- mutated cases was more pronounced in male/smokers (mean difference = 2.582 log₂ units, P < 0.001; ≈5.98-fold difference) than female/non-smokers (mean difference = 1.662 log₂ units, P = 0.02; ≈3.2-fold difference).

Conclusions. ITIH4 mRNA expression was consistently reduced in EGFR- mutated lung adenocarcinoma, with a greater effect among male/smoker samples. Although the exact pathways remain to be elucidated, these findings suggest a potential interaction between EGFR signaling and cytokine-mediated regulation of ITIH4. Further studies incorporating protein-level and pathway analyses are warranted to clarify the biological basis of this association.

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